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PubMed2004

Building an organ-specific carcinogenic database for SAR analyses.

FDA reviewers need a means to rapidly predict organ-specific carcinogenicity to aid in evaluating new chemicals submitted for approval. This research addressed the building of a database to use in developing a predictive model for such an application based on structure-activity relationships (SAR). The Internet availability of the Carcinogenic Potency Database (CPDB) provided a solid foundation on which to base such a model. The addition of molecular structures to the CPDB provided the extra ingredient necessary for SAR analyses. However, the CPDB had to be compressed from a multirecord to a single record per chemical database; multiple records representing each gender, species, route of administration, and organ-specific toxicity had to be summarized into a single record for each study. Multiple studies on a single chemical had to be further reduced based on a hierarchical scheme. Structural cleanup involved removal of all chemicals that would impede the accurate generation of SAR type descriptors from commercial software programs; that is, inorganic chemicals, mixtures, and organometallics were removed. Counterions such as Na, K, sulfates, hydrates, and salts were also removed for structural consistency. Structural modification sometimes resulted in duplicate records that also had to be reduced to a single record based on the hierarchical scheme. The modified database containing 999 chemicals was evaluated for liver-specific carcinogenicity using a variety of analysis techniques. These preliminary analyses all yielded approximately the same results with an overall predictability of about 63%, which was comprised of a sensitivity of about 30% and a specificity of about 77%.

Animals↗
PubMed2002

In vitro formation of organ specific proximate carcinogen of benzo(a)pyrene by rat homogenates.

In order to determine the organ specific carcinogenicity of benzo(a)pyrene (B(a)P), its metabolites, formed in vitro by incubation with the homogenates from liver, lungs, kidneys, intestine and brain of rats, were isolated by TLC and spectroscopy. B(a)P was found to be converted into a number of metabolites by different tissue homogenates. The results showed that the proximate carcinogenic metabolite, 7,8-dihydro-7,8-dihydroxy B(a)P was formed only when rat lung and kidney homogenates were incubated with B(a)P in vitro. The UV spectral analysis also confirmed the formation of this metabolite only on incubation of B(a)P with rat lung and kidney homogenates. As the proximate carcinogenic metabolite was only formed by incubating B(a)P with the homogenates from target organs, its organ specific carcinogenicity may be explained.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1987

Treatment of systemic and organ-specific autoimmune disease in mice by allogeneic bone marrow transplantation.

Autoimmune diseases have been clinically divided into those which are systemic and organ-specific. (NZB X NZW) F1, MRL/1, and BXSB mice have been utilized as models for systemic autoimmune diseases. When these mice which had already developed autoimmune diseases were irradiated and reconstituted with T cell-depleted allogeneic bone marrow cells, the recipient survived for more than 5 months without showing graft-versus-host reaction. Immunohistopathological studies revealed that deposits of immunoglobulin and complement into the glomeruli were markedly reduced. In addition, levels of circulating immune complexes and auto-antibodies such as anti-dsDNA and anti-Sm antibodies decreased. Three months after bone marrow transplantation, T cell dysfunction was restored, and hyperfunction of B cells and macrophages were normalized. These data prompted us to examine whether or not organ-specific autoimmune diseases can be treated by allogeneic bone marrow transplantation. NOD mice which develop insulitis and overt diabetes were used for this experiment. The mice showed marked infiltration of T cells into the pancreatic islets which resulted in selectively destroying beta cells. Most of the T cells are Lyt-1+, and some are Lyt-2,3+. When NOD mice (6 months old) were irradiated and reconstituted with bone marrow cells of young BALB/c nu/nu mice (less than 2 months), the NOD mice exhibited neither insulitis nor overt diabetes. Deposits of immunoglobulin in the mesangial area of the glomeruli disappeared 3 months after bone marrow transplantation. Assays for immunological functions revealed that NOD mice showed hyperfunction of T cells, B cells, and macrophages. In NOD mice reconstituted with BALB/c nu/nu bone marrow cells, these functions were normalized. Newly developed T cells are found to be tolerant of both bone marrow donor-type and host-type major histocompatibility complex determinants. These results suggest that bone marrow transplantation is a strategy to be considered as an approach to the treatment for both systemic and organ-specific autoimmune diseases in humans.

Animals↗
PubMed2005

Multiplicity of different cell- and organ-specific import routes for the NADPH-protochlorophyllide oxidoreductases A and B in plastids of Arabidopsis seedlings.

The NADPH-dependent protochlorophyllide (Pchlide) oxidoreductase (POR) is a photoenzyme that requires light for its catalytic activity and uses Pchlide itself as a photoreceptor. In Arabidopsis there are three PORs denoted PORA, PORB and PORC. The PORA and PORB genes are strongly expressed early in seedling development. In contrast to PORB the import of PORA into plastids of cotyledons is substrate-dependent and organ-specific. These differences in the import reactions between PORA and PORB most likely are due to different import mechanisms that are responsible for the uptake of these proteins. The two major core constituents of the translocon of the outer plastid envelope, Toc159 and Toc34, have been implicated in the binding and recognition of precursors of nuclear-encoded plastid proteins. Their involvement in conferring substrate dependency and organ specificity of PORA import was analyzed in intact Arabidopsis seedlings of wild type and the three mutants ppi3, ppi1 and ppi2 that are deficient in atToc34, atToc33, a closely related isoform of atToc34, and atToc159. Whereas none of these three Toc constituents is required for maintaining the organ specificity and substrate dependency of PORA import, atToc33 is indispensable for the import of PORB in cotyledons and true leaves suggesting that in these parts of the plant translocation of PORA and PORB occurs via two distinct import pathways. The analysis of PORA and PORB import into plastids of intact seedlings revealed an unexpected multiplicity of import routes that differed by their substrate, cell, tissue and organ specificities. This versatility of pathways for protein targeting to plastids suggests that in intact seedlings not only the constituents of the core complex of import channels but also other factors are involved in mediating the import of nuclear-encoded plastid proteins.

Arabidopsis↗
PubMed1987

[The role of T-lymphocytes in organ-specific autoimmune diseases].

Chronic debilitating diseases such as multiple sclerosis, demyelinating inflammatory polyradiculoneuropathy, rheumatoid arthritis, diabetes mellitus type I, Hashimoto thyroiditis, forms of uveitis and interstitial nephritis, share many characteristics. They are all organ-specific inflammatory diseases of unknown etiology but with strong evidence of tissue-destructive activity of the cellular immune system in the organs respectively affected, i.e. the central or peripheral nervous system, the joints, the islets of Langerhans, the thyroid gland, the retina, or the tubulo-interstitial renal tissue. Recognized animal models of all these diseases are experimentally induced autoimmune conditions that are transferable with autoreactive T-lymphocytes, in contrast to autoantibodies in humoral autoimmune diseases. In recent years, disease-transferring T-lymphocytes, have been successfully grown as lines and clones in vitro, thus finally proving the primary pathogenic role of autoreactive T-lymphocytes in these animal models. Such T-cell lines are valuable tools in further defining autoantigens, studying mechanisms of T-cell activation in vitro, following T-cell migration and organ-specific homing in vivo, and analyzing effector functions in the infiltrated organs. In addition, questions concerning the breakdown of immunological selftolerance and the basic principles of resistance to disease can be addressed, and possibilities of treatment can be approached. Although the basic etiology of the human organ-specific immune diseases is still unknown, these animal models have helped to throw light on some of the pathogenic mechanisms common to these various diseases.

Animals↗
PubMed1992

Organ-specific distribution of genotoxic effects in mice exposed to cooked food mutagens.

The induction of organ-specific genotoxic effects of five cooked food mutagens in Swiss albino mice was investigated in microbial animal-mediated assays. The indicator of the induction of DNA damage was a pair of Escherichia coli K12 strains, differing vastly in repair capacity (uvrB/recA versus uvr+/rec+). All compounds gave positive results in the tested dose range between 2.5 and 40 mg/kg body weight (i.p. administration, exposure time 120 min). 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) were slightly more genotoxic than 2-amino-3,8-dimethylimidazo[4,5-f]quinoline (MeIQx), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) which caused similar effects. When the compounds were administered orally, higher doses were required to induce repairable DNA damage. The pattern of organ-specific effects was essentially similar for all compounds; genotoxicity was most pronounced in livers and lungs, whereas in kidneys, spleen and testes comparatively lower effects were measured. The activity of PhIP, MeIQ and IQ in the blood was similar to that observed in the liver. The results obtained in vivo were compared with data gained in vitro with subcellular organ fractions. Our findings indicate the following. (i) The concentrations required to induce repairable DNA damage in microbial animal-mediated assays are substantially higher than might be expected on the basis of the liquid suspension tests. (ii) The ranking order of the genotoxicity of the various compounds in vitro is similar to that measured in vivo, but the differences in genotoxic potencies are less pronounced in the living animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Thymus and autoimmunity. Transplantation of the thymus from cyclosporin A-treated mice causes organ-specific autoimmune disease in athymic nude mice.

Organ-specific autoimmune diseases such as gastritis, oophoritis, thyroiditis, or insulitis developed in athymic nu/nu mice after engraftment of the thymus from euthymic nu/+ mice treated with cyclosporin A (CsA), a potent immuno-suppressant. The development of autoimmune disease in the nu/nu mice was prevented by inoculation of thymocyte suspensions prepared from normal nu/+ mice, but not by thymocyte suspensions from CsA-treated nu/+ mice. Cotransplantation of normal nu/+ mouse thymus with CsA-treated thymus also suppressed the development of autoimmune disease. Inoculation of spleen cell suspensions prepared from normal adult nu/+ mice prevented autoimmune disease, but inoculation of those from newborn nu/+ mice did not. Thus, CsA appears to interfere selectively with the thymic production of certain suppressor T cells controlling self-reactive (autoimmune) T cells, allowing the latter to expand and cause autoimmune disease.

Animals↗
PubMed1993

Organ-specific metastases in immunodeficient mice injected with human melanoma cells: a quantitative pathological analysis.

Pathological and morphometric techniques were used to investigate the potential of two human melanoma cell lines for organ colonization in three different immunodeficient mouse strains; nude (nu/nu), NIH triple immunodeficient (TID: nu/nu, bg/bg, xid/xid) and severe combined immunodeficient (SCID) mice. The MM-RU cell line gave rise exclusively to lung metastases, whereas the MM-AN cell line gave rise to lung and extrapulmonary metastases. Although the TID mice showed more pancreatic and brown fat lesions than nude or SCID mice, the overall pattern of distribution of organ metastases among the strains was similar, suggesting that cellular properties intrinsic to the melanoma cells are important for the colonization of specific organs. The metastatic nodules were well circumscribed in all organs and exhibited peripherally located macrophages, except for brain metastases, where a more invasive pattern along vasculature was observed. The differences in cellular infiltrate and infiltrative patterns of the tumors implicate features of the host microenvironment (organ-specific factors) which are, at least in part, independent of the host's genetic background or degree of immunodeficiency. Our findings suggest that intrinsic malignant cellular properties play an important role in organ-specific colonization by haematogenously metastasizing cells.

Adipose Tissue, Brown↗
PubMed1995

Organ-specific differential regulation of a promoter subfamily for the ribulose-1,5-bisphosphate carboxylase/oxygenase small subunit genes in tomato.

The tomato (Lycopersicon esculentum) gene family for the small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (RBCS) has been investigated to determine the role of promoter regions and DNA-protein interactions in the differential organ-specific transcription of individual genes. Transgenic plants expressing RBCS-promoter-beta-glucuronidase fusion genes have confirmed that promoter fragments ranging from 0.6 to 3.0 kb of the RBCS1, RBCS2, and RBCS3A genes were sufficient to confer the temporal, organ-specific, and differential expression pattern observed for the endogenous genes. The individual temporal and organ-specific beta-glucuronidase enzyme activities closely reflect the qualitative and quantitative transcription activities of the respective RBCS genes, including the strongly reduced activity of RBCS3A (L.A. Wanner, W. Gruissem [1991] Plant Cell 3: 1289-1303). In particular, tissue-specific activity of all three promoters is similar in developing fruit, with high activity in the locular tissue and extremely reduced activity in the pericarp. This specific pattern of gene activity was further substantiated by in situ analysis of RBCS mRNA levels. Together, the data suggest an interesting correlation between RBCS gene activity and sink strength in different fruit tissues. DNA-protein interaction studies have revealed a novel fruit-specific DNA-binding protein called FBF that specifically interacts with a sequence element directly upstream of the G-box in the RBCS3A promoter. FBF binding thus correlates with the reduced activity of this promoter in developing tomato fruit, rendering it a candidate for a fruit-specific negative regulator of transcription in tomato.

Base Sequence↗
PubMed2000

Organ-specific acellular matrix for reconstruction of the urinary tract.

In urology, replacement of organs or organ segments has proved problematic. Current techniques do not replicate complete organ function, and they cause well-known complications. With the acellular organ-specific matrix we have found a way to regenerate tissue components seen in the normal lower urinary tract. The time required for regeneration depends on the matrix size and function. The matrix is covered by urothelium migrating from the host, after which neovascularization occurs, followed by formation of smooth-muscle cells and nerves. In our studies, normal muscle lining and nerves providing functional tissue were demonstrable and no sign of antigenicity was evident, even after heterologous grafting. The regenerated rat bladder was evaluated by organ bath as well as by in vivo functional tests and demonstrated properties and functions similar to those of host tissue. Besides our obtaining encouraging results in the rat bladder, we also studied the organ-specific acellular matrix in other species (dog and rabbit) and other organ segments (ureter and urethra).

Animals↗
PubMed1986

Expression by human fetal organs of organ-specific cancer neoantigens as measured by leukocyte adherence inhibition.

Human cancers express organ-specific cancer neoantigens (OSN) as determined by in vitro leukocyte responses to extracts of cancers by the tumor host. In this study, we determined whether the OSNs were normal developmental proteins that were expressed by fetal organs and re-expressed with oncogenesis. Fetal extracts, principally of lung and colon but also of liver and kidney, were tested for their ability to induce leukocyte adherence inhibition (LAI) as compared to extracts from adult tissues of the same organ. Leukocytes from lung cancer patients showed positive LAI responses to 13- and 19-week fetal lung tissue. Likewise, leukocytes from colon cancer patients showed positive LAI responses to 14- and 19-week fetal colon tissue, whereas leukocytes from control subjects did not. Neither group responded positively to 21-week fetal organs. Criss-cross experiments showed that the fetal antigen was organ specific. Multiparous pregnant women showed positive LAI responses to cancer extracts but not to extracts from normal tissues of the same organ. The pattern of the LAI response was bell-shaped. Positive LAI responses to lung and breast cancer were detected at 4 to 7 months gestation and peaked at 5 months. To the fetal colon, LAI positive responses were detected at 5 to 8 months gestation, with the peak response at 6 months. The results indicate that OSN of cancers are also expressed by fetal organs and sufficient antigen is shed by fetal organs to sensitize pregnant women. Older fetal organs (21 weeks) and adult organs do not express an immunogenic or antigenic OSN.

Antigens, Neoplasm↗
PubMed1978

Genetics of esterases in Drosophila. VI. Gene system regulating the phenotypic expression of the organ-specific esterase in Drosophila virilis.

It is shown that the gene controlling the synthesis of the organ-specific S-esterase of Drosophila virilis ejaculatory bulbs is located on the second chromosome (at approximate position 192.1 +/- map units). The cells of the genital imaginal disks are determined for the synthesis of S-esterase 10-12 hr after the second molt. The organ-specific esterase can be detected after adult emergence only. It is preceded by an increase in RNA content and by enhancement of RNA synthesis in the cells of the ejaculatory bulbs. Interstock differences were found in the level of the activity of S-esterase, which is under the control of the X chromosome, as well as in the time of expression of enzyme activity, which is controlled by the fifth chromosome. It is suggested that the specific phenotypic expression of this enzyme depends on the system of genes with regulatory expression at both the transcriptional and posttranscriptional levels. The genetic control of the synthesis of the S-esterase described is a convenient model for studying mechanisms of gene activity regulation in eukaryotes.

Animals↗
PubMedDate not supplied

[Regularities of organ-specific expression of enzyme systems in cattle].

The organ specificity of creatine kinase, esterase, isocitrate dehydrogenase lactate dehydrogenase, nucleoside phosphorylase, adenylate kinase, hexokinase, malate dehydrogenase, malic enzyme, glucose-6-phosphate dehydrogenase of black-white cattle has been studied. Esterases, creatine kinase, adenylate kinase, hexokinase and glucose-6-phosphate dehydrogenase have a very wide spectrum of the organ variabilities. Liver and heart have the largest specificity of enzymes activity. Some peculiarities of isozyme spectrum are found in ovaries and spleen.

Adenylate Kinase↗
PubMed1995

Modulation of tumor cell gene expression and phenotype by the organ-specific metastatic environment.

The mechanistic basis of a metastatic cell's ability to proliferate in the parenchyma of certain organs and develop organ-specific metastases is under intense investigation. Signals from paracrine or autocrine pathways, alone or in combination, may regulate tumor cell proliferation with the eventual outcome dependent on the net balance of stimulatory and inhibitory factors. This article summarizes recent reports from our laboratory and others demonstrating that the organ microenvironment can profoundly influence the pattern of gene expression and the biological phenotype of metastatic tumor cells, including induction of melanocyte stimulating hormone receptor and production of melanin, regulation of terminal differentiation and apoptosis, resistance to chemotherapy, and regulation of growth at the organ-specific metastatic site. These recent data from both murine and human tumor models support the concept that the microenvironment of different organs can influence the pattern of gene expression and hence the phenotype of tumor cells at different steps of the metastatic process. These findings have obvious implications for the therapy of neoplasms in general and metastases in particular.

Animals↗
PubMed1986

Organ specific antigens of the human gastrointestinal tract.

We previously reported the characterization of a normal adult colonic mucin antigen which contained an organ specific immunodeterminant [Tissue Antigen 11, 362 (1978)]. In the present study we have investigated mucins produced at other levels of the gastrointestinal tract in order to determine if regional specificities exist. Mucins were isolated from normal adult stomach, jejunum, ileum and colon and used to prepare antisera in rabbits. By radioimmunoassay at least four distinct specificities were observed. Gastric, ileal and colonic mucins were shown to contain immunodeterminants which were organ specific. Antiserum directed toward jejunal mucin determinants was reactive with the entire gastrointestinal tract. However, by heterologous inhibition analyses employing purified mucins as inhibiting antigens, the anti-jejunum antiserum was shown to be capable of discriminating a determinant present in much higher epitope density within small intestinal mucins as compared to mucins of the stomach and colon. Thus, it appeared that immunologic determinants present within mucin type glycoproteins of the gastrointestinal tissues exhibit anatomic specificity. In each case the structure of the immunodeterminant was, or was dependent upon the presence of a sialic acid derivative.

Antigens↗
PubMedDate not supplied

Molecular mechanisms for organ-specific colon carcinoma metastasis.

The mechanistic basis of a metastatic cell's ability to proliferate in the parenchyma of certain organs and develop organ-specific metastases remains largely unknown. Signals from paracrine and/or autocrine pathways may regulate tumour cell proliferation, with the eventual outcome dependent on the net balance of stimulatory and inhibitory factors. Recent data demonstrate that organ microenvironments can modulate gene expression of tumour cells, including regulation of growth at the organ-specific metastatic site. Analyses of highly metastatic human colon carcinoma (hCC) cells selected in nude mice as well as in situ mRNA hybridisation analyses of archival colon carcinoma specimens correlated high levels of epidermal growth factor receptor with the malignant hCC cell's ability to grow in the liver parenchyma. These same metastatic cells can also respond to specific mitogens produced by tissue undergoing repair, demonstrating that physiological signals can be utilised by neoplastic cells. This article will address experimental evidence supporting the premise that organ-derived, paracrine growth factors regulate the growth of malignant cells that express the appropriate receptors.

Animals↗
PubMed2000

Full-length cDNA cloning and genomic organization of the mouse liver-specific organic anion transporter-1 (lst-1).

We have cloned a cDNA that codes for mouse liver-specific transporter-1, mouse lst-1. The cDNA is comprised of 3296 base pairs and it contains a coding sequence for a protein of 689 amino acids with 12 putative transmembrane domains. The deduced amino acid sequence of the mouse lst-1 shares 64 and 77% identities with the reported human and rat lsts, respectively. Northern blot analysis demonstrates that mouse lst-1 mRNA is expressed exclusively in liver. We also report here the structural organization of the mouse lst-1 gene as the first evidence for the structure of a gene encoding an lst. The mouse lst-1 gene spans approximately 60 kbp in length and consists of 16 exons, including two noncoding exons. All the introns are flanked by GT-AG consensus splice sequences. 5'-Rapid Amplification of cDNA Ends (RACE) analyses demonstrate three splice variant mRNAs involving the noncoding exon 2 and exon 3. The 5'-flanking region of the gene contains consensus CAAT and TATA boxes and several potential binding sites for transcription factors for CAAT enhancer binding protein (C/EBP) and hepatocyte nuclear factors (HNF-3beta, HFH-1, and HFH-2), transcription factors important for liver-specific gene expression.

5' Untranslated Regions↗
PubMed1996

Organ-specific autoantibodies are possible markers for reproductive failure: a prospective study in an in-vitro fertilization-embryo transfer programme.

This study was conducted to investigate the usefulness of organ-specific autoantibodies as possible markers for reproductive failure. Antithyroid and antiovarian autoantibody concentrations were measured in 78 patients with mechanical or unexplained infertility that were enrolled in an in-vitro fertilization (IVF)/embryo transfer programme with follow-up of the outcome. In all, 16 patients (20.5%) were positive for antithyroid antibodies, nine (11.5%) were positive for antiovarian autoantibodies and two (2.6%) were positive for both autoantibodies. All 23 patients who were positive for either antithyroid or antiovarian autoantibodies, or both, were defined as the study group, and 55 who were negative for autoantibodies were considered as the control group. No statistical difference in the incidence of autoantibodies was found between the patients with mechanical infertility and those with unexplained infertility. No differences were found in the mean number of oocytes retrieved, fertilization rates or mean numbers of transferred embryos between the study and the control groups. The pregnancy rate per cycle was 10.8% (7/65) in the study group, compared with 25.0% (24/96) in the control group (P < 0.05). We conclude that organ-specific autoantibodies such as antithyroid and antiovarian antibodies may serve as possible markers for reproductive failure. Further investigation is required to understand the possible immunopathological mechanism for reproduction failure in patients with organ-specific autoantibodies.

Adult↗