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PubMed1986

A preovulatory temperature gradient between the isthmus and ampulla of pig oviducts during the phase of sperm storage.

Fine thermistor probes positioned in each end of the same oviduct and connected to the same scale were used to measure temperature gradients in the lumen before and after spontaneous ovulation in normally-cyclic gilts. Readings were taken after full surgical closure of a mid-ventral incision and a subsequent period of stabilization, but whilst animals remained under general anaesthesia. A small but consistent difference in temperature was recorded between the proximal ampulla and distal isthmus of the same oviduct in each of 20 preovulatory gilts. In 10 of these animals that had not mated, the isthmus was a mean of 0.43 degree C cooler than the ampulla (range 0.2-0.7 degree C) whereas in 10 mated animals the isthmus was 0.69 degree C cooler (range 0.2-1.6 degree C); 3 animals in the latter group had within-oviduct differences of greater than or equal to 1 degrees C. By contrast, in 12 animals that had recently ovulated, the isthmus was a mean of only 0.1 degree C cooler than the ampulla; there was no measurable temperature gradient in 3 of the animals, whilst the isthmus was 0.1 degree C warmer in 2 animals. The preovulatory temperature differences are thought primarily to reflect the extent and activity of the vascular and lymphatic beds in the oviduct tissues and, together with specific chemical microenvironments, may facilitate the relatively prolonged period of sperm storage in the distal portion of the isthmus.

Animals↗

PubMedDate not supplied

Conceptual and practical implications of breast tissue geometry: toward a more effective, less toxic therapy.

Mathematics provides greater understanding of the complex process of tumorigenesis. Based on the Gompertzian phenomenon and the Norton-Simon hypothesis, enhanced cell kill can be obtained through a greater chemotherapy dose rate. Results from the 1995 Bonadonna et al. study and the CALGB/Intergroup C9741 study demonstrated that patients in the dose-dense arms had significantly longer disease-free survival and overall survival. Because of the demonstrated applicability of Gompertzian kinetics, attention has been turned to the etiology of the Gompertzian curve. Breast tumor dimensions, as with all tissue dimensions in biology, can be calculated by fractals. A less cell-dense tissue usually has a lower fractal dimension than a tissue with more cells (i.e., a higher cell density is usually due to a higher fractal dimension). Density is the number of cells divided by the tissue volume. When allowed to grow, the density of a tissue with a lower fractal dimension drops quickly. However, a tumor, since it has a higher fractal mass dimension, maintains a high density as it grows bigger, resulting in a more rapid growth rate and a larger final size. Fractal dimensions of infiltrating ductal adenocarcinomas of the breast are high (i.e., 2.98), which results in a very dense tissue compared with normal breast tissue (with a fractal dimension of about 2.25). As expected, the higher fractal dimension results in a high rate of growth. The reason for this high fractal dimension is that breast cancer can be considered as a conglomerate of many small Gompertzian tumors, each of which has a high cell density and hence ratio of mitosis to apoptosis. In mathematical terms, each component of the conglomerate can be considered a small metastasis in itself. Thus, the primary tumor is composed of multiple self-metastases that form around a seed from the tumor to itself. Conventional thinking is that cancers metastasize because they are large, but in fact it may be that they are large because they are self-metastatic. Many genes are associated with the biology of metastasis; these include: A) obligatory cancer genes (most of which regulate mitosis and mitotic rate); B) genes relating to self-metastasis and growth of tumors at local sites, conferring the ability to invade and grow with high cell density; and C) genes that relate to the ability of the cancer to metastasize to distant areas. Additionally, fibroblasts may send out abnormal growth signals causing abnormal breast tissue growth. Consequently, we are not only dealing with abnormal cancer cells, but also with the tissue that surrounds them, or the microenvironment, that is, the "Smith-Bissell" model. These new insights may lead us to change the thrust of our attack from genes involved in mitosis to those involved in metastasis, including metastasis to self, and to use and further improve dose-dense regimens.

Antineoplastic Agents↗

PubMed1988

Three-dimensional organization of the collagen fibrillar framework of the human and rat livers.

The collagen fibrillar framework in the human and rat liver was demonstrated by a cell-maceration/scanning electron microscope (SEM) method. Maceration of fixed tissues with alkali plus water successfully removed the cellular elements, exposing collagen fibrils which measured about 60 nm in diameter and were identified as such by transmission electron microscopy (TEM). The normal human liver contained 12.4 mg of collagen fibrils/g of wet tissue, while rat livers contained 1.3 mg of collagen fibrils/g of wet tissue. In the Glisson's sheaths were condensations of collagen fibrils which extended to the hepatic lobules. In the spaces of Disse collagen fibrils ran either solitarily or in bundles and formed sheaths for housing the sinusoids. The central veins and the sublobular veins were also surrounded by the collagen fibrillar sheaths which were continuous with those in the spaces of Disse. Between adjacent sheaths of sinusoids frequently stretched collagen fibrillar bundles which were confirmed by TEM to occur in inter-hepatocellular spaces continuous with the spaces of Disse. The collagen fibrillar layer of the human liver capsule was much thicker (70-100 microns in thickness) than that of the rat liver (less than 5 microns in thickness). The collagen fibrils of the capsule were also continuous with those in the spaces of Disse. The collagen fibrillar framework of the liver is presumed not only to mechanically support the tissue, but also to form a microenvironment for hepatocytes and cells in the Disse's space.

Adult↗

PubMed2026

Profibrogenic Gremlin-1 expression in prostate cancer and the clinicopathologic association.

BACKGROUND: Gremlin-1 (GREM1) is a profibrogenic molecule involved in TGF-β signaling. Recent studies have implicated GREM1 in androgen receptor (AR)-independent signaling and castration resistance in advanced prostate cancer. However, its compartment expression patterns and clinicopathologic significance in primary prostate cancer remain unclear. METHODS: GREM1 mRNA expression and clinicopathologic associations were analyzed in the Cancer Genome Atlas (TCGA) prostate adenocarcinoma (TCGA-PRAD), the Memorial Sloan Kettering Cancer Center (MSKCC), and the German Cancer Research Center (DKFZ) primary prostate cancer cohorts. Correlations between GREM1 and genes related to TGF-β signaling, extracellular matrix organization, fibroblast activation, and AR signaling were evaluated by Spearman analysis. GREM1 protein expression was examined by immunohistochemistry in commercial human prostate cancer tissue microarrays (TMAs) using compartment-specific QuPath-based H-scores. RESULTS: GREM1 expression was relatively elevated in prostate and bladder cancers. Across the three prostate cancer cohorts, higher GREM1 expression was associated with adverse pathologic features and was most consistently correlated with FAP. Inverse correlations were observed with selected AR-related genes, whereas no significant correlation was found with AR itself. Higher GREM1 expression was associated with shorter disease-free survival only in MSKCC but was not an independent prognostic factor after clinicopathologic adjustment. Quantitative immunohistochemistry in 43 patients showed higher epithelial than stromal GREM1 H-scores (median, 3.10 vs 1.41; P < 0.0001), with heterogeneous staining in both compartments. Neither epithelial nor stromal H-scores were associated with Gleason score or pathologic T stage. CONCLUSIONS: GREM1 mRNA expression in primary prostate cancer was associated with adverse clinicopathologic features, and a fibroblast-associated transcriptional context but did not demonstrate independent prognostic value. At the protein-level, GREM1 expression was heterogeneous in both epithelial and stromal compartments, with higher epithelial H-scores on average. These findings support further investigation of the biological significance of GREM1 expression in primary prostate cancer.

TCGA↗

PubMed2001

Array analysis of the genes regulated during neuronal differentiation of human embryonal cells.

Recent advances in genetic technology have provided a new platform on which the simultaneous analysis of a large number of genes is possible in a rapid and efficient fashion. To assess the differential expression of human genes during neuronal differentiation, we compared the transcript profiles of undifferentiated, partially differentiated, and fully differentiated NT2/D1 cultures with cDNA expression arrays. Approximately 75 genes (13% of the gene array pool) were differentially expressed during neuronal development of NT2/D1 cells. Genes coding for pyruvate kinase M2 isozyme, clathrin assembly proteins, calmodulin, fibronectin, laminin, thymosin beta-10, and many others were upregulated as NT2/D1 cells differentiated into neurons. In contrast, several kinases, phosphatases, and G-protein coupled receptor genes showed downregulation upon neuronal differentiation. The information provided here is an invaluable reference for characterizing the phenotype of these cells. This information can also be used in cell therapy and transplantation in which the graft microenvironment and interaction with the host tissue is crucial.

Base Sequence↗

PubMed2005

[The inherent liability to infection of various tissue for urethra reconstruction].

OBJECTIVE: Observing the long-term results of reconstructed urethra to reduce the postop infection rate of hypospadias. To explore the standard of selecting tissue for urethra reconstruction by comparing the different inherent liability to infection in use of different kinds of tissue for urethra reconstruction. METHODS: Neo-urethra inner wall and normal urethra were observed through urography and urethroscope. The tissue section of neo-urethra, normal urethra and tissue for urethra reconstruction were observed through light microscope, scanning electron microscope and transmission electron microscope. RESULTS: The structure and liability to infection of neo-urethra made of bladder mucosa, buccal mucosa or skin never changed after long time. Metaplasia never took place in neo-urethra. CONCLUSIONS: The structure and liability to infection of neo-urethra were the same as those of the congeneric tissue. Bladder or buccal mucosa is the best tissue for urethra reconstruction considering urethra microenvironment. Neo-urethra made of skin is more liable to infection by nature. The best opportunity of hypospadias operation should be before puberty.

Adolescent↗

PubMed2006

Stem cell plasticity and carcinogenesis.

Presently, there is more and more talk about tumors being a disease connected with stem cells. Both stem cells and tumor cells have many similarities, and there is much evidence that microenvironment, cytokines and signal pathways control tissue specificities and have a significant role in the process of carcinogenesis. Recent experimental results show that stem cells and tumor stem cells apparently play a key role in carcinogenesis. Tumors grow up, thanks to the activity of just few stem cells that continuously produce other proliferating progenitor tumor cells. Generally, tumor elements are thought to be either undifferentiated, or dedifferentiated cells. Actually, the truth is that tumors are made of more or less differentiated cells with variable rate of differentiation. We suppose that under certain conditions tumor stem cells may participate in regeneration without giving rise to tumor formation. It is also presumed that we may reprogram tumor stem cells and progenitor cells in a certain period of time and so initiate development of normal tissue. However, till now the real relation between normal and tumor cells is not clear. Finally, we wish to remind that plasticity of tumor and normal cells cannot be separated but should be considered as individual phenomenon expressing certain condition of an organism in time. This communication is only a probe and introduction into a discussion aimed at better understanding of carcinogenesis from the view of processes at the stem cell level. Stimulation of stem cell activation may lead to prophylactic approaches for therapy and prevention in carcinogenesis.

Animals↗

PubMed2005

[Mechanisms and medical implications of replicative senescence].

Normal somatic cells divide in vitro only for a limited number of times, and then enter a state of replicative senescence. In most human cells replicative senescence is triggered by critical shortening and uncapping of telomeres, which leads to the up-regulation of p53 and/or p16 suppressor proteins that inhibit cell divisions. Because both reconstruction of telomeres and inactivation of suppressor proteins enables the cells to grow further or even immortalize, it has been hypothesized that replicative senescence acts as a natural barrier against neoplastic transformation. On the other hand, however, recent reports suggest that the accumulation of senescent cells may jeopardize tissue integrity and create a specific microenvironment that promotes tumorogenesis in elderly people. In this review we describe recent advances in our knowledge on the mechanisms of replicative senescence and discuss its medical implications.

Aging↗

PubMed1981

[Formation of bone marrow organs following transplantation of cell suspensions to sponges].

Heterotopic transplantation of bone marrow monocellular suspensions in gelatin and collagenous sponges is highly effective in promoting osteal tissue formation and organization of hemopoietic microenvironment. This depends on the presence in the transplant of a framework for the growth of stromal mechanocytes. Formation of bone marrow organs proceeds at a greater efficacy on using trypsinized bone marrow cells versus those isolated by mechanical techniques.

Animals↗

PubMed1982

Tumor-selective modification of cellular microenvironment in vivo: effect of glucose infusion on the pH in normal and malignant rat tissues.

The pH distributions in transplanted neural (TV1A, BT1A) and hepatic (HV1A3) tumors and in brain and kidney of BDIX rats were analyzed as a function of serum glucose concentration (SGC), tumor size, and tissue architecture. Tissue damage during pH measurements in vivo could be minimized by the use of pH microelectrodes with tip diameters of less than or equal to 10 micrometers. In normoglycemic rats, the pH in TV1A tumors was only slightly lower than in brain or kidney. However, at 6 hr after the induction of hyperglycemia by continuous i.v. infusion of glucose, the average pH in TV1A tumors had fallen to 6.7 at an SGC of 27 mM and to 6.1 at an SGC of 50 mM. A similar glucose-mediated pH reduction was observed in BT1A and HV1A3 tumors. No significant increase in tissue acidity occurred in brain and kidney. The pH in tumors had reached its minimum at 2 hr after the onset of high-dose glucose infusion (SGC, 50 mM) and could be maintained at this level in hyperglycemic rats for at least 48 hr. In hyperglycemic hosts, an increased retention of acidic metabolites in the tumor tissue with decreasing vascular density was reflected by a tumor size (age)-dependent pH reduction and a higher degree of intratumoral pH variation. In partially necrotic tumors, pH values as low as 5.2 were recorded. Oral administration of NaHCO3 to tumor-bearing rats had no effect on the average pH in TV1A tumors.

Animals↗

PubMed1994

Wound infections.

Wound infections continue to be an important entity in terms of use of time and medical resources. Currently, the following risk factors are known to strongly predispose to wound infection: pre-existing medical illness, prolonged operative time, wound contamination, and contaminated or dirty wounds. Tissue level factors, including the local microenvironment, white cells, and cellular products that mediate inflammation, are important, and their manipulation holds promise for future therapies. For now, the judicious use of antibiotic prophylaxis and organized systems of wound surveillance are the most effective means to reduce the wound infection rate to its pathophysiologically attainable minimum.

Anti-Bacterial Agents↗

PubMed1993

Follicle epithelial M cells are a source of interleukin-1 in Peyer's patches.

The production of interleukin-1 (IL-1) by rabbit Peyer's patch M cells populating the follicle-associated epithelium (FAE) was studied. Sorted 5D9+ phagocytic epithelial M cells synthesized IL-1 after stimulation with lipopolysaccharide (LPS) in vitro, as evidenced by the ability of culture supernatants to induce the proliferation of the T-cell line D10.G4.1. Fixed LPS-stimulated M cells were less effective at mediating T-cell proliferation than supernatants from LPS-activated M cells. The magnitude of T-cell proliferation was M-cell concentration dependent, and proportional to the dose of LPS. The M-cell-mediated D10.G4.1 cell proliferation was inhibited > 75% with anti-IL-1 alpha, but < 50% with similar concentrations of anti-IL-1 beta. The results show that M cells secrete IL-1, and suggest the participation of M cells in the delivery of a localized co-stimulatory signal for T-cell and B-cell proliferation in the microenvironment of gut-associated lymphoid tissue (GALT).

Animals↗

PubMed2007

Microcontact printing of laminin on oxygen plasma activated substrates for the alignment and growth of Schwann cells.

Microenvironment mimicking biological situation is a vital issue in tissue regeneration. With much progress being made, one of the major challenges remains to develop a convenient method to fabricate the scaffold microenvironment suitable for cell attachment and proliferation. This article demonstrates the efficacy of microcontact printed laminin, an extracellular matrix protein, on three different oxygen plasma treatment substrates-tissue culture polystyrene, poly(methyl methacrylate) films, and chitosan films-for alignment and growth of the Schwann cells in in vitro culturing. Replica molding of polydimethylsiloxane elastomeric stamps, fabricated from patterned SU-8 structure on silicon master, was used to print laminin on the three substrates. Pattern and growth of Schwann cells for low (10(3) cells/cm(2)) and increased cell density (2 x 10(4) cells/cm(2)) on the varied substrates with and without microcontact printed laminin were characterized. Results of in vitro cell culture of Schwann cells showed a high degree of cell orientation on the laminin-micropatterned substrates for both cell densities. However, different cell seeding densities will strongly impact the morphology and orientation of Schwann cells. Microcontact printing proves to be a convenient means to pattern cell-recognition molecules on scaffold for cell-guilded growth in tissue regeneration.

Animals↗

PubMed2006

Number of CD4+ cells and location of forkhead box protein P3-positive cells in diagnostic follicular lymphoma tissue microarrays correlates with outcome.

PURPOSE: To examine the immune microenvironment in diagnostic follicular lymphoma (FL) biopsies and evaluate its prognostic significance. PATIENTS AND METHODS: Immunohistochemistry was used to study numbers and location of cells staining positive for immune cell markers CD4, CD7, CD8, CD25, CD68, forkhead box protein P3 (FOXP3), T-cell intracellular antigen-1, and Granzyme B in tissue microarrays of paraffin-embedded, diagnostic lymph node biopsies taken from 59 FL patients who lived less than 5 years (short-survival group; n = 34) and more than 15 years (long-survival group; n = 25). RESULTS: CD4 and FOXP3 expression were significantly different between the two groups. Samples from the long-survival group were more likely than those from the short-survival group to have CD4+ staining cells and to have FOXP3-positive cells in a perifollicular location. CONCLUSION: This study has identified differences in immune cell composition of the diagnostic FL lymph node immune microenvironment and these have the potential for use as prognostic biomarkers in a routine histopathology setting.

CD4-Positive T-Lymphocytes↗

PubMed1991

Variable receptor affinity and tissue sensitivity.

Vascular smooth muscle sensitivity to norepinephrine (NE), measured by contractile responses in vitro, varied in different arteries of the rabbit and also in the same vessels in other species. There was a good correlation between variation in the affinity of NE for the alpha 1-adrenoceptor and tissue sensitivity. The variation was continuous and probably not indicative of different receptor subtypes. Solubilization of alpha 1-adrenoceptors from the membrane changed the affinity for specific ligands while reconstitution restored it. Taken together, these results suggest the presence of a factor(s) within the receptor microenvironment capable of modulating affinity and hence tissue sensitivity to NE. In some blood vessels, receptor number was correlated significantly with affinity of the alpha 1-adrenoceptor for NE also. In general, the contribution of receptor number was considerably less than the affinity for NE.

Animals↗

PubMed1994

Control of lymphocyte homing.

The expression of immunity, both protective and pathologic, is critically dependent on the appropriate distribution of 'lymphoid resources' among the tissues of the body. The 'homing' mechanisms mediating this distribution have proven to have an astounding plasticity--directing, under strict microenvironmental control, the selective recruitment of specific lymphocyte subsets to the various secondary lymphoid tissues and extralymphoid immune effector sites. The past year has seen significant progress in our understanding in three areas: the molecular basis of lymphocyte interactions with endothelium, providing new insight into the complex multistep process of lymphocyte extravasation; the role of extravascular matrix and cells in retaining lymphocytes within tissues; and the mechanisms by which local microenvironments differentially regulate adhesion molecule expression and function so as to provide for site-selective lymphocyte homing.

Animals↗

PubMed2006

From molecules to matrix: construction and evaluation of molecularly defined bioscaffolds.

In this chapter, we describe the fundamental aspects of the preparation of molecularly-defined scaffolds for soft tissue engineering, including the tissue response to the scaffolds after implantation. In particular, scaffolds prepared from insoluble type I collagen fibres, soluble type II collagen fibres, insoluble elastin fibres, glycosaminoglycans (GAGs) and growth factors are discussed. The general strategy is to prepare tailor-made "smart" biomaterials which will create a specific microenvironment thus enabling cells to generate new tissues. As an initial step, all biomolecules used were purified to homogeneity. Next, porous scaffolds were prepared using freezing and lyophilisation, and these scaffolds were crosslinked using carbodiimides. Crosslinking resulted in mechanically stronger scaffolds and allowed the covalent incorporation of GAGs. Scaffold characteristics were controlled to prepare tailor-made scaffolds by varying e.g. collagen to elastin ratio, freezing rate, degree of crosslinking, and GAGs attachment. The tissue response to scaffolds was evaluated following subcutaneous implantations in rats. Crosslinked scaffolds maintained their integrity and supported the formation of new extracellular matrix. Collagen-GAG scaffolds loaded with basic fibroblast growth factor significantly enhanced neovascularisation and tissue remodelling. Animal studies of two potential applications of these scaffolds were discussed in more detail, i.e. for bladder and cartilage regeneration.

Animals↗

PubMed2004

Postmortem MR imaging of formalin-fixed human brain.

High-resolution postmortem neuroimaging of the brain can play a role in research programs by providing archival and reslicable images of brain specimens before permanent sectioning. These images can supplement evidence attained from both traditional neuropathological observations and in vivo neuroimaging. Differential brain tissue conspicuity, detectable with MRI, is determined by the density and mobility of water protons. Water content is about 70% in white matter, 80% in gray matter, and 99% in cerebrospinal fluid (CSF). To the extent that brain tissue contrast is determined by the number and microenvironment of water protons, timing parameters of MR image acquisition can interrogate this environment. Because the chemical environment of protons is different in living from dead tissue, optimal temporal imaging parameters, for example, for spin-echo imaging, commonly used for in vivo clinical and research study are different from those best for postmortem imaging. Here, we present a series of observations to identify relaxation times and optimal parameters for high-resolution structural imaging of formalin-fixed postmortem brain tissue using commercially available clinical scanners and protocols. Examples of high-resolution images and results from attempts at diffusion imaging are presented.

Aged↗