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At least 199 records · Page 11Linked to original sources
PubMed1990

The expression of phytohemagglutinin genes in Phaseolus vulgaris is associated with organ-specific DNA methylation patterns.

Using methylation sensitive restriction enzymes and DNA gel blot analyses, we have examined DNA methylation patterns at the chromosomal locus harboring the two phytohemagglutinin genes of Phaseolus vulgaris. In cotyledons, where the genes are highly expressed, several sites have become undermethylated, whereas the methylation status of other sites remains constant, both in cotyledons and in other organs. Taken together with measurements of mRNA levels, these studies provide evidence that organ-specific changes in DNA methylation patterns are associated with the organ-specific expression of nuclear genes in a dicotyledonous plant.

Base Sequence↗
PubMed2000

Organ-specific, carcinogen-induced increases in cell proliferation in p53-deficient mice.

Transgenic mice with germ-line p53 alleles disrupted by gene targeting are sensitive to the development of some spontaneous tumors and have provided researchers with much information with respect to cancer. In the present study, to cast light on the organ specificity of chemically induced carcinogenesis, we evaluated carcinogen-induced cell proliferation in target organs in heterozygote p53 knockout mice (p53-deficient mice). Groups of 9- or 10-week-old wild-type(+/+) and p53-deficient mice were respectively treated with one of the following carcinogens for 4 weeks: N-butyl-N-(4-hydroxybutyl)nitrosamine (0.0075% in drinking water); dimethylnitrosamine (0.001% in drinking water); dihydroxy-di-N-propylnitrosamine (0.1% in drinking water); 1,2-dimethylhydrazine (10 mg/kg body weight s.c. injection once a week); 4-nitroquinoline 1-oxide (4-NQO, 10 mg/kg b.w. s.c. injection once a week); or 7,12-dimethylbenz(a)anthracene (25 microg/kg body weight dermal application once a week). Cell proliferation was evaluated by measuring the 5-bromo-2'-deoxyuridine labeling indices in each target organ. The p53 and p21 statuses were evaluated by comparing the expressions of p53 protein, p21waf1/cip1 mRNA, and p21waf1/cip1 protein between the mice. 5-Bromo-2'-deoxyuridine labeling indices of the urinary bladder and the skin were significantly increased in p53-deficient mice as compared with the wild-type(+/+) mice. In the all organs examined, carcinogen-induced p21waf1/cip1 mRNA overexpression was detected with levels obviously lower in the p53-deficient animals. These data suggest that p53-deficient mice have an organ-specific increased sensitivity to the induction of cell proliferation in the urinary bladder and the skin. These are the same organs for which sensitivity to carcinogenesis has been reported. Because a decrease of p21waf1/cip1 protein overexpression was also observed in the organs in which cell proliferation did not appreciably differ from the level in wild-type(+/+) mice, this decrease might have no effect on sensitivity to cell proliferation and carcinogenesis. Alternatively, it might play an important role in the cell cycle regulation of only the sensitive organs.

Animals↗
PubMed1990

Organ specific genotoxicity and carcinogenicity.

1. The in vitro studies showed that organ specific metabolic activation does not appear to play a predominant role for the in vivo activities of the studied nitrosamines 2. The in vivo studies following 1 h exposure of rats with the nitrosamines can differentiate between organs susceptible for genotoxicity and and those which are not. Nontarget organs in carcinogenicity can not be identified exclusively. 3. The additional study of persistence of genotoxicity may identify organs susceptible for carcinogenicity. Presently, we are working on new techniques to detect DNA SSB and other events with microscale methods. This is necessary to allow a more complete elucidation of genotoxicity in remote target organs and with other carcinogens which may not induce DNA SSB. Accordingly in the near future we expect to have even more versatile tools available to study toxicokinetics of foreign compound. Meanwhile our work with N-nitrosamines is continuing in order to better understand their in vivo modes of action and to better evaluate their burden and risk for man.

Animals↗
PubMed1988

Organ-specific selection of viral variants during chronic infection.

This study demonstrates organ specific selection of viral variants during chronic lymphocytic choriomeningitis virus (LCMV) infection in its natural host. Isolates with different biological properties were present in the central nervous system (CNS) and lymphoid tissues of carrier mice infected at birth with the wt Armstrong strain of LCMV. Viral isolates from the CNS were similar to the wt Armstrong strain and induced potent virus-specific cytotoxic T lymphocyte (CTL) responses in adult mice and the infection was cleared within 2 wk. In contrast, LCMV isolates derived from the lymphoid tissues caused a chronic infection in adult mice associated with suppressed CTL responses. Revertants with wt Armstrong phenotype were present in the CNS of mice infected with a spleen isolate showing unequivocally the importance of host tissues in the selection of viral variants. These results provide a possible mechanism by which viral variants emerge in nature and suggest that tissue- and cell-specific selection is an important aspect of virus evolution.

Animals↗
PubMed1989

Studies on the structure of the organ-specific determinant of human colonic mucin.

We had previously shown that the human colon produces at least two immunochemically distinct mucins, one neutral and the other a sialomucin [Gold et al. J. biol. Chem. 256, 6354-6358 (1981)]. In addition, the sialomucin was shown to contain an immunodeterminant restricted to colonic epithelium and may thus prove useful as a tissue-specific marker. In the current study we have shown that a specific linkage of sialic acid to the oligosaccharide backbone has a major role in the organ-specific immunodeterminant structure. Treatment of intact colonic mucin with sialidase (Cl. perfringens) cleaved 20-80% of the sialic acid as measured colorimetrically. Immunoreactivity was decreased by 0-42% with respect to the untreated material. Saponification (0.1 N KOH, 20 min at room temp) caused an approximate 90% decrease in immunoreactivity for each mucin. Subsequent to saponification, neuraminidase cleaved most of the sialic acid from the mucins. The majority of sialic acid was observed to be O-acetylated, thus making it sialidase-insensitive. Gas chromatography-mass spectrometric analyses of the trimethylsilyl sialic acid derivatives indicated the presence of NeuNAc; NeuNAc, 9-OAc; and NeuNAc, 7,9 diOAc as the major sialyl derivatives. The radioimmunoassay data appeared to indicate that O-acetylated sialic acid was necessary for immunoreactivity. It should be noted that jejunal mucin and bovine submaxillary mucin also contain O-acetylated sialic acid, but did not inhibit in our radioimmunoassay. This may have been due to differences in the O-acetylation pattern or the linkage of sialic acid to the core carbohydrate. Analyses of the partially methylated alditol acetate derivatives by gas chromatography-mass spectrometry of the untreated, as well as the saponified and neuraminidase treated, mucins revealed that sialic acid was attached to the carbohydrate core either to galactose, N-acetylglucosamine, and/or N-acetylgalactosamine. Linear regression analyses comparing immunoreactivity with specific epitope concns, in conjunction with RIA analyses of known structures, suggested that the organ-specific immunodeterminant was (or was dependent upon the presence of) the structure GlcNAc (1,3)[O-acetylated Neu5Ac(2,6)] GalNAc.

Chemical Phenomena↗
PubMed1997

Regulation of gelatinase production and invasiveness by organ-specific fibroblasts in high- and low-metastatic clones from murine RCT sarcoma.

Regulation of gelatinase production, invasiveness and migration activity by organ-specific fibroblasts from embryo, subcutaneous and lung tissues of mice were investigated in high-metastatic RCT+ and low-metastatic RCT- clones established from a poorly differentiated murine sarcoma. In the conditioned media of RCT+ cells, mouse skin fibroblasts (MSF) obtained from the tissue of tumor origin (orthotopic) stimulated the production of the 105-kD gelatinase more than C3H/ 10T1/2 clone 8 (C3H/10 T1/2 CL8) or mouse lung fibroblasts (MLF). In the conditioned media of RCT- cells, however, cocultivation with fibroblasts showed only slight stimulatory effects on the production of the 105-kD gelatinase. In the invasion assay, using a reconstituted basement membrane (matrigel), RCT+ cells cocultivated with MSF showed significantly higher invasiveness than those cocultivated with C3H/10T1/2 CL8 or MLF. However, no significant differences were shown in the invasiveness of RCT- cells in cocultivation with three types of fibroblasts and in cultivation without fibroblasts. There was no significant difference in migration activity between RCT+ and RCT- cells cultivated alone. But in the cocultivation of both clones with MSF, the migration activity of RCT+ cells was significantly higher than that of RCT- cells. These findings suggest that MSF might delineate the difference in characteristics related to the metastatic potential of RCT+ and RCT- cells through regulation by organ-specific factors.

Animals↗
PubMed1979

A tumor-associated organ-specific antigen characteristic of spontaneously metastatic rat mammary carcinomas.

An organ-specific tumor-associated antigen (TAA) was present in several metastatic and nonmetastatic mammary carcinomas induced in WF female rats by 3-methylcholanthrene. The level of TAA was high in 2 metastatic carcinomas tested (TMT-081 and SMT-2A) and much lower--by a factor of 50--200--in 2 nonmetastatic mammary carcinomas (MT-100 and MT-W9B). The TAA in the 2 metastatic tumors was identical, as demonstrated by immunodiffusion and supported by cross-reactivity with antibody against TAA from TMT-081 in a binding inhibition radioimmunoassay. The TAA was shed in relatively large amounts by the metastatic tumors maintained in short-term organ culture. The high level and shedding of TAA thus appeared to be characteristics of the metastatic tumors but not of the nonmetastatic ones. This suggests that TAA on the cell membrane or in the circulation may be involved in the metastatic process as a factor blocking potentially cytotoxic cells or in other ways leading to suppression of the immune response against the tumor.

Animals↗
PubMed1986

Class II major histocompatibility complex and organ specific autoimmunity in man.

T helper lymphocytes only recognize the antigen to which they are directed if it is 'presented' to them by a cell expressing the same class II major histocompatibility complex (MHC) antigen as themselves. Since the target cells of most organ specific autoimmune diseases do not normally express class II MHC proteins on their surface, any cell specific surface antigens they possess may never have been presented, and therefore immunological tolerance to them may not exist. The target cells in several organ specific autoimmune diseases have been shown to express class II MHC aberrantly and this expression may have allowed presentation of such cell specific surface antigens to potentially autoreactive T helper lymphocytes. It has therefore been proposed that aberrant expression of class II MHC antigens may be an initiating factor in certain autoimmune diseases.

Antigen-Presenting Cells↗
PubMed2004

A high prevalence of organ-specific autoimmunity in patients with bipolar disorder.

BACKGROUND: In a previous study, we reported an increased prevalence of thyroperoxidase antibodies (TPOA) in patients with bipolar disorder. Here we report the prevalence of other organ-specific autoantibodies: H/K adenosine triphosphatase (ATPA), glutamic acid decarboxylase-65 (GAD65A), and GAD-67 (GAD67A). METHODS: ATPA, GAD65A, and GAD67A were determined (via a commercially available enzyme linked immunosorbent assay for ATPA, and a standardized radio immunoassays for GAD65A and GAD67A)in the sera of 239 patients with DSM-IV bipolar disorder, in 74 patients with DSM-IV schizophrenia, and in 220 healthy control subjects. RESULTS: The positivity prevalences for ATPA and GAD65A (but not GAD67A) were elevated in bipolar patients compared with those in healthy control subjects (11.7 vs. 6.1% and 11.3 vs. 2.6% respectively; p <.05). Schizophrenia patients did not show such statistically higher prevalence. The elevated prevalence of ATPA and GAD65A in bipolar disorder was associated with neither rapid cycling nor the use of lithium. Interestingly, the presence of GAD65A (and not that of TPOA and ATPA) tended to be associated with the activity of bipolar disorder. The level of TPOA was negatively correlated with the serum level of sIL-2R, a measure of T cell activation. CONCLUSION: Bipolar disorder is associated with organ-specific autoimmunity to the antigens TPO, H/K ATPase, and GAD65.

Autoantibodies↗
PubMed1982

In vitro mode of action, pharmacokinetics, and organ specificity of poly (maleic acid-styrene)-conjugated neocarzinostatin, SMANCS.

The organ specificity and pharmacokinetics of SMANCS, poly (maleic acid-styrene)-conjugated neocarzinostatin (NCS), were investigated in rats. The drug activity accumulated primarily in the regional lymph nodes after subcutaneous injection. After intravenous injection, the drug was found in the kidney, lymph nodes, and bladder in very high concentrations, and in lesser concentrations in the bone marrow, lung, small intestine, liver and spleen. The urinary excretion rate and total recovery of the drug after intravenous injection were higher than those after subcutaneous injection. SMANCS, having a molecular weight of 2.5 x 10(4) daltons, was degraded in vivo to NCS (mol. wt. about 1.1 x 10(4)). This was also confirmed in vitro by incubating the drug with cell homogenates. SMANCS caused strand scission of DNA similarly to NCS in lymphoblastoid cells. However, in a cell-free system using colicin E1 plasmid DNA, a high concentration of SMANCS was required to produce DNA degradation detectable by the alkaline sucrose gradient method.

Animals↗
PubMed2005

Human NK cells lyse organ-specific endothelial cells: analysis of adhesion and cytotoxic mechanisms.

Human organ-specific microvascular endothelial cells (ECs) were established and used in the present study to investigate their susceptibility to natural killer cell line (NKL)-induced lysis. Our data indicate that although IL-2-stimulated NKL (NKL2) cells adhered to the human peripheral (HPLNEC.B3), mesenteric lymph node (HMLNEC), brain (HBrMEC), and lung (HLMEC) and skin (HSkMEC.2) ECs, they significantly killed these cells quite differently. A more pronounced lysis of OSECs was also observed when IL-2-stimulated, purified peripheral blood NK cells were used as effector cells. In line with the correlation observed between adhesion pattern and the susceptibility to NKL2-mediated killing, we demonstrated using different chelators that the necessary adhesion step was governed by an Mg(2+)-dependent, but Ca(2+)-independent, mechanism as opposed to the subsequent Ca(2+)-dependent killing. To identify the cytotoxic pathway used by NKL2 cells, the involvement of the classical and alternate pathways was examined. Blocking of the Ca(2+)-dependent cytotoxicity pathway by EGTA/MgCl(2) significantly inhibited endothelial target cell killing, suggesting a predominant role for the perforin/granzyme pathway. Furthermore, using confocal microscopy, we demonstrated that the interaction between NKL2 effectors and ECs induced cytochrome c release and Bid translocation in target cells, indicating an involvement of the mitochondrial pathway in NKL2-induced EC death. In addition, although all tested cells were sensitive to the cytotoxic action of TNF, no susceptibility to TRAIL or anti-Fas mAb was observed. The present studies emphasize that human NK cell cytotoxicity toward ECs may be a potential target to block vascular injury.

Cations, Divalent↗
PubMed2002

Monocyte/macrophage initiation of organ-specific autoimmunity: the ultimate 'bystander' hypothesis?

It is postulated that organ-specific autoimmune diseases could be initiated by dysregulated peripherally activated monocytes/macrophages penetrating into target organs nonspecifically. Failure of regulation of pro-inflammatory monocytes/macrophages might then result in autoimmune disease if secondary over-expansion of pre-existing autoantigen-specific T cell populations occurs in genetically predisposed individuals.

Animals↗
PubMed1995

Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases.

CD4+ T cells play a key role in regulating immune system function. When these regulatory processes go awry, organ-specific autoimmune diseases may develop. Here, Roland Liblau, Steven Singer and Hugh McDevitt explore the thesis that a particular subset of CD4+ T cells, namely T helper 1 (Th1) cells, contributes to the pathogenesis of organ-specific autoimmune diseases, while another subset, Th2 cells, prevents them.

Animals↗
PubMed1997

Organ-specific adhesion of neuroblastoma cells in vitro: correlation with their hepatic metastasis potential.

Neuroblastoma (NB) is the most common solid malignant tumor found in pediatric patients and the liver is one of the major sites of metastasis. To investigate the organ specificity of metastatic distribution, the adherence behavior of tumor cells was studied. The data presented are based on studies using a metastatic murine cell line C1300. In vivo, not only intrasplenic but also intravascular injection of C1300 NB cells consistently results in hepatic metastasis formation in syngeneic A/J mice. An in vitro assay was used in which C1300 NB cell attachment to cryostat sections of liver, spleen, brain, kidney and lung obtained from normal A/J mice was measured to compare organ-specific adhesion. A good correlation was found between their metastatic potential in the liver and the adhesion to the liver sections; C1300 NB cells adhered preferentially to liver cryostat sections. Enzyme assays indicated that cell surface glycoproteins were involved in cell adhesion. An adhesion assay with extracellular matrix proteins demonstrated that C1300 NB cells adhered preferentially to vitronectin and fibronectin, and the adherence was strongly inhibited by Arg-Gly-Asp (RGD)-containing peptides. Furthermore, adhesion of C1300 NB cells to liver cryostat sections could be blocked by the synthetic peptide GRGDS. This indicates that the interaction between RGD-containing matrix adhesion protein and cells has an important role for the specific adhesion of C1300 NB cells. The results suggested that tumor cell adhesion to liver cryostat sections could provide a useful tool in the study of host-tumor interactions in the metastasis of NB.

Animals↗
PubMed2005

Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors.

Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers. Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas. Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.

Antineoplastic Agents↗
PubMed2001

Organ-specific activation of activator protein-1 in transgenic mice by 12-o-tetradecanoylphorbol-13-acetate with different administration methods.

12-O-Tetradecanoylphorbol-13-acetate (TPA) is widely used as a tumor promoter with organotropy in skin and esophagus. TPA-induced, organ-specific tumor promotion is not correlated with the distribution of its receptor, protein kinase C (PKC). Using five administration methods (painting, drinking, gavage feeding, i.p. injection, and i.v. injection), we analyzed TPA-stimulated activator protein-1 (AP-1) activity in various organs (liver, kidney, brain, lung, spleen, heart, stomach, colon, esophagus, and skin) from transgenic mice expressing the AP-1 luciferase reporter gene. Topical application of TPA by painting the skin on the back of mice raised AP-1 activity 122.6-fold, and the highest peak of AP-1 activity was at 12 h after administration of TPA. Drinking water containing TPA caused a 25.8-fold induction of AP-1 activity in the skin, whereas gavage feeding with TPA caused a 34.2-fold induction of AP-1 in the skin. Intraperitoneal or i.v. injection of TPA induced a 49.56-fold or 20.4-fold increase in AP-1 activity in the skin, respectively. The highest peaks of AP-1 activity in the skin were at 12 h after drinking, feeding, or injection of TPA. More interesting, in the esophagus, i.p. injection of TPA raised AP-1 activity 13.9-fold, drinking TPA raised AP-1 activity 8.4-fold, and painting with TPA caused a 2.4-fold induction of AP-1 activity. In the colon, i.p. injection of TPA raised AP-1 activity 3.9-fold, drinking TPA induced a 1.2-fold increase in AP-1 activity, but painting with TPA had no effect. AP-1 activity in other organs was not detectable after administration of TPA by painting, drinking, or injection. Phosphorylation of extracellular signal-regulated kinases in the skin increased at 12 h after painting, drinking, or i.p. injection of TPA. In addition, phosphorylation of p38 kinase was raised slightly after TPA administration, but phosphorylation of c-Jun NH(2)-terminal kinases was not detected at any time point after TPA administration. Similar changes in MAP kinases were also seen in the esophagus after TPA administration. These results indicate that the skin is the most sensitive organ to TPA induction of AP-1 activity. The data suggest that the organ-specific, tumor-promoting effect of TPA may be through AP-1 activation and phosphorylation of ERKs and p38 kinase.

Animals↗