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Results for “Cellular Microenvironment”

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PubMed2004

Cancer vaccine development: on the way to break immune tolerance to malignant cells.

Exploiting a naturally occurring defense system, the immunotherapeutic approach embodies an ideal nontoxic treatment for cancer. Despite the evidence that immune effectors can play a significant role in controlling tumor growth either in natural conditions or in response to therapeutic manipulation, the cascade of molecular events leading to tumor rejection by the immune system remains to be fully elucidated. Nevertheless, some recent tumor immunology advancements might drastically change the way to design the next generation of cancer vaccines, hopefully improving the effectiveness of this therapeutic approach. In the present work, we will focus on three main areas of particular interest for the development of novel vaccination strategies: (a) cellular or molecular mechanisms of immune tolerance to malignant cells; (b) synergism between innate and adaptive immune response; (c) tumor-immune system interactions within the tumor microenvironment.

Animals↗

PubMed1990

Lymphocyte trafficking in psoriasis: a new perspective emphasizing the dermal dendrocyte with active dermal recruitment mediated via endothelial cells followed by intra-epidermal T-cell activation.

Prominent within the inflammatory infiltrate of psoriasis are HLA-DR positive T lymphocytes and factor XIIIa positive dermal dendrocytes. Many investigators studying psoriasis have assumed that the HLA-DR positive T cells are activated, and thereby capable of producing lymphokines such as gamma interferon. However, by immunohistochemical analysis, greater than 95% of the dermal T cells in psoriatic lesions are Ki-67 negative, which suggests that they are in a resting or non-cycling (Go) state. In contrast to the dermal T-cell population, the epidermal T-cell population contains a greater population of Ki-67 positive lymphocytes. The entry of the T cells into the epidermis is, therefore, apparently associated with an important activation event, which in all likelihood involves interaction with the keratinocyte. The presence of activated intraepidermal T cells has been substantiated by the ability to detect gamma interferon mRNA by polymerase chain reaction in epidermal sheets of psoriatic lesions. The pathophysiologic implication in psoriasis for these distinctions and compartmentalization involving dermal and epidermal T cells are placed into the context of a cascade of cellular trafficking events, which are further dissected into a specific network of molecular mediators of inflammation. This report suggests that more attention should be placed on the microenvironment of the skin, with specific emphasis on the mechanism by which T cells accumulate in the dermis and epidermis, and elucidation of the selective inductive and recruitment capabilities of endothelial cells, perivascular dermal dendrocytes, and keratinocytes.

Cell Movement↗

PubMed2005

Activated T-lymphocytes with myelosuppressive properties in patients with chronic idiopathic neutropenia.

To characterize the cellular components responsible for the impaired granulopoiesis in chronic idiopathic neutropenia (CIN), we investigated the origin of the proapoptotic cytokine producing cells in the bone marrow (BM) microenvironment of CIN patients. We found that the interferon gamma (IFN gamma) and/or Fas-ligand expressing cells in patient BM mononuclear cells and long-term BM culture stroma cells were the CD3(+) T-lymphocytes but not the CD14(+) monocytes/macrophages. The percentage of activated T-lymphocytes was increased in patients' BM as indicated by the proportions of human leucocyte antigen (HLA)-DR(+), CD25(+), CD38(+), CD69(+) and Fas(+) cells within the CD3(+) fraction. Intracellular IFN gamma expression was higher in the BM than peripheral blood of the patients and was associated with increased BM T-lymphocyte numbers. In crossover experiments, patient CD3(+) T-lymphocytes conferred autologous and allogeneic haemopoietic progenitor cell colony inhibition. Patients' T-cell receptor repertoire and polymerase chain reaction analysis did not reveal any clonal T-lymphocyte expansion, suggesting the absence of a direct, antigen-driven recognition of CD34(+) myeloid progenitor cells by patient T-lymphocytes. We conclude that CIN patients have increased number of activated T-lymphocytes in the BM, probably in the setting of a localized polyclonal immune reaction and that these cells confer an inhibitory effect on myelopoiesis through myelosuppressive cytokines including Fas-ligand and IFN gamma.

Adolescent↗

PubMed2004

Potential immaturity of the T-cell and antigen-presenting cell interaction in cord blood with particular emphasis on the CD40-CD40 ligand costimulatory pathway.

There are reports of immaturity of the neonatal immune system, which may explain the low incidence of graft-versus-host-disease (GVHD) after cord blood transplantation. The CD40 ligand (CD40L)-CD40 interaction is important in regulating the cellular immune response. We hypothesized that the neonatal immune system may show immaturity in this interaction. We studied the function of the CD40L-CD40 interaction in the T-cell interaction with B cells and monocytes in cord blood compared with adult blood in vitro. Consistent with previous reports, CD4+ T cells do not express CD40L after T-cell activation. In whole blood, adult monocytes, but not neonatal monocytes, were activated following T-cell activation. However, the activation of adult monocytes was not dependent on the CD40L-CD40 interaction. Using the CD40L trimer (Lt), we showed that cord B cells have comparable responses to CD40 ligation to those of the adult B cells. Both cord and adult monocytes do not respond as well as B cells and this is probably related to low density of expression of CD40. However, interferon-gamma up-regulated CD40 on adult monocytes but not on cord monocytes. This potentiated the adult monocyte response to CD40 ligation by CD40Lt. Our findings suggest that the neonatal CD40L-CD40 pair is immature in the cellular immune response involving monocytes and that interferon-gamma fails to activate neonatal monocytes for a response to CD40L. These findings suggest that in the inflammatory microenvironment of cord blood transplantation neonatal monocytes may play a minor role in the effector arm of the immune response. This finding may be one of several mechanisms for the low incidence of GVHD that is observed following cord blood transplantation. Also the ligand-receptor immaturity may contribute to the increased susceptibility of newborns to certain infections.

Antigen-Presenting Cells↗

PubMed1994

Soluble intercellular adhesion molecules in human schistosomiasis: correlations with disease severity and decreased responsiveness to egg antigens.

Granuloma formation, the principal pathologic consequence of infection with Schistosoma mansoni, is a complex process involving intricate cell-cell interactions in which intercellular adhesion molecules are likely to participate. To examine this possibility, sera of schistosomiasis patients in various clinical groups were assayed for the presence of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble E-selectin (sE-selectin). Comparisons were made between groups with different infection intensities (as predicted by fecal egg count) as well as between groups with severe (hepatosplenic) or milder (intestinal) pathology. All groups had elevated levels of sICAM-1 compared with controls. Also, patients in the high egg-excreting and hepatosplenic groups had significantly higher levels of serum sICAM-1 than patients in the low-egg-excreting and intestinal groups, respectively. The levels of sE-selectin were significantly elevated in the sera of all patients except those in the hepatosplenic group compared with controls. Patients in the intestinal group had significantly higher levels of sE-selectin in their sera than did hepatosplenic group patients, but serum sE-selectin levels of high- and low-egg-excreting patients were comparable. A striking finding of this study was the inverse correlation observed between sICAM-1 levels and peripheral blood mononuclear cell responses to schistosome soluble egg antigens (SEA) but not with responses to other schistosome antigens, purified protein derivative, or mitogen. Because ICAM-1 can perform a costimulatory function in antigen-presenting cell-T cell interactions, it is possible that shedding of ICAM-1 in the granuloma microenvironment interrupts proper costimulation, leading to unresponsive SEA-specific T cells. In this way, sICAM-1 could be one factor contributing to the observed modulation of cellular responses to SEA in chronic human schistosomiasis.

Adolescent↗

PubMed2005

Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells.

Previous studies have reported that mesenchymal stem cells (MSC) may be isolated from the synovial membrane by the same protocol as that used for synovial fibroblast cultivation, suggesting that MSC correspond to a subset of the adherent cell population, as MSC from the stromal compartment of the bone marrow (BM). The aims of the present study were, first, to better characterize the MSC derived from the synovial membrane and, second, to compare systematically, in parallel, the MSC-containing cell populations isolated from BM and those derived from the synovium, using quantitative assays. Fluorescent-activated cell sorting analysis revealed that both populations were negative for CD14, CD34 and CD45 expression and that both displayed equal levels of CD44, CD73, CD90 and CD105, a phenotype currently known to be characteristic of BM-MSC. Comparable with BM-MSC, such MSC-like cells isolated from the synovial membrane were shown for the first time to suppress the T-cell response in a mixed lymphocyte reaction, and to express the enzyme indoleamine 2,3-dioxygenase activity to the same extent as BM-MSC, which is a possible mediator of this suppressive activity. Using quantitative RT-PCR these data show that MSC-like cells from the synovium and BM may be induced to chondrogenic differentiation and, to a lesser extent, to osteogenic differentiation, but the osteogenic capacities of the synovium-derived MSC were significantly reduced based on the expression of the markers tested (collagen type II and aggrecan or alkaline phosphatase and osteocalcin, respectively). Transcription profiles, determined with the Atlas Human Cytokine/Receptor Array, revealed discrimination between the MSC-like cells from the synovial membrane and the BM-MSC by 46 of 268 genes. In particular, activin A was shown to be one major upregulated factor, highly secreted by BM-MSC. Whether this reflects a different cellular phenotype, a different amount of MSC in the synovium-derived population compared with BM-MSC adherent cell populations or the impact of a different microenvironment remains to be determined. In conclusion, although the BM-derived and synovium-derived MSC shared similar phenotypic and functional properties, both their differentiation capacities and transcriptional profiles permit one to discriminate the cell populations according to their tissue origin.

Activins↗

PubMed1999

[Absence of correlation between the concentrations of carcinoembryonic antigen (CEA) and the tumor growth factor beta 2 (TGFB2) in the two main types of breast macrocysts].

In order to study the possible correlation between carcinoembryonic antigen (CEA) and cellular proliferation, we assayed the concentrations of this substance in the fluid of 77 bening macrocysts of the breast classified according to their Na+/K+ ratio and compared them with those of transforming growth factor beta 2. CEA levels correlated positively and significantly with the cationic ratio, the concentrations of albumin, glucose, Cl- and pH and were higher (range: 2.5-81.5, median 12.8 vs range: 0.4-41.5, median 3.2 ng/ml (p: 0.00000) in type 2 (Na+/K+ > 3) than in type 1 (Na+/K+ < 3) cysts. There was no correlation between CEA and TGFb2, nor between the former and dehydroepiandrosterone sulphate levels. These results led us to suggest that the high CEA concentrations in type 2 cysts seem to be the consequence of loos of cellular differentiation and disruption of the cyst wall lining as well as the acquisition of embryonary properties by the latter as a consequence of a reduced hormonal microenvironment.

Adult↗

PubMed1989

Analysis of the fine distribution of thymic epithelial microenvironmental molecules by immuno-electron microscopy.

Normal T cell development depends upon an interaction between progenitor cells and their microenvironment. Previously raised monoclonal antibodies to subtypes of human thymic epithelium were used with gold-coupled reagents in immuno-electron microscopy to study the fine cellular distribution of the molecules to which these Mabs bind. Mab MR6, thought to recognize the human IL-4 receptor, shows strong surface labeling of cortical epithelial cells and thymic nurse cells, and very weak staining of thymocytes, medullary macrophages and interdigitating cells. Mab 1st 8.18 labels the surface of Hassall's corpuscles and associated medullary epithelial cells. The molecules detected by these two antibodies are therefore located in a position where they are available to interact with external cellular and soluble signals within the thymus. In contrast Mabs MR10 and 19 recognize Intracellular molecules within subcapsular, perivascular and some medullary epithelium. These molecules may represent soluble material awaiting secretion from the cell; alternatively, they may be internal structural proteins.

Antibodies, Monoclonal↗

PubMed1994

Homogeneous stromal cell population from normal human adult bone marrow expressing alpha-smooth muscle actin filaments.

BACKGROUND: Hematopoietic microenvironment has a crucial role homing and regulating precursor cell growth both in physiologic and pathologic conditions. Fibroblast, endothelial cells, macrophages, adipocytes, and myoid cells, are the cellular component recognized in human bone marrow cultures. The presence of myoid cells in human bone marrow has been observed during fatal life, whereas during adult life, it is strictly related to pathologic conditions. EXPERIMENTAL DESIGN: The aim of this study was to isolate a homogeneous stromal cell population. The mononuclear fraction obtained from the vertebral body of living humans was cultured without hydrocortisone and horse serum to inhibit foam cell differentiation. RESULTS: The immunocytochemistry and electron microscopy characterization indicate that the cellular population we isolated had an homogeneous "myoid" differentiation. Moreover, these cells were able to support blast cell colony formation in vitro. CONCLUSIONS: This method allowed the preparation of homogeneous myoid cell cultures depleted of other bone marrow stromal components. The isolation of a single stromal population is relevant in order to study the function of contractile filaments in allowing close-binding interactions with hematopoietic precursor cells.

Actins↗

PubMed1996

Cytokine regulation of HIV replication induced by dendritic cell-CD4-positive T cell interactions.

It has been established that human immunodeficiency virus (HIV) replication occurs throughout the course of disease in the lymphoid tissue. We have developed a model system to study the effect of cytokines and other agents on HIV replication using cocultures of DCs and T cells that reflect the cell-to-cell interactions that occur in the microenvironment of lymphoid tissue. Dendritic cells from peripheral blood, when pulsed with small amounts of HIV, induce infection in autologous, unstimulated CD4-positive T cells. Using this system, cytokines, anti-cytokine antibodies, and inhibitors of cellular activation were added to cultures and the effects on cellular proliferation and activation and HIV production were measured. Cytokines that increased T cell proliferation, such as IL-2 and IL-4, enhanced HIV replication, while the effect of IL-12 was more complex. HIV production was inhibited by blocking endogenously produced IL-2, as well as by adding IL-10, which blocks IL-2 secretion, antigen-presenting cell function, and T cell activation. Proinflammatory cytokines induced modest enhancement of viral replication in cocultures of HIV-pulsed DCs and CD4-positive T cells. Thus, using a model of HIV replication that more closely mimics the in vivo microenvironment of lymphoid tissue may allow a better analysis of the effect of cytokines and cytokine networks, as well as agents that modify immune activation on HIV replication.

B-Lymphocytes↗

PubMed1985

Energy metabolism and transduction in smooth muscle.

Early investigations into the nature of the coupling between energy transduction and metabolism in smooth muscle, particularly from the laboratories of Bülbring and Lundholm, suggested that specific metabolic pathways could independently supply energy for ion transport and actin-myosin interactions. Subsequent work has solidified the concept that oxidative phosphorylation is specifically coupled to tension generation and maintenance, whereas, aerobic glycolysis is not only a vital characteristic of smooth muscle metabolism, but also is likely to be independently coupled to Na-K transport at the plasmalemma. The independence of oxidative and glycolytic metabolism is reflected as a compartmentation of carbohydrate metabolism in the porcine carotid artery. The coupling of these independent metabolic pathways with specific energy utilizing processes, indicates a means by which energy production and transduction can be closely and efficiently regulated. The coupling of glycogenolysis to mitochondrial respiration may have evolved as a direct response to the energetic needs of VSM. That is, the large glycogenolytic response in the initial minutes of stimulation may be necessary to maximize the cellular production of ATP during the presteady state. Likewise, the coupling between aerobic glycolysis and Na-K transport indicates a sensitive and efficient means of coordinating energy metabolism with ion transport at the membrane level. Additionally, the regulation of substrate supply, i.e. glucose transport, also may be closely coordinated with changes in ion transport. One may speculate that alterations in the microenvironment of each compartment can independently regulate intermediary metabolism and therefore allow the cell to quickly and efficiently respond to localized stimuli. Thus, stimulation of Na-K transport could effectively regulate energy production at the membrane level without mobilizing or competing with the energy transduction of other cellular processes. This compartmentation of energy utilization may be highly advantageous, since oxidative metabolism is closely coordinated with mechanical activity and therefore regulation of blood flow. Future investigations will attempt to elucidate which intracellular signals which are responsible for the regulation of these functionally independent compartments of energy metabolism and transduction in VSM. In more general terms, our findings provide a basis from which future questions concerning the regulation of cellular metabolism must be directed. The cellular cytoplasm can no longer be envisioned as a homogeneous compartment, but rather a complex array of functional subcompartments which may be individual

Animals↗

PubMed1982

Depletion of reserve in the hemopoietic system: I. Self-replication by stromal cells related to chronologic age.

Transplanted devascularized mouse femurs and spleens or spleens ligated in situ all undergo a period of massive necrosis followed by a period of cellular regeneration and reconstitution of tissue components. This renewal of stromal tissue is endogenous to the organ and proliferates inward from a thin rim of surviving cells. Components of the femoral or splenic stroma constitute a hemopoietic microenvironment whose functions include the lodgment, commitment to differentiation and support of the proliferation of hemopoietic stem cells and their differentiating descendents. By using measures of the ability to support hemopoiesis, and the histological appearance of the reconstituted hemopoietic organs, it was shown that the degree of regeneration of the stroma was inversely related to its chronological age. Thus, although age-related changes in stromal cells are not readily demonstrable in hemopoietic tissue during a normal lifespan, they are in process and can be made obvious under anoxic conditions causing cell death followed by an unusual demand for cell replication. Key cellular components of such aged tissues apparently have either lessened resistance to anoxia or a reduction in replicative potential or both. The second alternative interpretation suggests an analogy in vivo to mesenchymal-cell clonal attenuation observed in vitro.

Aging↗

PubMed1994

Age- and microenvironment-associated influences by platelet-derived growth factor on T cell function.

Platelet-derived growth factor (PDGF) is produced by numerous cell types in response to a variety of activation signals. Although the role of PDGF in cellular proliferation is well established, the immunomodulatory effects of this peptide growth factor are only now being delineated. We previously established that PDGF alters the profile of lymphokines produced by activated T cells obtained from the peripheral lymph nodes of adult mice. We now report that T cells residing in lymphoid organs that receive their major afferent lymphatic drainage from gut mucosa are relatively resistant to the effects of this growth factor. As the vast majority of peripheral T cells are in the recirculating T cell pool, these findings suggest that tissue-specific microenvironmental factors function to regulate the sensitivity of T cells to PDGF-mediated influences. Additional studies have determined that the normal process of aging is accompanied by a systemic loss in T cell responsiveness to PDGF. Although the T cells of immature (2-wk-old) and young adult mice are responsive to the immunomodulatory influences of PDGF, T cells of aged animals (> 100 wk) are relatively resistant to its effects. Some of the immune abnormalities noted to occur during the aging process appear to represent a consequence of the dysregulated production of IL-6. We therefore evaluated whether IL-6 was responsible for modifying the sensitivity of T cells to PDGF. Data presented herein demonstrate that IL-6 abrogates the ability of PDGF to modify lymphokine production by T cells after activation. Therapeutic measures capable of reducing spontaneous IL-6 production in aged mice restored the ability of their T cells to respond to PDGF, suggesting that the dysregulated production of IL-6 within the aged host interferes with the ability of PDGF to convey important microenvironmental information to T cells residing in peripheral lymphoid organs.

Aging↗

PubMed2026

Deconstructing Exceptional Responses to Immune Checkpoint Inhibition in Recurrent or Metastatic Head and Neck Carcinoma: A Site-Specific Clinical-Biological Synthesis.

Background: Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is an aggressive malignancy with a historically poor prognosis. Although immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have established a new first-line standard of care, durable clinical benefit is restricted to a minority of patients, while primary or acquired resistance remains a major clinical challenge. This narrative review aims to provide a conceptual clinical-biological synthesis of immunotherapy in R/M HNSCC through an anatomical and biomarker-driven lens, with a focus on characterizing potential shared features of "exceptional responders". Methods: A targeted narrative literature search was conducted across PubMed/MEDLINE and to identify key clinical trials and representative clinical reports of exceptional response to ICIs in R/M HNSCC. The literature was not systematically synthesized to construct a conceptual clinical-biological framework of response and resistance. Results: Landmark clinical data confirm durable survival benefits with frontline pembrolizumab-based regimens in selected PDL-1 positive populations compared to historical chemotherapy. Qualitative appraisal of illustrative cases and translational cohorts suggests a potential biological hypothesis: exceptional responders, defined as patients achieving unexpected, multi-year complete radiological, pathological, or metabolic remissions, often align with a favorable confluence of a pre-existing "hot" or inflamed tumor microenvironment, preserved antigen presentation machinery, and elevated antigenic novelty driven by viral oncoproteins (HPV, EBV) or high mutational/indel burdens. Conversely, primary and acquired resistance are conceptually associated with defects in antigen processing, immunosuppressive cellular barriers, and alternative immune checkpoints. Conclusions: Immunotherapy has fundamentally transformed R/M HNSCC management, yet exceptional single-agent responses remain rare. Rather than a definitive or proven biological biomarker, the proposed blueprint represents an integrative hypothesis highlighting the complex interplay of baseline immune inflammation, genomic features, and viral drivers. Translating these observations into broader clinical benefit will require validated biomarker-driven personalization and rationally designed combination regimens.

Epstein-Barr virus (EBV)↗

PubMed2005

Social support, psychological distress, and natural killer cell activity in ovarian cancer.

PURPOSE: Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). PATIENTS AND METHODS: Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. RESULTS: Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL. CONCLUSION: Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

Adult↗

PubMed1979

Immunoregulatory responses in experimental disseminated histoplasmosis: depression of T-cell-dependent and T-effectory responses by activation of splenic suppressor cells.

The cellular immune responses of mice with disseminated histoplasmosis are markedly diminished in association with the generation of potent immunosuppressor activity by spleen cells. The zenith of suppressor activity was observed during most active infection, from 1 to 3 weeks after inoculation. During this time there was: (i) depression of the delayed-type hypersensitivity response to sheep erythrocytes and histoplasmin, (ii) impairment of concanavalin A- and histoplasmin-induced blastogenic transformations by splenocytes in vitro, (iii) depressed cytotoxic activity of spleen cells from infected mice, and (iv) marked suppression by splenocytes from infected mice of the primary antibody response to sheep erythrocytes by normal spleen cell cultures. With resolution of the infection by week 8, there was a shift of immunoregulatory function from dominant suppressor activity to expression of helper activity. At this time, delayed-type hypersensitivity responses to the above antigens were vigorous; furthermore, the cytotoxic activity and plaque-forming cell response of splenocytes from 8-week-infected mice were equal to or greater than normal control values. The shift in the immunoregulatory response from a suppressor to a helper mode indicated that the net amount of help or suppression measured at any given time during infection represented the algebraic sum of both helper and suppressor activities mediated by different populations or subpopulations of cells within the splenic microenvironment of infected mice.

Animals↗

PubMed2006

Modeling evaluation of the fluid-dynamic microenvironment in tissue-engineered constructs: a micro-CT based model.

Natural cartilage remodels both in vivo and in vitro in response to mechanical stresses, hence mechanical stimulation is believed to be a potential tool to modulate extra-cellular matrix synthesis in tissue-engineered cartilage. Fluid-induced shear is known to enhance chondrogenesis in engineered cartilage constructs. The quantification of the hydrodynamic environment is a condition required to study the biochemical response to shear of 3D engineered cell systems. We developed a computational model of culture medium flow through the microstructure of a porous scaffold, during direct- perfused culture. The 3D solid model of the scaffold micro-geometry was reconstructed from 250 micro-computed tomography (micro-CT) images. The results of the fluid dynamic simulations were analyzed at the central portions of the fluid domain, to avoid boundary effects. The average, median and mode shear stress values calculated at the scaffold walls were 3.48, 2.90, and 2.45 mPa respectively, at a flow rate of 0.5 cm(3)/min, perfused through a 15 mm diameter scaffold, at an inlet fluid velocity of 53 microm/s. These results were compared to results estimated using a simplified micro-scale model and to results estimated using an analytical macro-scale porous model. The predictions given by the CT-based model are being used in conjunction with an experimental bioreactor model, in order to quantify the effects of fluid-dynamic shear on the growth modulation of tissue-engineered cartilage constructs, to potentially enhance tissue growth in vitro.

Bioreactors↗

PubMed2002

Expression of glucose transporter-1 in cervical cancer and its precursors.

OBJECTIVE: Increased glucose uptake and utilization is a known phenomenon exhibited by malignant cells. Overexpression of the glucose transporter protein family is thought to be the principal mechanism by which these cells achieve up-regulation. Our purpose is to determine glucose transporter-1 (GLUT 1) expression in squamous carcinoma of the cervix and precursor lesions. METHODS: Archival histologic sections were obtained from 31 cases of invasive squamous cell carcinoma (SCC) of the uterine cervix, 15 cases of high-grade cervical intraepithelial neoplasia, 5 cases of low-grade, and 9 normal cervices. Immunohistochemistry for GLUT 1 protein was performed using polyclonal GLUT 1 antibody (Dako, Carpinteria, CA) and the labeled streptavidin-biotin procedure. RESULTS: Compared to the internal control, the pattern of staining varied from weak (1+) to strong (3+) reactions. In normal cervix, 1+ GLUT 1 staining was seen in the basal cells of the squamous epithelium. All 31 (100%) cases of SCC were positive for GLUT 1. Positive reactions seemed more intense in tumor cells that were farther away from the stromal blood supply. There was a correlation between intensity of reaction for GLUT 1 and histologic grade of tumor (P = 0.0027) and with progression from normal or dysplastic lesions to invasive cancer (P = 0.0001). Intensity was a predictor of the presence of poorly differentiated tumor type. Low-grade CIN staining was seen in less than one-third of the epithelium, while in high-grade lesions the reaction was present in over one-half of the epithelium. CONCLUSIONS: GLUT 1 is overexpressed in cervical carcinoma. The process appears to be related to grade of tumor but not to the progression from preneoplastic lesions. The results suggest that GLUT 1 overexpression is a late phenomenon in cellular transformation. Furthermore, the possible relation of expression to tumor blood supply suggests that the malignant cells may have an adaptive environmental ability to compensate for a compromised microenvironment.

Adult↗