The pleiotropic roles of ADAM9 in the biology of solid tumors

A disintegrin and a metalloprotease (ADAM) 9 is a metzincin cell-surface protease involved in several biological processes such as myogenesis, fertilization, cell migration, inflammatory response, proliferation, and cell–cell interactions. ADAM9 has been found over-expressed in several solid tumors entities such as glioma, melanoma, prostate cancer, pancreatic ductal adenocarcinoma, gastric, breast, lung, and liver cancers. Immunohistochemical analyses highlight ADAM9 expression by actual cancer cells and associate its abundant presence with clinicopathological features such as shortened overall survival, poor tumor grade, de-differentiation, therapy resistance, and metastasis formation. In each of these tumors, ADAM9 may contribute to tumor biology via proteolytic or non-proteolytic mechanisms. For example, in liver cancer, ADAM9 has been found to shed MHC class I polypeptide-related sequence A, contributing towards the evasion of tumor immunity. ADAM9 may also contribute to tumor biology in non-proteolytic ways probably through interaction with different integrins. For example, in melanoma, the interaction between ADAM9 and β1 integrins facilitates tumor stroma cross talks, which then promotes invasion and metastasis via the activation of MMP1 and MMP2. In breast cancer, the interaction between β1 integrins on endothelial cells and ADAM9 on tumor cells facilitate tumor cell extravasation and invasion to distant sites. This review summarizes the present knowledge on ADAM9 in solid cancers, and the different mechanisms which it employ to drive tumor progression.     

Rate of tryptophan hydroxylation in vivo in brain nuclei of genetically hypertensive rats of the Lyon strain

Summary The rate of tryptophan hydroxylation in vivo is unaltered in brain areas of 5, 9 and 21 week-old Lyon genetically Hypertensive (LH) rats as compared to both Lyon Normotensive (LN) and Low Blood Pressure (LL) rats, except for a decrease in the C1 area of the medulla oblongata in 9 week-old animals.Acknowledgment. The authors wish to thank Dr M.F. Belin, Dr J.F. Pujol and Mrs J. Sacquet for their help during this study. This work was supported by the Fondation pour la Recherche Médicale Française and the C.N.R.S.     

Rate of tryptophan hydroxylation in vivo in brain nuclei of genetically hypertensive rats of the Lyon strain

The rate of tryptophan hydroxylation in vivo is unaltered in brain areas of 5, 9 and 21 week-old Lyon genetically Hypertensive (LH) rats as compared to both Lyon Normotensive (LN) and Low Blood Pressure (LL) rats, except for a decrease in the C1 area of the medulla oblongata in 9 week-old animals.     

Conversion of γ-hydroxybutyrate to γ-aminobutyrate by mouse brain in vivo

Zusammenfassung -Hydroxybutyrat wird im Maushirn in-Aminobutyrat und in verschiedene -Aminosäuren umgewandelt.

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Supported by the Medical Research Council of Canada.     

Failure of hemicholinium-3 to inhibit the uptake of3H-choline in mouse brain in vivo

Zusammenfassung Es wird die Wirkung von Hemicholinium-3-dibromid und Troxopyrrolidinium chlorid auf die Aufnahme von [³H]Cholin im Gehirn der Maus studiert. Beide Substanzen hatten keine Wirkung, und es ist wahrscheinlich, dass der Mechanismus der Cholinaufnahme in das Gehirn vom dem der Cholinaufnahme in die cholinergischen Nervendigungen verschieden ist.     

Entry of water,metabolic substrates and extracellular space markers into various structures of mouse brain in vivo

Résumé Une méthode nouvelle est présentée pour étudier des corrélations qui existent entre le cerveau et le comportement des animaux.

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This study was supported in part by a grant from the Eli Lilly Company.     

The emerging roles of ribosomal histidyl hydroxylases in cell biology,physiology and disease

Hydroxylation is a novel protein modification catalyzed by a family of oxygenases that depend on fundamental nutrients and metabolites for activity. Protein hydroxylases have been implicated in a variety of key cellular processes that play important roles in both normal homeostasis and pathogenesis. Here, in this review, we summarize the current literature on a highly conserved sub-family of oxygenases that catalyze protein histidyl hydroxylation. We discuss the evidence supporting the biochemical assignment of these emerging enzymes as ribosomal protein hydroxylases, and provide an overview of their role in immunology, bone development, and cancer.     

In vivo effects of immunostimulating lipopeptides on mouse liver microsomal cytochromes P-450 and on paracetamol-induced toxicity

Summary Immunomodulating lipopeptides lauroyl-L-Ala--D-Glu-LL-A2pmNH2-Gly (RP 44.102) and lauroyl-L-Ala--D-Glu-LL-A2pmNH2 (RP 56.142) were found to protect mice against the hepatotoxicity of paracetamol, which is due to cytochrome P-450 dependent formation of toxic metabolites and radicals. In fact they decreased the amount of hepatic microsomal cytochrome P-450, and the level of CCl₄-induced lipid peroxidation. In contrast lauroyl-L-Ala--D-Glu-DD-A2pmNH2 (RP 53.204), which only differs by the configuration of the two chiral carbons of A2pm (diaminopimelic acid) and is not an immunomodulating agent, failed to protect against poisoning by paracetamol and had no effect on the level of hepatic cytochrome P-450 or the microsomal CCl₄-induced lipid peroxidation. This provides a clear connection between the immunostimulating properties of a compound and its effects on xenobiotic biotransformations.     

In vivo effects of immunostimulating lipopeptides on mouse liver microsomal cytochromes P-450 and on paracetamol-induced toxicity

Immunomodulating lipopeptides lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2-Gly (RP 44.102) and lauroyl-L-Ala-gamma-D-Glu-LL-A2pmNH2 (RP 56.142) were found to protect mice against the hepatotoxicity of paracetamol, which is due to cytochrome P-450 dependent formation of toxic metabolites and radicals. In fact they decreased the amount of hepatic microsomal cytochrome P-450, and the level of CCl4-induced lipid peroxidation. In contrast lauroyl-L-Ala-gamma-D-Glu-DD-A2pmNH2 (RP 53.204), which only differs by the configuration of the two chiral carbons of A2pm (diaminopimelic acid) and is not an immunomodulating agent, failed to protect against poisoning by paracetamol and had no effect on the level of hepatic cytochrome P-450 or the microsomal CCl4-induced lipid peroxidation. This provides a clear connection between the immunostimulating properties of a compound and its effects on xenobiotic biotransformations.     

The comparative biology of neuromelanin and lipofuscin in the human brain

Neuromelanin and lipofuscin are two pigments produced within the human brain that, until recently, were considered inert cellular waste products of little interest to neuroscience. Recent research has increased our understanding of the nature and interactions of these pigments with their cellular environment and suggests that these pigments may, indeed, influence cellular function. The physical appearance and distribution of the pigments within the human brain differ, but both accumulate in the aging brain and the pigments share some structural features. Lipofuscin accumulation has been implicated in postmitotic cell aging, while neuromelanin is suggested to function as an iron-regulatory molecule with possible protective functions within the cells which produce this pigment. This review presents comparative aspects of the biology of neuromelanin and lipofuscin, as well as a discussion of their hypothesized functions in brain and their possible roles in aging and neurodegenerative disease.     

Preliminary virological and immunological studies of the salivary gland tumor of C3H/He mouse

Riassunto Dai dati riferiti si mettono in evidenza due punti: il primo dimostra nel tumore in esame l'assenza di particelle virali e di effetto citopatico specifico per il virus polioma. Inoltre non si mettono in evidenza anticorpi fissanti il complemento o emoagglutinoinbenti per il virus polioma negli animali portatori di tumori. II secondo punto dimostra che durante il suo sviluppo il tumore della ghiandola salivare é incapace di indurre una risposta immunologica apprezzabile.     

Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance

Mouse models of DNA repair deficiency are useful tools for determining susceptibility to disease. Cancer predisposition and premature aging are commonly impacted by deficiencies in DNA repair, presumably as a function of reduced genomic fitness. In this review, a comprehensive analysis of all DNA repair mutant mouse models has been completed in order to assess the importance of haploinsufficiency for these genes. This analysis brings to light a clear role for haploinsufficiency in disease predisposition. Unfortunately, much of the data on heterozygous models are buried or underinvestigated. In light of a better understanding that the role of DNA repair haploinsufficiency may play in penetrance of other oncogenic or disease causing factors, it may be in the interest of human health and disease prevention to further investigate the phenotypes in many of these mouse models.     

In vivo and in vitro deiodination of silver iodide

Résumé La stabilité de l'iodure d'argent a été étudiée in vivo, par rapport à l'élimination de l'argent et du iode radioactif. Le foie semble responsable de la désiodation. Dans le foie, au bout de 6 h, 83% de l'iode est eliminé, mais seulement 16% de l'argent. Les expériences in vitro indiquent que le facteur responsable de la désiodation est thermostable et plus concentré dans le foie et dans le sang.     

Regulation of estrogen "receptors" in mammary tumors: action of prolactin in vivo

The effect of prolactin on estradiol receptors was determined in cytosol of estrogen-dependent mammary tumors of Sprague Dawley rats. Tumors were induced with 20 mg dimethylbenzanthracene, rats were ovariectomized, and the rats showing regression in tumor weight were given 1 mg sheep or rat prolactin for 5 days. Receptors were separated by dextran-charcoal and analyzed by sucrose gradient. Prolactin, milk proteins, serum proteins, and 1-alpha-feto-proteins were excluded immunologically. The estradiol receptors resembled uterine receptors in affinity, specificity, sedimentation, and nuclear transfer under estradiol influence. Castration diminished receptor content exponentially 170 f moles to 16 f moles/mg protein within 10 days; prolactin increased the number of receptors to 87 f moles compared with 15 in controls. Affinity, cellular location, and uterine receptor content were unaffected. Sheep and rat prolactin acted similarly. These results justify hypophysectomy as therapy for certain estrogen-dependent breast tumors.     

The role of p53 in tumour suppression: lessons from mouse models

The use of mouse models has greatly contributed to our understanding of the role of p53 in tumour suppression. Mice homozygous for a deletion in the p53 gene develop tumours at high frequency, providing essential evidence for the importance of p53 as a tumour suppressor. Additionally, crossing these knockout mice or transgenic expression p53 dominant negative alleles with other tumour-prone mouse strains has allowed the effect of p53 loss on tumour development to be examined further. In a variety of mouse models, absence of p53 facilitates tumorigenesis, thus providing a means to study how the lack of p53 enhances tumour development and to define genetic pathways of p53 action. Depending on the particular model system, loss of p53 either results in deregulated cell-cylce entry or aberrant apoptosis (programmed cell death), confirming results found in cell culture systems and providing insight into in vitro function of p53. Finally, as p53 null mice rapidly develop tumours, they are useful for evaluating agents for either chemopreventative or therapeutic activities.