Brown tumor of lumber spint in patient with chronic renal failure

Brown tumors are erosive bone lesions caused by increased osteoclastic activity. They usually occur in the severe forms of secondary  hyperparathyroidism, as in patients with hemodialysis-dependent chronic renal disease. Involvement of the lumbar spine with this tumor causing neural compression is extremely rare. We report a 49-year-old man, who had been on haemodialysis for CRF for over 15 years, presented with leg weakness and back pain over the thoracolumbar junction. There were no motor or sensory disturbances. Spinal MRI revealed osteolytic lesions of the ribs and lumbar vertebrae L1. The clinical and radiological abnormalities resolved after parathyroidectomy and spine surgery

Cavernome intramedullaire: a propos d’un cas

Le cavernome intramédullaire, malformation vasculaire rare, représente environ 5 à 12 % des malformations vasculaires spinales et 3 % des malformations vasculaires intra-durales. Il peut être longtemps asymptomatique ou se manifester par une altération brutale ou progressive des fonctions médullaires. Le diagnostic repose sur l’imagerie par résonance magnétique (IRM) médullaire et l’anatomopathologie. La chirurgie représente l’essentiel de la prise en charge, néanmoins elle n’est pas dénudée de complications. Nous rapportons un cas de cavernome intramédullaire chez une patiente de 24 ans, admise dans un tableau de compression médullaire dorsale lente avec une paraparésie évoluant depuis 2 ans. L’IRM médullaire a objectivé une lésion intramédullaire en regard deT7-T8. La patiente a bénéficié d’une exérèse totale de la tumeur et l’histologie a confirmé le cavernome intramédullaire. L’évolution a été marquée par une aggravation partielle du déficit moteur. A travers cette observation, les auteurs discutent les aspects cliniques, radiologiques ainsi que la prise en charge de cette pathologie rare.Mots clés: Cavernome, intramédullaire, malformation vasculair

Small-molecule targeting of translation initiation for cancer therapy

Translation initiation plays a critical role in the regulation of cell growth and tumorigenesis. We report here that inhibiting translation initiation through induction of eIF2α phosphorylation by small-molecular-weight compounds restricts the availability of the eIF2·GTP·Met-tRNAi ternary complex and abrogates the proliferation of cancer cells in vitro and tumor growth in vivo. Restricting the availability of the ternary complex preferentially down-regulates the expression of growth-promoting proteins and up-regulates the expression of ER stress response genes in cancer cells as well as in tumors excised from either animal models of human cancer or cancer patients. These findings provide the first direct evidence for translational control of gene-specific expression by small molecules in vivo and indicate that translation initiation factors are bona fide targets for development of mechanism-specific anti-cancer agents

Chemical Genetics Identify eIF2α Kinase Heme Regulated Inhibitor as Anti-Cancer Target

Translation initiation plays a critical role in cellular homeostasis, proliferation, differentiation and malignant transformation. Consistently, increasing the abundance of the eIF2·GTP·Met-tRNAi translation initiation complex transforms normal cells and contributes to cancer initiation and the severity of some anemia. The chemical modifiers of the eIF2·GTP·Met-tRNAi ternary complex are therefore invaluable tools for studying its role in the pathobiology of human disorders and for determining if this complex can be pharmacologically targeted for therapeutic purposes. Using a cell based assay, we identified N,N’-diarylureas as novel inhibitors of the ternary complex abundance. Direct functional-genetics and biochemical evidence demonstrated that the N,N’-diarylureas activate heme regulated inhibitor kinase, thereby phosphorylate eIF2α and reduce abundance of the ternary complex. Using tumor cell proliferation in vitro and tumor growth in vivo as paradigms, we demonstrate that N,N’-diarylureas are potent and specific tools for studying the role eIF2·GTP·Met-tRNAi ternary complex in the pathobiology of human disorders

Synthesis of Rigidified eIF4E/eIF4G Inhibitor-1 (4EGI-1) Mimetic and Their in Vitro Characterization as Inhibitors of Protein–Protein Interaction

The 4EGI-1 is the prototypic inhibitor of eIF4E/eIF4G interaction, a potent inhibitor of translation initiation in vitro and in vivo and an efficacious anticancer agent in animal models of human cancers. We report on the design, synthesis, and in vitro characterization of a series of rigidified mimetic of this prototypic inhibitor in which the phenyl in the 2-(4-(3,4-dichlorophenyl)thiazol-2-yl) moiety was bridged into a tricyclic system. The bridge consisted one of the following: ethylene, methylene oxide, methylenesulfide, methylenesulfoxide, and methylenesulfone. Numerous analogues in this series were found to be markedly more potent than the parent prototypic inhibitor in the inhibition of eIF4E/eIF4G interaction, thus preventing the eIF4F complex formation, a rate limiting step in the translation initiation cascade in eukaryotes, and in inhibition of human cancer cell proliferation

Memòria Digital de Catalunya

Localització: Barcelona, Biblioteca de Catalunya, ms. 1070/4 (f. 116-197)Núm. 700, a la coberta ms.A port.: "Novedades"Còpia de representacióEsmenes i cancel·lacions ms.Al f. 154v, rúbrica amb el nom del copista: "Fiol."Data obtinguda de la coberta. Data a portada: 1879F. 143, 144, 148v, 153, 174v i 185 en blancIndicacions escèniquesFuente de ingreso: Compra a Elisa Castells, Vda. de Joan Almirall i Forast

Depletion of eIF2.GTP.Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo

Most sporadic breast and ovarian cancers express low levels of the breast cancer susceptibility gene, BRCA1. The BRCA1 gene produces two transcripts, mRNAa and mRNAb. mRNAb, present in breast cancer but not in normal mammary epithelial cells, contains three upstream open reading frames (uORFs) in its 5′UTR and is translationally repressed. Comparable tandem uORFs are characteristically seen in mRNAs whose translational efficiency paradoxically increases when the overall translation rate is decreased due to phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α). Here we show fish oil derived eicosopanthenoic acid (EPA) that induces eIF2α phosphorylation translationally up-regulates the expression of BRCA1 in human breast cancer cells. We demonstrate further that a diet rich in EPA strongly induces expression of BRCA1 in human breast cancer xenografts

Depletion of eIF2.GTP.Met-tRNAi translation initiation complex up-regulates BRCA1 expression in vitro and in vivo

Most sporadic breast and ovarian cancers express low levels of the breast cancer susceptibility gene, BRCA1. The BRCA1 gene produces two transcripts, mRNAa and mRNAb. mRNAb, present in breast cancer but not in normal mammary epithelial cells, contains three upstream open reading frames (uORFs) in its 5′UTR and is translationally repressed. Comparable tandem uORFs are characteristically seen in mRNAs whose translational efficiency paradoxically increases when the overall translation rate is decreased due to phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α). Here we show fish oil derived eicosopanthenoic acid (EPA) that induces eIF2α phosphorylation translationally up-regulates the expression of BRCA1 in human breast cancer cells. We demonstrate further that a diet rich in EPA strongly induces expression of BRCA1 in human breast cancer xenografts

Structureeactivity relationship study of 4EGI-1, small molecule eIF4E/eIF4G proteineprotein interaction inhibitors

International audienceProteineprotein interactions are critical for regulating the activity of translation initiation factors and multitude of other cellular process, and form the largest block of untapped albeit most challenging targets for drug development. 4EGI-1, (E/Z)-2-(2-(4-(3,4-dichlorophenyl)thiazol-2-yl)hydrazono)-3-(2- nitrophenyl)propanoic acid, is a hit compound discovered in a screening campaign of small molecule libraries as an inhibitor of translation initiation factors eIF4E and eIF4G proteineprotein interaction; it inhibits translation initiation in vitro and in vivo. A series of 4EGI-1-derived thiazol-2-yl hydrazones have been designed and synthesized in order to delineate the structural latitude and improve its binding affinity to eIF4E, and increase its potency in inhibiting the eIF4E/eIF4G interaction. Probing a wide range of substituents on both phenyl rings comprising the 3-phenylpropionic acid and 4-phenylthiazolidine moieties in the context of both E- and Z-isomers of 4EGI-1 led to analogs with enhanced binding affinity and translation initiation inhibitory activities