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At least 577 records · Page 32Linked to original sources
PubMed2000

Endometrial-myometrial interface: relationship to adenomyosis and changes in pregnancy.

The endometrial-myometrial interface (EMI) is an important region of the human uterus, which has attracted little research attention. This mucosal-muscular interface has characteristic features when compared with other similar interfaces in the human body. It lacks an intervening tissue layer and as a result, the endometrium sits directly on the myometrium rendering it vulnerable to invasion by the endometrium. Both endometrium and myometrium are sensitive to sex steroids, and their structure and function depend to a large extent on the sex hormonal milieu. Endometrium, which forms one border of the EMI, is a complex tissue consisting of several polarized microenvironments. At a cellular level, sex steroids interact with local mediators secreted by a variety of cell types and are important in maintaining the complex structure and function of the endometrium. Basal endometrium contains prominent aggregates of leukocytes that may be important in controlling local cell growth and function. Myometrium also has a distinct zonal anatomy. The recently described junctional zone differs structurally and functionally from the outer myometrium, although these functions are not yet clearly understood. Embryologically, it originates from müllerian ducts together with endometrium, whereas the outer myometrium has a non-müllerian origin. During early pregnancy, the EMI is disturbed by invading trophoblast. Alterations of myometrial intercellular matrix proteins together with expression of appropriate receptors by the trophoblast seem to regulate this unique interaction. The EMI also is disrupted in adenomyosis. The sequence of events taking place at the EMI during development of this pathology is still debated.

Endometriosis↗
PubMed2000

Biological repair of thyroid cartilage defects by osteogenic protein-1 (bone morphogenetic protein-7) in dog.

The efficacy of human recombinant osteogenic protein-1 (OP-1; bone morphogenetic protein-7) in regeneration of dog larynx was examined by treating thyroid cartilage defects (1.5 cm2) in dogs with thyroid allografts covered with host perichondrium or fascia. Prior to implantation allografts were frozen, thawed and demineralized. The treatment groups were as follows: I--Allograft control implant (n = 3); II--Implants coated with 500 micrograms OP-1 (n = 4); III--Implants coated with 100 micrograms OP-1 (n = 3); IV--Implants coated with 500 micrograms OP-1 and covered with neck fascia (n = 3); and V--Implants extracted with 1 M NaCl and guanidine hydrochloride, and coated with 500 micrograms OP-1 (n = 4). Dogs were sacrificed four months following surgery. Each larynx was removed, carefully dissected and a three-dimensional reconstruction of the defect area was performed on serial sections. The results revealed that the implants of control dogs remained intact with no apparent reduction in size and new tissue formation. OP-1 enriched thyroid allografts, dose dependently induced bone, cartilage and ligament-like structures comprising up to 80% of the total regenerated defect area. Boundaries of the defects healed by formation of new bone when bone resided within the old thyroid cartilage layers. Old cartilage not containing bone within its layers healed by complete integration with newly formed cartilage. Both new bone and cartilage were embedded into layers of new ligament-like tissue which expressed specific morphologic and molecular markers. The three newly formed tissues were tightly connected into a "bone-cartilage-ligament continuum" of tissues, suggesting that OP-1 served as a multiple tissue morphogen in this specific microenvironment.

Animals↗
PubMed2006

Novel therapeutic target: the PERKs of inhibiting the integrated stress response.

Oxygen supports the life of all aerobic organisms and virtually every cell type is capable of sensing decreased tissue oxygenation or hypoxia. Hypoxic microenvironments are known to exist within developing solid tumors as a result of insufficient vascular delivery of oxygen, which can limit the efficient growth and spread of the malignancy. On the other hand, clinical and experimental evidence has demonstrated that reduction in tumor blood flow can diminish the efficacy of standard anticancer therapeutics including radiotherapy and chemotherapy. Indeed, low oxygenation can accelerate malignant progression and metastasis resulting in poorer prognosis irrespective of the chosen treatment regiment. We and others have shown that tumor cells cultured under hypoxic conditions and cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). One of the key master switches in the ISR is the dynamically regulated protein kinase known as PERK. Tumors that lack PERK activity are small and compromised in their ability to translate mRNAs involved in angiogenesis and tumor survival. PERK can be activated by a number of distinct endoplasmic reticulum (ER) stress as well as hypoxia and promotes a tumor microenvironment that favors the formation of functional microvessels and ultimately tumor growth. We hypothesize that ER stress induced by sub-lethal doses of anti-cancer therapeutics could actually facilitate tumor progression by activation of the ISR. We propose that inhibitors of PERK may synergize with a variety of cancer therapeutics that directly or indirectly induce the ISR.

Adaptation, Physiological↗
PubMed1999

Immunocytochemical study of cells in the vitreous of proliferative vitreoretretinopathy.

PURPOSE: To identify the cellular components of vitreous samples obtained during vitrectomy for proliferative vitreoretinopathy (PVR). METHODS: With the use of three intermediate filament (IF) proteins, vimentin, glial fibrillary acidic protein (GFAP), and cytokeratin (CK), cytocentrifuge slides of 14 fresh vitreous aspirates were detected with immunohistochemical technique. RESULTS: All the specimens contained epithelial-like proliferative cells with or without pigment and some membrane-like pieces. Immunocytochemical staining showed that 76.0-90.0% cells stained for CK, 17.4-29.6% cells expressed GFAP, and 80.1-91.0% cells were positive for vimentin. CONCLUSIONS: Majority of cells in the vitreous samples originated from retinal pigment epithelial cells (RPE) and glial cells in PVR. Expression of IF proteins may be determined by tissue of origin and local microenvironment.

Adolescent↗
PubMed2003

[Significance of a novel fetal RNA-binding protein p62 expression in hepatocellular carcinoma].

OBJECTIVE: To investigate the histological characteristics of hepatocellular carcinoma with p62 expression, and the correlation of p62 protein with biological characteristics of the cancer cells such as proliferation and metastasis. METHODS: The immunohistochemical expression of p62 and Ki-67 were studied in 40 primary hepatocellular carcinomas. RESULTS: 67.5% (27/40) exhibited positive staining of p62 protein in the cytoplasm of malignant cells, of which the strong positivity was mainly found in pathologic grade III cases. The cases with strong positive staining of p62 exhibited extensive fibrosis in the stroma and massive necrosis of the tumor. These cases also exhibited high proliferation activity, the mean Ki-67 labeling index was 28.3% +/- 15.1%, which was significantly higher than that in p62 negative ones (t = 3.087, P = 0.005). Three of five cases with lung or celiac lymph node metastasis exhibited strong positive staining of p62. CONCLUSION: There is some relationship between the expression of p62 protein, proliferation activity and metastasis of cancer cells as well as with the microenvironment which have abundant fibrous tissue in the stroma.

Adult↗
PubMed1987

Osteoporosis: the structural and reparative consequences for the skeleton.

We have discussed the biomechanical and biomaterial properties of bone with emphasis on the microenvironment. The microdensity of bone tissues determines the resistance to compressive forces (strength = density2). The structural orientation of bone determines the ability of bone to withstand torsion and bending forces. Highly remodeled bone is brittle and fractures easily because of the multiple reversal planes within the bone plates. Conversely, augmentation of bone on the periphery by modeling leads to increased material microstrength and structural macrostrength. Consequently, appositional modeling augments whereas remodeling diminishes bone strength. Hip fractures, spinal fractures, Colles' fractures, and pelvic fractures have been discussed in terms of their pathophysiology and treatment. An algorithm (Fig. 4-7) has been presented for the differential diagnosis of patients with recently discovered spinal compression fractures. Lastly, a discussion of exercise demonstrated its beneficial role, especially in the retention of bone mass.

Biomechanical Phenomena↗
PubMed1998

CTL effector function within the central nervous system requires CD4+ T cells.

CTL responses induced during most viral infections are independent of help derived from the CD4+ T cell population. However, clearance of virus from the central nervous system (CNS) during infection with the neurotropic JHM strain of mouse hepatitis virus is inhibited in the absence of CD4+ T cells. Adoptive transfer of activated CD8+ T cells with virus-specific cytolytic activity into CD4+ T cell-depleted hosts demonstrated that CD4+ T cells were one component of the host response required for expression of CTL effector function(s) within the CNS. Analysis of mice infected with the JHM strain of mouse hepatitis virus demonstrated that, in contrast to CD8+ T cells, few CD4+ T cells entered the brain parenchyma. Although fewer CD8+ T cells entered the brain parenchyma in mice depleted of CD4+ T cells, access of CTL was not inhibited in the absence of CD4+ T cells. The number of apoptotic lymphocytes in the CNS increased in the absence of CD4+ T cells, suggesting that CTL enter the CNS during viral infection in a CD4-independent manner. However, these cells rapidly undergo apoptosis, indicating that expression of CTL effector function with the parenchyma of the CNS is CD4 dependent. These data raise the possibility that programmed cell death of CD8+ T cells within the CNS is due to the increased Ag present in the CNS of infected CD4 depleted mice or that autocrine cytokines, which maintain CTL activity within peripheral tissues, are inhibited in the microenvironment of the CNS.

Animals↗
PubMed1998

In situ immune response in gut-associated lymphoid tissue (GALT) following oral antigen in TCR-transgenic mice.

Oral administration of Ag results in systemic hyporesponsiveness termed oral tolerance. The regulatory cells induced by oral Ag are effective in the suppression of Th1-type autoimmune diseases. We examined the cytokine microenvironment in gut-associated lymphoid tissue in response to orally administered OVA in OVA TCR-transgenic mice. Mice were fed a low (0.5 mg) or high (500 mg) dose of OVA one time or five times. Immunohistochemical analysis demonstrated increased IL-4, IL-10, and TGF-beta in the gut within 6 h of a low-dose feeding and after five low-dose or high-dose feedings. IFN-gamma and IL-2 either decreased or showed no change, with the exception of a small transient increase in IL-2 at 6 h after a low dose. Increases in IL-4 and IL-10 were found in the dome of the Peyer's patch, and increases in TGF-beta were observed in the interfollicular region and the villi. IL-10 was also substantially increased in the villi. IL-4 and IL-10 were produced predominately by CD4+ T cells. TGF-beta was found predominately in macrophages and CD4+ T cells. Peyer's patches had a marked up-regulation of TGF-beta mRNA as measured by RT-PCR. These results demonstrate the differential activation of cytokine production in discrete regions of gut-associated lymphoid tissue. The induction of cytokines known to inhibit autoimmune disease at the site of Ag absorption indicates an important role for the mucosal immune system in the establishment of oral tolerance.

Administration, Oral↗
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↗
PubMed2006

Microstructured extracellular matrices in tissue engineering and development.

Microscale heterogeneity in the extracellular matrix (ECM) provides spatial information that allows tissues to develop and function properly in vivo. This heterogeneity in composition (chemistry) and structure (geometry) creates distinct microenvironments for the cells that comprise a tissue. In response, populations of cells can coordinate their behaviors across micrometer-to-millimeter length scales to function as a unified whole. We believe techniques to mimic the microscale heterogeneity of the ECM in vitro will revolutionize studies that examine how large groups of cells interact. Micropatterned ECMs used for engineering perfused microvascular networks and functional epidermis and for understanding symmetry-breaking events in epithelial morphogenesis illustrate potential applications in tissue engineering and development.

Animals↗
PubMed1997

Indomethacin is a potent inhibitor of pristane and plastic disc induced plasmacytomagenesis in a hypersusceptible BALB/c congenic strain.

Continuous indomethacin (INDO) administration in the drinking water (10 to 20 microg/mL) profoundly inhibited plasmacytoma (PCT) development initiated by three 0.2- or 0.5-mL intraperitoneal (i.p.) injections of pristane in hypersusceptible BALB/c.DBA/2-Idh1-Pep3 congenic mice. The most effective inhibitions were obtained with continuous INDO treatment. When treatment was delayed until 50 to 60 days after the first pristane injection, there was approximately a 50% reduction in PCT incidence. The primary action of pristane is the induction of a chronic inflammation in the peritoneal connective tissues and the formation of a microenvironment where PCTs develop. INDO, a powerful inhibitor of prostaglandin synthases (cyclooxygenases 1 and 2), did not inhibit the formation of mesenteric oil granuloma nor the appearance of cells in this chronic inflammatory tissue carrying c-myc illegitimately joined to an Ig heavy chain switch region, ie, the t(12;15) chromosomal translocation. INDO inhibited PCT induction by the i.p. implantation of 21 x 2 mm polycarbonate discs. These solid objects predominantly induce the formation of a patchy fibroplastic tissue on contacting peritoneal surfaces. These and previous data indicate that indomethacin inhibits an intermediate stage in PCT development after the arrival of cells bearing the T(12;15) translocation in the oil granuloma and before these cells acquire transplantability to a pristane-conditioned host. The biological mechanism that explains how INDO inhibits PCT development is not yet established but appears to result from decreased production of prostaglandins in chronic inflammatory tissues (oil granuloma, fibroplasia), suggesting that prostaglandins play an active role in oil and solid plastic induced PCT formation.

Administration, Oral↗
PubMed2003

Increased TIA-1 gene expression in the tumor microenvironment after locoregional administration of tumor necrosis factor-alpha to patients with soft tissue limb sarcoma.

Although it is known that TNF-alpha is effective in the treatment of advanced solid tumors such as melanoma and soft tissue sarcoma, the molecular mechanism underlying its anticancer activity remains unclear. Nineteen patients with locally advanced soft tissue sarcoma underwent isolated limb perfusion with doxorubicin alone (n = 9) or combined with TNF-alpha (n = 10). mRNA from posttreatment tumor biopsies was linearly amplified to create an RNA bank. The transcriptional levels of 22 genes were analyzed by qrt-PCR. On the basis of in vivo findings, we investigated the in vitro gene expression of different cell types representing the tumor microenvironment cell population. TIA-1, which encodes an RNA-binding protein with translation-regulatory functions, was the only gene differentially expressed between the 2 study groups, its transcriptional levels in tumor biopsies from patients receiving TNF-alpha being higher than in those from patients not given the cytokine. In vitro, TIA-1 was expressed by endothelial cells, fibroblasts, CTLs and NK cells. TNF-alpha significantly upregulated TIA-1 gene expression only in endothelial and NK cells. Furthermore, TIA-1 transcriptional levels significantly increased during NK activity, which was enhanced by TNF-alpha. These findings support the hypothesis that TNF-alpha-induced TIA-1 overexpression might sensitize endothelial cells to proapoptotic stimuli present in the tumor microenvironment and enhance NK cell cytotoxic activity against cancer cells.

Antigens, CD↗
PubMed2001

Tumour metastasis: is tissue an issue?

Single tumour cells, or multicellular aggregates, escape into blood and lymphatic vessels from a primary solid tumour as it progresses. However, the ability of such cells to develop into metastatic outgrowths is very limited, as shown by the poor prognostic power of the presence of circulating tumour cells in cancer patients. An explanation for this low efficiency may be a temporary absence of a suitable microenvironment once the tumour cells escape from their original tissue compartment. On the basis of histopathological observations, experimental studies, and the generally accepted poor prognosis of histopathologically confirmed intravascular tumour location, we propose that the structural and functional organisation of intravascular tumour cells as a tissue has a key role in providing the optimum microenvironment for sustained malignant dissemination. Such a tissue may be a fixed or a mobile intravascular microsatellite, or an intravascular micrometastasis, which locally develops into an overt in-transit metastasis.

Humans↗
PubMed2005

Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms.

The majority of human and rodent cancers display various antigens which could elicit cellular and humoral immune responses. Such immunity, however, often fails to prevent progressive growth of cancers. It has long been speculated that tumor antigens may not be presented in appropriate fashion, which subsequently fails to elicit a strong immune response. Recent studies, however, indicate that immunization by formulated tumor antigens or even transfer of pre-activated T lymphocytes also have limited impact on cancer growth despite the fact that these methods could often enhance immune responses in cancer patients. These findings imply that even afferent arm of immunity are strengthen, it is not necessarily being translated to tumor regression. It is possible that the development of evasion mechanisms in tumor microenvironment play a critical role in the resistance of therapeutic immune responses. Recent studies provide compelling evidence that human and rodent cancers develop evasion mechanisms by aberrantly expressing normal proteins, which are required for normal tissue homeostasis, to either build a microenvironment locally or reach other organs systemically. In this review, we will focus our discussion on two recently described molecules, B7-H1 and B7-H4, in the context of their roles in the evasion of tumor immunity and possible approaches for therapeutic manipulation.

Antigens, CD↗
PubMed2001

Transplantation of brain cells assembled around a programmable synthetic microenvironment.

Cell therapy is a promising method for treatment of hematopoietic disorders, neurodegenerative diseases, diabetes, and tissue loss due to trauma. Some of the major barriers to cell therapy have been partially addressed, including identification of cell populations, in vitro cell proliferation, and strategies for immunosuppression. An unsolved problem is recapitulation of the unique combinations of matrix, growth factor, and cell adhesion cues that distinguish each stem cell microenvironment, and that are critically important for control of progenitor cell differentiation and histogenesis. Here we describe an approach in which cells, synthetic matrix elements, and controlled-release technology are assembled and programmed, before transplantation, to mimic the chemical and physical microenvironment of developing tissue. We demonstrate this approach in animals using a transplantation system that allows control of fetal brain cell survival and differentiation by pre-assembly of neo-tissues containing cells and nerve growth factor (NGF)-releasing synthetic particles.

Animals↗
PubMed2005

Multicellular spheroids of bone marrow stromal cells: a three-dimensional in vitro culture system for the study of hematopoietic cell migration.

Cell fate decisions are governed by a complex interplay between cell-autonomous signals and stimuli from the surrounding tissue. In vivo cells are connected to their neighbors and to the extracellular matrix forming a complex three-dimensional (3-D) microenvironment that is not reproduced in conventional in vitro systems. A large body of evidence indicates that mechanical tension applied to the cytoskeleton controls cell proliferation, differentiation and migration, suggesting that 3-D in vitro culture systems that mimic the in vivo situation would reveal biological subtleties. In hematopoietic tissues, the microenvironment plays a crucial role in stem and progenitor cell survival, differentiation, proliferation, and migration. In adults, hematopoiesis takes place inside the bone marrow cavity where hematopoietic cells are intimately associated with a specialized three 3-D scaffold of stromal cell surfaces and extracellular matrix that comprise specific niches. The relationship between hematopoietic cells and their niches is highly dynamic. Under steady-state conditions, hematopoietic cells migrate within the marrow cavity and circulate in the bloodstream. The mechanisms underlying hematopoietic stem/progenitor cell homing and mobilization have been studied in animal models, since conventional two-dimensional (2-D) bone marrow cell cultures do not reproduce the complex 3-D environment. In this review, we will highlight some of the mechanisms controlling hematopoietic cell migration and 3-D culture systems.

Animals↗
PubMed1986

Chemosensitivity testing in V79 spheroids: drug delivery and cellular microenvironment.

Chinese hamster V79 multicell spheroids growing in tissue culture exhibit many of the same properties as solid tumors outgrowing their blood supply, including the spontaneous development of both noncycling and hypoxic cell populations expected to be resistant to many chemotherapeutic agents. Cell-sorting techniques were used to select cells as a function of their position (depth) within the spheroid to test this prediction. "Sensitivity profiles" of cells from various regions within spheroids after treatment with doxorubicin, bleomycin, 5-fluorouracil, carmustine, cisplatin, chlorambucil, and mitomycin are presented. Additionally, exposure of preseparated cells was used to distinguish inherent sensitivity from environmental or locational factors. For these drugs, penetration was a problem only for doxorubicin; in contrast, the microenvironment in the intact spheroid had a much greater influence on cell sensitivity.

Animals↗