4EGI-1 targets breast cancer stem cells by selective inhibition of translation that persists in CSC maintenance, proliferation and metastasis

Cancer death is a leading cause of global mortality. An estimated 14.1 million new cancer cases and 8.2 million cancer deaths occurred worldwide in 2012 alone. Cancer stem cells (CSCs) within tumors are essential for tumor metastasis and reoccurrence, the key factors of cancer lethality. Here we report that 4EGI-1, an inhibitor of the interaction between translation initiation factors eIF4E1 and eIF4G1 effectively inhibits breast CSCs through selectively reducing translation persistent in breast CSCs. Translation initiation factor eIF4E1 is significantly enhanced in breast CSCs in comparison to non-CSC breast cancer cells. 4EGI-1 presents increased cytotoxicity to breast CSCs compared to non-CSC breast cancer cells. 4EGI-1 promotes breast CSC differentiation and represses breast CSC induced tube-like structure formation of human umbilical vein endothelial cells (HUVECs). 4EGI-1 isomers suppress breast CSC tumorangiogenesis and tumor growth in vivo. In addition, 4EGI-1 decreases proliferation in and induces apoptosis into breast CSC tumor cells. Furthermore, 4EGI-1 selectively inhibits translation of mRNAs encoding NANOG, OCT4, CXCR4, c-MYC and VEGF in breast CSC tumors. Our study demonstrated that 4EGI-1 targets breast CSCs through selective inhibition of translation critical for breast CSCs, suggesting that selective translation initiation interference might be an avenue targeting CSCs within tumors

Psychoanalysis at Almuhasiby: An Rooting Study

This study aimed at discovering methods of psychological analysis from the perspective of Almuhasiby and the way he described them in both of his books: Keeping God\u27s rights and Self Manners. The study relied on both methods: descriptive analysis and deductive inference. The research has included the following concepts respectively. First, introducing Almuhasiby and his books. Second, the concept of psychological analysis in general and the definition of psychological analysis according to Almuhasiby. Third, the methods of psychological analysis suggested by Almuhasiby. Results showed that Islamic heritage books have included aspects of psychological analysis and its methods. Moreover, the research found out that Almuhasiby has indicated the concept of psychological analysis and its methods in both of his books; Keeping God\u27s rights and Self Manners by illustrating psychological disorders and proposing solutions for them depending on pure Islamic instructions that are based on Quran, Sunnah and the biographies of the rightly-guided caliphs. The research has recommended holding scientific conferences, seminars, and lectures concerned with the study of this topic. Moreover, benefiting from the Islamic educational heritage through the Islamic rooting of the human and social science

Psychoanalysis at Almuhasiby -An Rooting Dtudy-

This study aimed at discovering methods of psychological analysis from the perspective of Almuhasiby and the way he described them in both of his books: Keeping God\u27s rights and Self Manners. The study relied on both methods: descriptive analysis and deductive inference. The research has included the following concepts respectively. First, introducing Almuhasiby and his books. Second, the concept of psychological analysis in general and the definition of psychological analysis according to Almuhasiby. Third, the methods of psychological analysis suggested by Almuhasiby. Results showed that Islamic heritage books have included aspects of psychological analysis and its methods. Moreover, the research found out that Almuhasiby has indicated the concept of psychological analysis and its methods in both of his books; Keeping God\u27s rights and Self Manners by illustrating psychological disorders and proposing solutions for them depending on pure Islamic instructions that are based on Quran, Sunnah and the biographies of the rightly-guided caliphs. The research has recommended holding scientific conferences, seminars, and lectures concerned with the study of this topic. Moreover, benefiting from the Islamic educational heritage through the Islamic rooting of the human and social science

Tumor suppression by small molecule inhibitors of translation initiation

Translation initiation factors are over-expressed and/or activated in many human cancers and may contribute to their genesis and/or progression. Removal of physiologic restraints on translation initiation causes malignant transformation. Conversely, restoration of physiological restrains on translation initiation reverts malignant phenotypes. Here, we extensively characterize the anti-cancer activity of two small molecule inhibitors of translation initiation: #1181, which targets the eIF2-GTP-Met-tRNAi ternary complex, and 4EGI-1, which targets the eIF4F complex. In vitro, both molecules inhibit translation initiation, abrogate preferentially translation of mRNAs coding for oncogenic proteins, and inhibit proliferation of human cancer cells. In vivo, both #1181 and 4EGI-1 strongly inhibit growth of human breast and melanoma cancer xenografts without any apparent macroscopic- or microscopic-toxicity. Mechanistically, #1181 phosphorylates eIF2α while 4EGI-1 disrupts eIF4G/eIF4E interaction in the tumors excised from mice treated with these agents. These data indicate that inhibition of translation initiation is a new paradigm in cancer therapy

Effect of Nebulized Bovine Surfactant for Experimental Otitis Media with Effusion

ObjectivesIn this study, we evaluated the efficacy of nebulized bovine pulmonary surfactant on experimentally induced otitis media with effusion (OME) in guinea pigs.MethodsTwenty guinea pigs were divided into three groups. Four untreated animals served as normal controls. Experimental OME was established in both ears of the remaining 16 animals by a transbullar injection of 10 µL of Pseudomonas aeruginosa lipopolysaccharide in saline. Thereafter, the guinea pigs received nebulized phosphate buffered saline (n=8) or nebulized bovine pulmonary surfactant (n=8). Nebulization was given daily for 7 days. On day 8, all the animals' passive opening pressure (POP) of the Eustachian tube was measured and histopathological observations of the bulla were made by light microscopy.ResultsNebulized bovine pulmonary surfactant significantly reduced the POP compared to that of saline nebulization. The bovine pulmonary surfactant improved the tubal patency and produced less histopathologcally-evident edematous bullar mucosa.ConclusionNebulization of bovine pulmonary surfactant plays an important role in treating otitis media with effusion in guinea pigs. Our results suggest that the chosen nebulized bovine pulmonary surfactant can be of good clinical benefit for treating OME in the future

Virulence Characteristics of Klebsiella and Clinical Manifestations of K. pneumoniae Bloodstream Infections

Differences in clinical manifestations are due to virulence factors expressed by the organism

The Major Surface-Associated Saccharides of Klebsiella pneumoniae Contribute to Host Cell Association

Analysing the pathogenic mechanisms of a bacterium requires an understanding of the composition of the bacterial cell surface. The bacterial surface provides the first barrier against innate immune mechanisms as well as mediating attachment to cells/surfaces to resist clearance. We utilised a series of Klebsiella pneumoniae mutants in which the two major polysaccharide layers, capsule and lipopolysaccharide (LPS), were absent or truncated, to investigate the ability of these layers to protect against innate immune mechanisms and to associate with eukaryotic cells. The capsule alone was found to be essential for resistance to complement mediated killing while both capsule and LPS were involved in cell-association, albeit through different mechanisms. The capsule impeded cell-association while the LPS saccharides increased cell-association in a non-specific manner. The electrohydrodynamic characteristics of the strains suggested the differing interaction of each bacterial strain with eukaryotic cells could be partly explained by the charge density displayed by the outermost polysaccharide layer. This highlights the importance of considering not only specific adhesin:ligand interactions commonly studied in adherence assays but also the initial non-specific interactions governed largely by the electrostatic interaction forces

Surfactant protein-D and pulmonary host defense

Surfactant protein-D (SP-D) participates in the innate response to inhaled microorganisms and organic antigens, and contributes to immune and inflammatory regulation within the lung. SP-D is synthesized and secreted by alveolar and bronchiolar epithelial cells, but is also expressed by epithelial cells lining various exocrine ducts and the mucosa of the gastrointestinal and genitourinary tracts. SP-D, a collagenous calcium-dependent lectin (or collectin), binds to surface glycoconjugates expressed by a wide variety of microorganisms, and to oligosaccharides associated with the surface of various complex organic antigens. SP-D also specifically interacts with glycoconjugates and other molecules expressed on the surface of macrophages, neutrophils, and lymphocytes. In addition, SP-D binds to specific surfactant-associated lipids and can influence the organization of lipid mixtures containing phosphatidylinositol in vitro. Consistent with these diverse in vitro activities is the observation that SP-D-deficient transgenic mice show abnormal accumulations of surfactant lipids, and respond abnormally to challenge with respiratory viruses and bacterial lipopolysaccharides. The phenotype of macrophages isolated from the lungs of SP-D-deficient mice is altered, and there is circumstantial evidence that abnormal oxidant metabolism and/or increased metalloproteinase expression contributes to the development of emphysema. The expression of SP-D is increased in response to many forms of lung injury, and deficient accumulation of appropriately oligomerized SP-D might contribute to the pathogenesis of a variety of human lung diseases