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1
Dinarello, CA. "Biologic basis for interleukin-1 in disease." Blood 87, no. 6 (March 15, 1996): 2095–147. http://dx.doi.org/10.1182/blood.v87.6.2095.bloodjournal8762095.
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To understand the role of the proinflammatory cytokine interleukin-1 (IL-1) in disease, investigators have studied how production of the different members of the IL-1 family is controlled, the various biologic activities of IL-1, the distinct and various functions of the IL-1 receptor (IL-1R) family, and the complexity of intracellular signaling. Mice deficient in IL-1Beta, IL-1Beta converting enzyme, and IL-1R type I have also been studied. Humans have been injected with IL- 1 (either IL-1alpha or IL-1beta) for enhancing bone marrow recovery and for cancer treatment. The IL-1-specific receptor antagonist (IL-1Ra) has also been tested in clinical trials. The topics discussed in this review include production and activities of IL-1 and IL-1Ra molecules, the effects of IL-1 on gene expression, functions of cell-bound and soluble IL-1 receptors, the importance of the IL-1R accessory protein, newly discovered signal transduction pathways, naturally occurring cytokines limiting IL-1 production or activity, the effects of blocking cyclooxygenase and nitric oxide, and the outcomes of IL-1 and IL-1 Ra in human trials. Special attention is paid to IL-1beta converting enzyme and programmed cell death. The roles of IL-1 in hematopoiesis, leukemia, atherosclerosis, and growth of solid tumors are also discussed. This is a lengthy review, with 586 citations chosen to illustrate specific areas of interest rather than a compendium of references. At the end of each section, a short commentary summarizes what the author considers established or controversial topics linking the biology of IL-1 to mechanisms of disease.
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Nelson, Amy R., Barbara Fingleton, Mace L. Rothenberg, and Lynn M. Matrisian. "Matrix Metalloproteinases: Biologic Activity and Clinical Implications." Journal of Clinical Oncology 18, no. 5 (March 1, 2000): 1135. http://dx.doi.org/10.1200/jco.2000.18.5.1135.
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ABSTRACT: Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.
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Kittler, EL, H. McGrath, D. Temeles, RB Crittenden, VK Kister, and PJ Quesenberry. "Biologic significance of constitutive and subliminal growth factor production by bone marrow stroma." Blood 79, no. 12 (June 15, 1992): 3168–78. http://dx.doi.org/10.1182/blood.v79.12.3168.3168.
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Abstract The “stromal” or adherent cells of long-term murine Dexter explant bone marrow cultures provide the best in vitro model of the bone marrow microenvironment. Colony-stimulating factor-1 (CSF-1) is produced constitutively by these cells and is easily detected, but most investigators have not found constitutive production of the other hemolymphopoietic cytokines. We have previously reported the detection of granulocyte-macrophage-CSF (GM-CSF) in murine stromal cultures and its induction by the lectin Pokeweed mitogen. The present studies analyzing stromal cytokine messenger RNA (mRNA) production by standard Northern blot analysis show constitutive production of mRNAs for CSF-1, GM-CSF, granulocyte-CSF (G-CSF), c-kit ligand (KL), and interleukin-6 (IL-6), but not IL-3, IL-4, or IL-5 by 3-week irradiated or nonirradiated murine Dexter stromal cells. Exposure of stromal cells to Pokeweed mitogen or IL-1 16 hours before RNA harvest induces the messages for GM-CSF, G-CSF, KL, and IL-6, but not IL-3, IL-4, IL-5, or CSF-1. Polymerase chain reaction amplification of cDNA made with reverse transcriptase from stromal RNA using two separate sets of IL-3- specific primers shows the presence of IL-3 message in irradiated stromal cells, which is only detectable with this more sensitive technique. The factor-dependent cell lines FDC-P1 and 32D are supported by the stromal cells without the addition of exogenous growth factors, demonstrating a cytokine activity in these cultures that is inhibited by the addition of anti-IL-3 or anti-GM-CSF antibodies. These data indicate that murine Dexter stromal cells constitutively produce CSF-1, GM-CSF, G-CSF, IL-6, KL, and IL-3. This growth factor production could explain the support of granulocyte, macrophage, and megakaryocyte production and stem cell maintenance in Dexter-type long-term murine bone marrow cultures.
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Kittler, EL, H. McGrath, D. Temeles, RB Crittenden, VK Kister, and PJ Quesenberry. "Biologic significance of constitutive and subliminal growth factor production by bone marrow stroma." Blood 79, no. 12 (June 15, 1992): 3168–78. http://dx.doi.org/10.1182/blood.v79.12.3168.bloodjournal79123168.
Full textAbstract:
The “stromal” or adherent cells of long-term murine Dexter explant bone marrow cultures provide the best in vitro model of the bone marrow microenvironment. Colony-stimulating factor-1 (CSF-1) is produced constitutively by these cells and is easily detected, but most investigators have not found constitutive production of the other hemolymphopoietic cytokines. We have previously reported the detection of granulocyte-macrophage-CSF (GM-CSF) in murine stromal cultures and its induction by the lectin Pokeweed mitogen. The present studies analyzing stromal cytokine messenger RNA (mRNA) production by standard Northern blot analysis show constitutive production of mRNAs for CSF-1, GM-CSF, granulocyte-CSF (G-CSF), c-kit ligand (KL), and interleukin-6 (IL-6), but not IL-3, IL-4, or IL-5 by 3-week irradiated or nonirradiated murine Dexter stromal cells. Exposure of stromal cells to Pokeweed mitogen or IL-1 16 hours before RNA harvest induces the messages for GM-CSF, G-CSF, KL, and IL-6, but not IL-3, IL-4, IL-5, or CSF-1. Polymerase chain reaction amplification of cDNA made with reverse transcriptase from stromal RNA using two separate sets of IL-3- specific primers shows the presence of IL-3 message in irradiated stromal cells, which is only detectable with this more sensitive technique. The factor-dependent cell lines FDC-P1 and 32D are supported by the stromal cells without the addition of exogenous growth factors, demonstrating a cytokine activity in these cultures that is inhibited by the addition of anti-IL-3 or anti-GM-CSF antibodies. These data indicate that murine Dexter stromal cells constitutively produce CSF-1, GM-CSF, G-CSF, IL-6, KL, and IL-3. This growth factor production could explain the support of granulocyte, macrophage, and megakaryocyte production and stem cell maintenance in Dexter-type long-term murine bone marrow cultures.
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Daynes, R. A., T. Dowell, and B. A. Araneo. "Platelet-derived growth factor is a potent biologic response modifier of T cells." Journal of Experimental Medicine 174, no. 6 (December 1, 1991): 1323–33. http://dx.doi.org/10.1084/jem.174.6.1323.
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Freshly isolated lymph node (LN) cells cultured in serum-containing medium were restricted to produce primarily interleukin 2 (IL-2) subsequent to T cell activation. Only minimal amounts of IL-4, IL-5, or interferon gamma (IFN-gamma) were produced under these conditions. Similar populations of LN cells cultured in serum-free medium were able to produce a variety of lymphokines after T cell activation, with the relative quantities of each species being dependent upon the lymphoid organ source of the lymphocytes. A similar relationship in the patterns of lymphokines produced by activated T cell hybridomas maintained under serum-free conditions was also observed, whereas activation in serum-supplemented media resulted in a predominant restriction to the secretion of IL-2. Additional studies determined that the entity in serum responsible for restricting T cell function in vitro was platelet-derived growth factor (PDGF). The PDGF-BB isoform was established to be the most active in the regulation of T cell function, enhancing IL-2 while depressing the production of IL-4, IL-5, and IFN-gamma at concentrations below 1 ng/ml. PDGF-AB was also found to be quite active, however, this isoform of PDGF was incapable of influencing IFN-gamma production at the concentrations tested. PDGF-AA was very weakly active. It therefore appears that PDGF, acting primarily through a beta receptor subunit (either alpha/beta- or beta/beta-type receptors) is able to influence profoundly the behavior of T cells, with some of its modulatory effects exhibiting isoform specificity. This is reflected by an enhancement in the production of IL-2, while simultaneously depressing the secretion of IL-4, IL-5, and IFN-gamma (PDGF-BB only) after T cell activation. Kinetic studies, where cell supernatants were analyzed both 24 and 48 h after T cell activation, suggested that "desensitization" to PDGF influences can occur naturally in vitro. Those species of lymphokines that were inhibited by PDGF over the first 24 h after activation could be produced at normal levels over the subsequent 24-h period. Finally, lymphokines maintained in the presence of PDGF-BB for greater than 24 h before their activation lost sensitivity to this growth factor. These cells regained responsiveness to PDGF after an additional incubation period in PDGF-free medium. Collectively, our data imply that the pattern of T cell lymphokines produced, plus the kinetics of their production after activation, are being controlled by the potent serum growth factor PDGF.(ABSTRACT TRUNCATED AT 400 WORDS)
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Mallis, Panagiotis, Catherine Stavropoulos-Giokas, and Efstathios Michalopoulos. "Introduction to the Special Issue on Stem Cell and Biologic Scaffold Engineering." Bioengineering 6, no. 3 (August 21, 2019): 72. http://dx.doi.org/10.3390/bioengineering6030072.
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Tissue engineering and regenerative medicine is a rapidly evolving research field that effectively combines stem cells and biologic scaffolds in order to replace damaged tissues. Biologic scaffolds can be produced through the removal of resident cellular populations using several tissue engineering approaches, such as the decellularization method. In addition, tissue engineering requires the interaction of biologic scaffolds with cellular populations. Stem cells are characterized by unlimited cell division, self-renewal, and differentiation potential, distinguishing themselves as a frontline source for the repopulation of decellularized matrices and scaffolds. However, parameters such as stem cell number, in vitro cultivation conditions, and specific growth media composition need further evaluation. The ultimate goal is the development of “artificial” tissues similar to native ones, which is achieved by properly combining stem cells and biologic scaffolds, thus bringing artificial tissues one step closer to personalized medicine. In this special issue of Bioengineering, we highlight the beneficial effects of stem cells and scaffolds in the emerging field of tissue engineering. The current issue includes articles regarding the use of stem cells in tissue engineering approaches and the proper production of biologically based scaffolds like nerve conduit, esophageal scaffold, and fibrin gel.
7
Newcom, SR, LH Muth, and ET Parker. "Production of monoclonal antibodies that detect Hodgkin's high molecular weight transforming growth factor-beta." Blood 75, no. 12 (June 15, 1990): 2434–37. http://dx.doi.org/10.1182/blood.v75.12.2434.2434.
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Abstract High molecular weight transforming growth factor-beta (TGF beta) is a physiologically active TGF secreted by nodular sclerosing Reed- Sternberg cells. Five monoclonal murine antibodies were prepared that distinguished Hodgkin's TGF beta from platelet-derived TGF beta using an enzyme-linked immunosorbent assay, neutralization of biologic activity, and Western blotting. These monoclonal antibodies directed at unique antigenic determinants (epitopes) of Hodgkin's TGF beta will allow further characterization of the role of Hodgkin's TGF beta in Hodgkin's disease and related entities.
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Newcom, SR, LH Muth, and ET Parker. "Production of monoclonal antibodies that detect Hodgkin's high molecular weight transforming growth factor-beta." Blood 75, no. 12 (June 15, 1990): 2434–37. http://dx.doi.org/10.1182/blood.v75.12.2434.bloodjournal75122434.
Full textAbstract:
High molecular weight transforming growth factor-beta (TGF beta) is a physiologically active TGF secreted by nodular sclerosing Reed- Sternberg cells. Five monoclonal murine antibodies were prepared that distinguished Hodgkin's TGF beta from platelet-derived TGF beta using an enzyme-linked immunosorbent assay, neutralization of biologic activity, and Western blotting. These monoclonal antibodies directed at unique antigenic determinants (epitopes) of Hodgkin's TGF beta will allow further characterization of the role of Hodgkin's TGF beta in Hodgkin's disease and related entities.
9
Tosato, G., and KD Jones. "Interleukin-1 induces interleukin-6 production in peripheral blood monocytes." Blood 75, no. 6 (March 15, 1990): 1305–10. http://dx.doi.org/10.1182/blood.v75.6.1305.1305.
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Abstract Interleukin-6 (IL-6), a multifunctional cytokine produced in monocytes, fibroblasts, endothelial cells, and keratinocytes, is induced by a variety of stimulating signals, including lipopolysaccharide (LPS), poly (I), poly (C), IL-1, tumor necrosis factor (TNF), and platelet- derived growth factor. Some of these signals induce IL-6 effectively only in one cell type, and this selectivity of induction may explain selectivity of biologic effects. In the present study, we show that IL- 1 beta, previously known to be a potent inducer of IL-6 in fibroblasts, endothelial cells, and keratinocytes, but not in monocytes, is also a potent inducer of IL-6 in peripheral blood monocytes. High level IL-6 activity that could be neutralized by specific antibodies to IL-6 was detected in supernatants of IL-1-stimulated monocytes. Maximal induction required IL-1 concentrations of 10 ng/mL. As judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, IL-6 species of relative molecular mass of 19 to 26 Kd could be specifically immunoprecipitated from supernatants of IL-1- induced monocytes. Size heterogeneity is a reported feature of IL-6 produced in a variety of cell types, and monocyte-derived IL-6 induced by either IL-1 or LPS displayed similar size heterogeneity. The highly purified recombinant IL-1 beta preparation used contained little, if any, LPS. In addition, monocyte production of IL-6, induced by IL-1 beta, was specifically neutralized by anti-IL-1 beta antibodies, demonstrating that IL-1, rather than a contaminant in the IL-1 preparation, was responsible for IL-6 induction. A number of biologic activities have been ascribed both to IL-1 and IL-6. The finding that IL-1 induced IL-6 in monocytes may help in defining the spectrum of biologic activities of each of these interactive cytokines.
10
Tosato, G., and KD Jones. "Interleukin-1 induces interleukin-6 production in peripheral blood monocytes." Blood 75, no. 6 (March 15, 1990): 1305–10. http://dx.doi.org/10.1182/blood.v75.6.1305.bloodjournal7561305.
Full textAbstract:
Interleukin-6 (IL-6), a multifunctional cytokine produced in monocytes, fibroblasts, endothelial cells, and keratinocytes, is induced by a variety of stimulating signals, including lipopolysaccharide (LPS), poly (I), poly (C), IL-1, tumor necrosis factor (TNF), and platelet- derived growth factor. Some of these signals induce IL-6 effectively only in one cell type, and this selectivity of induction may explain selectivity of biologic effects. In the present study, we show that IL- 1 beta, previously known to be a potent inducer of IL-6 in fibroblasts, endothelial cells, and keratinocytes, but not in monocytes, is also a potent inducer of IL-6 in peripheral blood monocytes. High level IL-6 activity that could be neutralized by specific antibodies to IL-6 was detected in supernatants of IL-1-stimulated monocytes. Maximal induction required IL-1 concentrations of 10 ng/mL. As judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions, IL-6 species of relative molecular mass of 19 to 26 Kd could be specifically immunoprecipitated from supernatants of IL-1- induced monocytes. Size heterogeneity is a reported feature of IL-6 produced in a variety of cell types, and monocyte-derived IL-6 induced by either IL-1 or LPS displayed similar size heterogeneity. The highly purified recombinant IL-1 beta preparation used contained little, if any, LPS. In addition, monocyte production of IL-6, induced by IL-1 beta, was specifically neutralized by anti-IL-1 beta antibodies, demonstrating that IL-1, rather than a contaminant in the IL-1 preparation, was responsible for IL-6 induction. A number of biologic activities have been ascribed both to IL-1 and IL-6. The finding that IL-1 induced IL-6 in monocytes may help in defining the spectrum of biologic activities of each of these interactive cytokines.
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Haznedaroglu, Ibrahim C., Hakan Goker, Mehmet Turgut, Yahya Buyukasik, and Mustafa Benekli. "Thrombopoietin as a Drug: Biologic Expectations, Clinical Realities, and Future Directions." Clinical and Applied Thrombosis/Hemostasis 8, no. 3 (July 2002): 193–212. http://dx.doi.org/10.1177/107602960200800301.
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After the cloning of thrombopoietin (c-mpl ligand, Tpo) in 1994, 2 recombinant thrombopoietic growth factors, full-length glycosylated recombinant human Tpo (reHuTPO) and polyethylene glycol conjugated megakaryocyte growth and development factor (PEG-reHuMGDF), have been studied in humans in a variety of clin- ical settings. Both thrombopoietins are generally well tolerated if ad- ministered intravenously (IV). The c-mpl ligands produce a dose-re- lated enhancement of platelet levels, reduce nonmyeloablative chemotherapy-induced mild thrombocytopenia, and mobilize hematopoietic progenitors. On September 11, 1998, the development of PEG-reHuMGDF was suspended in the U.S., due to formation of the neutralizing anti-Tpo antibody. Those neutralizing antibodies lead to thrombocytopenia and pancytopenia in some patients receiv- ing subcutaneous (SC) PEG-reHuMGDF. Japanese investigators in- dicate that the probability of antibody formation against PEG- reHuMGDF is low when the drug is administered IV instead of SC. reHuTPO has a more favorable safety profile from the point of anti- body production. The c-mpl ligands can improve apheresis yields when administered to normal platelet donors. Preliminary data about the use of PEG-reHuMGDF in myelodysplasia, aplastic anemia, and immune thrombocytopenic purpura are promising. Tpo is usually not effective in myeloablative thrombocytopenia when bone marrow hematopoietic progenitors are not present. The major obstacle for the thrombopoietins is their delayed action for managing clinical thrombocytopenia. This review will focus on the biologic basis, cur- rent clinical experience, and future directions for the use of throm- bopoietic molecules as drugs. The identification of a safe, effective, and potent pharmacologic platelet growth factor could significantly improve the management of thrombocytopenia-induced bleeding.
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Nixon, N. A., M. B. Hannouf, and S. Verma. "The evolution of biosimilars in oncology, with a focus on trastuzumab." Current Oncology 25 (June 14, 2018): 171. http://dx.doi.org/10.3747/co.25.3942.
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Cancer therapy has evolved significantly with increased adoption of biologic agents (“biologics”). That evolution is especially true for her2 (human epidermal growth factor receptor-2)–positive breast cancer with the introduction of trastuzumab, a monoclonal antibody against the her2 receptor, which, in combination with chemotherapy, significantly improves survival in both metastatic and early disease.Although the efficacy of biologics is undeniable, their expense is a significant contributor to the increasing cost of cancer care. Across disease sites and indications, biosimilar agents are rapidly being developed with the goal of offering cost-effective alternatives to biologics. Biosimilars are pharmaceuticals whose molecular shape, efficacy, and safety are similar, but not identical, to those of the original product. Although these agents hold the potential to improve patient access, complexities in their production, evaluation, cost, and clinical application have raised questions among experts. Here, we review the landscape of biosimilar agents in oncology, with a focus on trastuzumab biosimilars. We discuss important considerations that must be made as these agents are introduced into routine cancer care.
13
Dogadina, Marina. "The role of biologic techniques in improving the life state of flowering shrubs." BIO Web of Conferences 25 (2020): 05007. http://dx.doi.org/10.1051/bioconf/20202505007.
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The key to the normal growth and development of flowering shrubs is to provide optimal living conditions in the juvenile period. Obtaining high-quality planting material in a nursery using biologized techniques is a fundamental component of their future resistance to a complex of abiotic and biotic factors. The use of vermicompost (6 t / ha) as a fertilizer base and biologically active substances contributed to the production of high-quality seedlings. The applied biologic techniques contributed to the improvement of the growth and development of flowering shrubs, which influenced the reduction of damage by pests and diseases, the formation of healthy, decorative and attractive plants. Based on the analysis of the vital state, we ranked flowering shrubs according to their prospects for use in landscape design of the territory of urban ecosystems. Promising species for landscaping urban ecosystems in terms of a set of indicators are: Berberis thunbergii DC., Chaenomeles japonica (Thunb.) Lindl.), Lonicera caprifolium L., Physocarpus opulifolius L., Philadelphus coronaries L., Sorbaria sorbifolia L., Syringa velutina L. и Weigela florida DC.
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Kehrl, J. H., L. M. Wakefield, A. B. Roberts, S. Jakowlew, M. Alvarez-Mon, R. Derynck, M. B. Sporn, and A. S. Fauci. "Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth." Journal of Experimental Medicine 163, no. 5 (May 1, 1986): 1037–50. http://dx.doi.org/10.1084/jem.163.5.1037.
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This study examines the potential role of transforming growth factor beta (TGF-beta) in the regulation of human T lymphocyte proliferation, and proposes that TGF-beta is an important autoregulatory lymphokine that limits T lymphocyte clonal expansion, and that TGF-beta production by T lymphocytes is important in T cell interactions with other cell types. TGF-beta was shown to inhibit IL-2-dependent T cell proliferation. The addition of picograms amounts of TGF-beta to cultures of IL-2-stimulated human T lymphocytes suppressed DNA synthesis by 60-80%. A potential mechanism of this inhibition was found. TGF-beta inhibited IL-2-induced upregulation of the IL-2 and transferrin receptors. Specific high-affinity receptors for TGF-beta were found both on resting and activated T cells. Cellular activation was shown to result in a five- to sixfold increase in the number of TGF-beta receptors on a per cell basis, without a change in the affinity of the receptor. Finally, the observations that activated T cells produce TGF-beta mRNA and that TGF-beta biologic activity is present in supernatants conditioned by activated T cells is strong evidence that T cells themselves are a source of TGF-beta. Resting T cells were found to have low to undetectable levels of TGF-beta mRNA, while PHA activation resulted in a rapid increase in TGF-beta mRNA levels (within 2 h). Both T4 and T8 lymphocytes were found to make mRNA for TGF-beta upon activation. Using both a soft agar assay and a competitive binding assay, TGF-beta biologic activity was found in supernatants conditioned by T cells; T cell activation resulted in a 10-50-fold increase in TGF-beta production. Thus, TGF-beta may be an important antigen-nonspecific regulator of human T cell proliferation, and important in T cell interaction with other cell types whose cellular functions are modulated by TGF-beta.
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Prudhomme, N., C. Gianetto-Hill, R. Pastora, W. F. Cheung, E. Allen-Vercoe, M. D. McLean, D. Cossar, and J. Geddes-McAlister. "Quantitative proteomic profiling of shake flask versus bioreactor growth reveals distinct responses of Agrobacterium tumefaciens for preparation in molecular pharming." Canadian Journal of Microbiology 67, no. 1 (January 2021): 75–84. http://dx.doi.org/10.1139/cjm-2020-0238.
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The preparation of Agrobacterium tumefaciens cultures with strains encoding proteins intended for therapeutic or industrial purposes is an important activity prior to treatment of plants for transient expression of valuable protein products. The rising demand for biologic products such as these underscores the expansion of molecular pharming and warrants the need to produce transformed plants at an industrial scale. This requires large quantities of A. tumefaciens culture, which is challenging using traditional growth methods (e.g., shake flask). To overcome this limitation, we investigate the use of bioreactors as an alternative to shake flasks to meet production demands. Here, we observe differences in bacterial growth among the tested parameters and define conditions for consistent bacterial culturing between shake flask and bioreactor. Quantitative proteomic profiling of cultures from each growth condition defines unique growth-specific responses in bacterial protein abundance and highlights the functional roles of these proteins, which may influence bacterial processes important for effective agroinfiltration and transformation. Overall, our study establishes and optimizes comparable growth conditions for shake flask versus bioreactors and provides novel insights into fundamental biological processes of A. tumefaciens influenced by such growth conditions.
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Uggla, C., M. Aguilar-Santelises, A. Rosen, H. Mellstedt, and M. Jondal. "Spontaneous production of interleukin 1 activity by chronic lymphocytic leukemic cells." Blood 70, no. 6 (December 1, 1987): 1851–57. http://dx.doi.org/10.1182/blood.v70.6.1851.1851.
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Abstract Chronic lymphocytic leukemic B cells (B-CLL) were found to produce an IL 1-like growth factor spontaneously in vitro for mouse thymocytes. This factor was comitogenic with concanavalin A (Con A) and nonmitogenic combinations of phorbol ester and calcium ionophore but not with phyto-hemagglutinin (PHA). Growth factor production was dose- related to the number of in vitro cultured cells and detectable at 6 hours using high cell concentrations. A small number of admixed normal T cells was not important for factor production. No growth of autologous B-CLL or allogeneic thymocytes was induced by the factor. A chromatographic high-performance liquid chromatography (HPLC) analysis and inhibition experiments with a polyclonal rabbit anti interleukin 1 (IL 1) antiserum indicated that the B-CLL-derived growth factor belonged to the IL 1 family. This was supported by the direct demonstration of IL 1 beta in supernatants from B-CLL by radioimmunoassay. Possible biologic implications for B-CLL-derived IL 1 are discussed in relation to tumor cell growth in different clinical stages.
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Uggla, C., M. Aguilar-Santelises, A. Rosen, H. Mellstedt, and M. Jondal. "Spontaneous production of interleukin 1 activity by chronic lymphocytic leukemic cells." Blood 70, no. 6 (December 1, 1987): 1851–57. http://dx.doi.org/10.1182/blood.v70.6.1851.bloodjournal7061851.
Full textAbstract:
Chronic lymphocytic leukemic B cells (B-CLL) were found to produce an IL 1-like growth factor spontaneously in vitro for mouse thymocytes. This factor was comitogenic with concanavalin A (Con A) and nonmitogenic combinations of phorbol ester and calcium ionophore but not with phyto-hemagglutinin (PHA). Growth factor production was dose- related to the number of in vitro cultured cells and detectable at 6 hours using high cell concentrations. A small number of admixed normal T cells was not important for factor production. No growth of autologous B-CLL or allogeneic thymocytes was induced by the factor. A chromatographic high-performance liquid chromatography (HPLC) analysis and inhibition experiments with a polyclonal rabbit anti interleukin 1 (IL 1) antiserum indicated that the B-CLL-derived growth factor belonged to the IL 1 family. This was supported by the direct demonstration of IL 1 beta in supernatants from B-CLL by radioimmunoassay. Possible biologic implications for B-CLL-derived IL 1 are discussed in relation to tumor cell growth in different clinical stages.
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Bataille, R., B. Barlogie, ZY Lu, JF Rossi, T. Lavabre-Bertrand, T. Beck, J. Wijdenes, J. Brochier, and B. Klein. "Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma." Blood 86, no. 2 (July 15, 1995): 685–91. http://dx.doi.org/10.1182/blood.v86.2.685.bloodjournal862685.
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In patients with advanced multiple myeloma (MM) there is an excess of production of interleukin-6 (IL-6) in vivo, and elevated serum levels are associated with plasmablastic proliferative activity and short survival. These data prompted us to perform a clinical trial with a murine anti-IL-6 monoclonal antibody (MoAb) to neutralize the excess of this putatively deleterious factor in these patients. Ten MM patients with extramedullary involvement frequently were treated with anti-IL-6 MoAb. The MoAb was administered intravenously to 9 patients; 1 patient with malignant pleural effusion received intrapleural therapy. Of the 3 patients who succumbed to progressive MM after less than 1 week of treatment (including the only 1 treated locally), 2 with evaluable data exhibited marked inhibition of plasmablastic proliferation. Among the 7 patients remaining more homogeneous receiving the anti-IL-6 MoAb for more than 1 week, 3 had objective antiproliferative effect marked by a significant reduction of the myeloma cell labelling index within the bone marrow. One of these 3 patients achieved a 30% regression of tumor mass. However, none of the patients studied achieved remission or improved outcome as judged by standard clinical criteria. Of major interest, objective antiproliferative effects were associated with complete inhibition of C-reactive protein (CRP) synthesis and low daily IL-6 production in vivo. On the other hand, the lack of effect in 4 patients was associated with a higher IL-6 production and inability of the MoAb to neutralize it. Anti-IL-6 was also associated with resolution of low-grade fever in all the patients and with worsening thrombocytopenia and mild neutropenia. The generation of human antibodies to Fc fragment of the murine anti-IL-6 MoAb observed in 1 patient was associated with dramatic progression. These data show that anti-IL-6 MoAb can suppress the proliferation of myeloma cells and underscore the biologic role of IL-6 for myeloma growth in vivo. Furthermore, suppression of CRP and worsening of neutropenia/thrombocytopenia both indicate that IL-6 is critically involved in acute-phase responses and granulopoiesis/thrombopoiesis.
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Fukushima-Nakase, Yoko, Yoshinori Naoe, Ichiro Taniuchi, Hajime Hosoi, Tohru Sugimoto, and Tsukasa Okuda. "Shared and distinct roles mediated through C-terminal subdomains of acute myeloid leukemia/Runt-related transcription factor molecules in murine development." Blood 105, no. 11 (June 1, 2005): 4298–307. http://dx.doi.org/10.1182/blood-2004-08-3372.
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Abstract AML1/Runx1 is a frequent target of human leukemia–associated gene aberration and encodes a transcription factor with nonredundant biologic functions in initial development of definitive hematopoiesis, T-cell development, and steady-state platelet production. AML1/Runx1 and 2 closely related family genes, AML2/Runx3 and AML3/Runx2/Cbfa1, present in mammals, comprise the Runt-domain transcription factor family. Although they have similar structural and biochemical properties, gene-targeting experiments have identified distinct biologic roles. To directly determine the presence of functional overlap among runt-related transcription factor (Runx) family molecules, we replaced the C-terminal portion of acute myeloid leukemia 1 (AML1) with that derived from its family members, which are variable in contrast to conserved Runt domain, using the gene knock-in method. We found that C-terminal portions of either AML2 or AML3 could functionally replace that of AML1 for myeloid development in culture and within the entire mouse. However, while AML2 substituted for AML1 could effectively rescue lymphoid lineages, AML3 could not, resulting in a smaller thymus and lymphoid deficiency in peripheral blood. Substitution by the C-terminal portion of AML3 also led to high infantile mortality and growth retardation, suggesting that AML1 has as yet unidentified effects on these phenotypes. Thus, the C-terminal portions of Runx family members have both similar and distinct biologic functions.
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Rosen, E. M., A. Joseph, L. Jin, S. Rockwell, J. A. Elias, J. Knesel, J. Wines, J. McClellan, M. J. Kluger, and I. D. Goldberg. "Regulation of scatter factor production via a soluble inducing factor." Journal of Cell Biology 127, no. 1 (October 1, 1994): 225–34. http://dx.doi.org/10.1083/jcb.127.1.225.
Full textAbstract:
Scatter factor (SF) (also known as hepatocyte growth factor [HGF]) is a fibroblast-derived cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. SF may play major roles in development, repair, and carcinogenesis. However, the physiologic signals that regulate its production are not well delineated. We found that various human tumor cell lines that do not produce SF secrete factors that stimulate SF production by fibroblasts, suggesting a paracrine mechanism for regulation of SF production. Conditioned medium from these cell lines contained two distinct scatter factor-inducing factor SF-IF activities: a high molecular weight (> 30 kD), heat sensitive activity and a low molecular weight (< 30 kD) heat stable activity. Further studies revealed that SF-producing fibroblasts also secrete factors that stimulate their own SF production. We characterized the < 30-kD SF-IF activity from ras-3T3 (clone D4), a mouse cell line that overproduces both SF and SF-IF. The < 30-kD filtrate from ras-3T3 conditioned medium induced four- to sixfold increases in expression of SF biologic activity, immunoreactive protein, and mRNA by multiple SF-producing fibroblast lines. Ras-3T3 SF-IF activity was stable to boiling, extremes of pH, and reductive alkylation, but was destroyed by proteases. We purified ras-3T3 SF-IF about 10,000-fold from serum-free conditioned medium by a combination of ultrafiltration, cation exchange chromatography, and reverse phase chromatography. The purified protein exhibited electrophoretic mobility of about 12 kD (reduced) and 14 kD (nonreduced) by SDS-PAGE. The identity of the protein was verified by elution of biologic activity from gel slices. Purified SF-IF stimulated SF production in a physiologic concentration range (about 20-400 pM). Its properties and activities were distinct from those of IL-1 and TNF, two known inducers of SF production. We suggest that SF-IF is a physiologic regulator of SF production.
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Barra-Bucarei, Lorena, Macarena Gerding González, Andrés France Iglesias, Gonzalo Silva Aguayo, Matías Guerra Peñalosa, and Pedro Vergara Vera. "Beauveria bassiana Multifunction as an Endophyte: Growth Promotion and Biologic Control of Trialeurodes vaporariorum, (Westwood) (Hemiptera: Aleyrodidae) in Tomato." Insects 11, no. 9 (September 2, 2020): 591. http://dx.doi.org/10.3390/insects11090591.
Full textAbstract:
The tomato, Solanum lycopersicum L. is one of the most consumed vegetables in the world; nevertheless, it is affected by biotic and abiotic factors that reduce its productivity. The whitefly is globally considered as the main pest under protected crop conditions, where biologic control using endophytic fungi emerges as a sustainable alternative. We evaluated the indirect effects of five native endophytic strains of Beauveria bassiana on the reproduction of greenhouse whiteflies and the growth of tomatoes. The plant growth substrate was inoculated with five strains of this endophyte and the resulting plants were then exposed to whiteflies afterwards. The effect that endophytic strains had on phosphate solubilization, iron siderophore production, plant height, and plant biomass were evaluated. The evaluated endophytes reduced the number of eggs per cm2 on leaflets compared to the control and behaved similarly to the commercial synthetic insecticide. Leaflets inoculated with strains RGM-557, RGM-644 and RGM-731 showed fewer nymphs than the control and those treated with insecticide. RGM-557 and RGM-731 produced the greatest plant heights; RGM-731 obtained the greatest plant biomass. Our study provides evidence that native endophytic strains of B. bassiana have a biocontrol effect on whiteflies and could be used to promote tomato growth.
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Timár, Csaba I., Ákos M. Lőrincz, Roland Csépányi-Kömi, Anna Vályi-Nagy, György Nagy, Edit I. Buzás, Zsolt Iványi, et al. "Antibacterial effect of microvesicles released from human neutrophilic granulocytes." Blood 121, no. 3 (January 17, 2013): 510–18. http://dx.doi.org/10.1182/blood-2012-05-431114.
Full textAbstract:
Abstract Cell-derived vesicles represent a recently discovered mechanism for intercellular communication. We investigated their potential role in interaction of microbes with host organisms. We provide evidence that different stimuli induced isolated neutrophilic granulocytes to release microvesicles with different biologic properties. Only opsonized particles initiated the formation of microvesicles that were able to impair bacterial growth. The antibacterial effect of neutrophil-derived microvesicles was independent of production of toxic oxygen metabolites and opsonization or engulfment of the microbes, but depended on β2 integrin function, continuous actin remodeling, and on the glucose supply. Neutrophil-derived microvesicles were detected in the serum of healthy donors, and their number was significantly increased in the serum of bacteremic patients. We propose a new extracellular mechanism to restrict bacterial growth and dissemination.
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Pemberton, S. George, Brian Jones, and Gregory Edgecombe. "The influence of Trypanites in the diagenesis of Devonian stromatoporoids." Journal of Paleontology 62, no. 01 (January 1988): 22–31. http://dx.doi.org/10.1017/s0022336000058832.
Full textAbstract:
Stromatoporoids from the Late Devonian (early Frasnian) Waterways Formation near Fort McMurray, Alberta, contain well preservedTrypanitesMägdefrau. The stromatoporoid heads are formed of an initial growth ofClathrocoilona inconstansStearn that is encased by a second stage growth ofTrupetostroma papulosumStearn. These two stages were separated by a period of no growth and erosion. The first two generations of boring penetrated the skeleton ofC. inconstanswhile the third generation borings penetrated bothC. inconstansandT. papulosum.The borings in the stromatoporoids are filled with light colored micrite, dark colored micrite, skeletal fragments, dolomite, non-ferroan calcite, and ferroan calcite. Analysis of the borings, the growth stages of the stromatoporoids, the boring fill, and the orientation of the geopetal fabrics indicates that the stromatoporoids were subjected to repeated cycles of growth-boring-filling and reorientation. This complex interaction of biologic and physical reworking had a profound influence on the diagenetic transformation of the stromatoporoid heads. This example clearly illustrates the role that biogenic agents can play in the production of diagenetic fabrics of hard carbonate substrates.
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Montisano, D. F., T. Mann, and R. G. Spragg. "H2O2 increases expression of pulmonary artery endothelial cell platelet-derived growth factor mRNA." Journal of Applied Physiology 73, no. 6 (December 1, 1992): 2255–62. http://dx.doi.org/10.1152/jappl.1992.73.6.2255.
Full textAbstract:
Endothelial cells subjected to cell injury are capable of producing platelet-derived growth factor (PDGF), a mitogen for the stimulation of fibroblast and smooth muscle cell proliferation. Cultured bovine pulmonary artery endothelial cells were exposed to low concentrations of H2O2 for 30 min. Total cell RNA was isolated and subjected to Northern analysis with use of a v-sis PDGF cDNA probe. Results demonstrate a fourfold increase in cell PDGF mRNA immediately after exposure of bovine pulmonary artery endothelial cells to 50 microM H2O2. Evidence of expression of PDGF was sought in samples of cell supernatant collected 48 h after exposure. No evidence of PDGF activity or PDGF antigen could be demonstrated in those supernatants. Although the biologic activities of PDGF suggest that PDGF production by endothelial cells may contribute to the pulmonary pathology associated with acute lung injury, our results suggest that posttranscriptional events may prevent expression of PDGF under the experimental conditions of this investigation.
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Eggo, Margaret C., Laura K. Bachrach, and Gerard N. Burrow. "Role of non-TSH factors in thyroid cell growth." Acta Endocrinologica 116, no. 1_Suppl (August 1987): S231—S237. http://dx.doi.org/10.1530/acta.0.114s231.
Full textAbstract:
Abstract. The effects of insulin, the tumour promotor tetradecanoyl phorbol acetate (TPA), TSH and combinations of these factors on growth and DNA synthesis have been examined in the FRTL-5 cell strain and in sheep thyroid cells. In addition the regulation of the production by sheep thyroid cells of the insulin-like growth factors (IGF) by TSH and their possible autocrine roles have been investigated. We found that insulin and the IGF's stimulated DNA synthesis in both rat FRTL-5 cells and sheep cells. TPA also stimulated growth in both cell types, and its effects were additive to those of insulin. In the FRTL-5 cells, TPA was a less potent stimulator of growth than TSH, but the effects of TPA and TSH were not additive which may imply growth stimulation through a common pathway. In sheep cells TSH was not mitogenic and did not appear to activate protein kinase C, the receptor for TPA. Sheep cells, unlike FRTL-5 cells, were found to produce IGF-I and IGF-II, and their syntheses were regulated by TSH. Sheep cells were also found to produce IGF-binding proteins which may modulate the biologic effects of the IGF's. Sheep thyroid IGF binding proteins were found to copurify with urokinase-like plasminogen activator on immunoaffinity chromatography. The production of this serine protease has also been shown to be regulated by TSH.
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Men, Clara J., Andrea L. Kossler, and Sara T. Wester. "Updates on the understanding and management of thyroid eye disease." Therapeutic Advances in Ophthalmology 13 (January 2021): 251584142110277. http://dx.doi.org/10.1177/25158414211027760.
Full textAbstract:
Thyroid eye disease (TED) is a complex disease associated with myriad clinical presentations, including facial disfigurement, vision loss, and decreased quality of life. Traditionally, steroid therapy and/or radiation therapy were commonly used in the treatment of active TED. While these therapies can help reduce inflammation, they often do not have a sustainable, significant long-term effect on disease outcomes, including proptosis and diplopia. Recent advances in our understanding of the pathophysiology of TED have shifted the focus of treatment toward targeted biologic therapies. Biologics have the advantage of precise immune modulation, which can have better safety profiles and greater efficacy compared to traditional approaches. For instance, the insulin-like growth factor-1 receptor (IGF-1R) has been found to be upregulated in TED patients and to colocalize with the thyroid-stimulating hormone receptor (TSHR), forming a signaling complex. Teprotumumab is an antibody targeted against IGF-1R. By inhibiting the IGF-1R/TSHR signaling pathway, teprotumumab may reduce the production of proinflammatory cytokines, hyaluronan secretion, and orbital fibroblast activation in patients with TED. Due to promising phase II and III clinical trial results, teprotumumab has become the first biologic US Food and Drug Administration (FDA)-approved for the treatment of TED. In addition, there are currently ongoing studies looking at the use of antibodies targeting the neonatal Fc receptor (FcRn) in various autoimmune diseases, including TED. FcRn functions to transport immunoglobulin G (IgG) and prevent their lysosomal degradation. By blocking the recycling of IgG, this approach may dampen the body’s immune response, in particular the pathogenic IgG implicated in some autoimmune diseases. Advances in our understanding of the pathophysiology of TED, therefore, are leading to more targeted therapeutic options, and we are entering an exciting new phase in the management of TED. This review will cover recent insights into the understanding of TED pathophysiology and novel treatment options as well as ongoing studies of new potential treatment options for TED.
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Wan, Ning, and Chao Feng Shao. "The Experience and Challenges of China’s National Sustainable Communities (CNSCs)." Advanced Materials Research 962-965 (June 2014): 2499–504. http://dx.doi.org/10.4028/www.scientific.net/amr.962-965.2499.
Full textAbstract:
In response to the situation that social development was seriously lagging behind economic development, China began implementing national sustainable communities (CNSCs) from 1986. The goal is to achieve the simultaneous development of life, production and environment, and achieve the synchronous growth of economic effect, biologic effect and social effect. To date, China has built 120 national sustainable communities, involving regions of different development levels and development conditions in the east, center and west parts of China. Successful experiences are analyzed systematically, including updated development concept, technology-driven, scientific planning program, public participation and social promotion. Some key problems are encountered, such as uneven distribution of resources and the geographical conditions, and administrative region boundary segmentation which affect CNSCs development, complexity and accumulation of resources and environmental problems.
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Pemberton, S. George, Brian Jones, and Gregory Edgecombe. "The influence of Trypanites in the diagenesis of Devonian stromatoporoids." Journal of Paleontology 62, no. 1 (January 1988): 22–31. http://dx.doi.org/10.1017/s0022336000017959.
Full textAbstract:
Stromatoporoids from the Late Devonian (early Frasnian) Waterways Formation near Fort McMurray, Alberta, contain well preserved Trypanites Mägdefrau. The stromatoporoid heads are formed of an initial growth of Clathrocoilona inconstans Stearn that is encased by a second stage growth of Trupetostroma papulosum Stearn. These two stages were separated by a period of no growth and erosion. The first two generations of boring penetrated the skeleton of C. inconstans while the third generation borings penetrated both C. inconstans and T. papulosum. The borings in the stromatoporoids are filled with light colored micrite, dark colored micrite, skeletal fragments, dolomite, non-ferroan calcite, and ferroan calcite. Analysis of the borings, the growth stages of the stromatoporoids, the boring fill, and the orientation of the geopetal fabrics indicates that the stromatoporoids were subjected to repeated cycles of growth-boring-filling and reorientation. This complex interaction of biologic and physical reworking had a profound influence on the diagenetic transformation of the stromatoporoid heads. This example clearly illustrates the role that biogenic agents can play in the production of diagenetic fabrics of hard carbonate substrates.
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Bellamy, William T., Lynne Richter, Davuud Sirjani, Concepcion Roxas, Betty Glinsmann-Gibson, Yvette Frutiger, Thomas M. Grogan, and Alan F. List. "Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes." Blood 97, no. 5 (March 1, 2001): 1427–34. http://dx.doi.org/10.1182/blood.v97.5.1427.
Full textAbstract:
Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine generation. To delineate the potential role of VEGF in patients with myelodysplastic syndrome (MDS), VEGF protein and receptor expression and its functional significance in MDS bone marrow (BM) were evaluated. In BM clot sections from normal donors, low-intensity cytoplasmic VEGF expression was detected infrequently in isolated myeloid elements. However, monocytoid precursors in chronic myelomonocytic leukemia (CMML) expressed VEGF in an intense cytoplasmic pattern with membranous co-expression of the Flt-1 or KDR receptors, or both. In situ hybridization confirmed the presence of VEGF mRNA in the neoplastic monocytes. In acute myelogenous leukemia (AML) and other MDS subtypes, intense co-expression of VEGF and one or both receptors was detected in myeloblasts and immature myeloid elements, whereas erythroid precursors and lymphoid cells lacked VEGF and receptor expression. Foci of abnormal localized immature myeloid precursors (ALIP) co-expressed VEGF and Flt-1 receptor, suggesting autocrine cytokine interaction. Antibody neutralization of VEGF inhibited colony-forming unit (CFU)-leukemia formation in 9 of 15 CMML and RAEB-t patient specimens, whereas VEGF stimulated leukemia colony formation in 12 patients. Neutralization of VEGF activity suppressed the generation of tumor necrosis factor-α and interleukin-1β from MDS BM–mononuclear cells and BM–stroma and promoted the formation of CFU-GEMM and burst-forming unit-erythroid in methylcellulose cultures. These findings indicate that autocrine production of VEGF may contribute to leukemia progenitor self-renewal and inflammatory cytokine elaboration in CMML and MDS and thus provide a biologic rationale for ALIP and its adverse prognostic relevance in high-risk MDS.
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Eubank, Tim D., Julie M. Roda, Haowen Liu, Todd O'Neil, and Clay B. Marsh. "Opposing roles for HIF-1α and HIF-2α in the regulation of angiogenesis by mononuclear phagocytes." Blood 117, no. 1 (January 6, 2011): 323–32. http://dx.doi.org/10.1182/blood-2010-01-261792.
Full textAbstract:
Abstract Macrophages contribute to tumor growth through the secretion of the proangiogenic molecule vascular endothelial growth factor (VEGF). We previously observed that monocytes treated with the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produce a soluble form of the VEGF receptor-1 (sVEGFR-1), which neutralizes VEGF biologic activity. The VEGF and VEGFR-1 promoters both contain a hypoxia regulatory element, which binds the hypoxia-inducible factor (HIF) transcription factors under hypoxic conditions. Based on this observation, we examined VEGF and sVEGFR-1 production from monocytes cultured at various O2 concentrations. The amount of sVEGFR-1 production observed from GM-CSF-treated monocytes increased with decreasing levels of O2. This sVEGFR-1 was biologically active and sequestered VEGF. To evaluate the role of the HIFs in sVEGFR-1 production, we used macrophages with a genetic deletion of HIF-1α. HIF-1α−/− macrophages cultured with GM-CSF at hypoxia secreted diminished amounts of VEGF compared with HIF-1α+/+ macrophages, whereas sVEGFR-1 secretion was unaffected. In contrast, siRNA-mediated knockdown of HIF-2α inhibited the production of sVEGFR-1 in response to GM-CSF and low O2, whereas VEGF production was unaffected. These studies suggest that hypoxia, generally thought to promote angiogenesis, can induce antiangiogenic behavior from macrophages within a GM-CSF–rich environment. Furthermore, these results suggest specific and independent roles for HIF-1α and HIF-2α in hypoxic macrophages.
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Ishikawa, H., H. Tanaka, K. Iwato, O. Tanabe, H. Asaoku, M. Nobuyoshi, I. Yamamoto, M. Kawano, and A. Kuramoto. "Effect of glucocorticoids on the biologic activities of myeloma cells: inhibition of interleukin-1 beta osteoclast activating factor-induced bone resorption." Blood 75, no. 3 (February 1, 1990): 715–20. http://dx.doi.org/10.1182/blood.v75.3.715.715.
Full textAbstract:
Abstract Regulatory effects of glucocorticoids (dexamethasone) on myeloma cells as well as bone resorption in multiple myeloma were investigated. Glucocorticoids significantly inhibited proliferation of myeloma cells, and decreased the messenger RNA (mRNA) expressions of interleukin-6 (IL- 6) and secretory type immunoglobulin G (IgG). The inhibitory effects of glucocorticoids on myeloma cell proliferation could be due to the decreased expression of IL-6 mRNA, decreased IL-6 production, and thus suppression of autocrine growth by IL-6, which is an autocrine growth factor for myeloma cells as reported previously (Nature 332:83, 1988). Glucocorticoids also inhibited M-protein secretion by decreasing the levels of secretory type Ig mRNA. On the other hand, because IL-1 beta rather than lymphotoxin is considered to be a major osteoclast activating factor (OAF) produced by myeloma cells, and glucocorticoids decreased the expression of IL-1 beta mRNA and markedly suppressed the bone resorbing activity induced by IL-1 beta OAF in 45Ca-release bone resorption assay, it is suggestive that glucocorticoids could inhibit bone resorption induced by IL-1 beta OAF in multiple myeloma. Therefore, from these data it is concluded that glucocorticoids could be more effective chemotherapeutic agents in multiple myeloma than we expected, especially with regards to the inhibitory effects on proliferation and M-protein secretion from myeloma cells, as well as bone resorption by myeloma cells.
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Ishikawa, H., H. Tanaka, K. Iwato, O. Tanabe, H. Asaoku, M. Nobuyoshi, I. Yamamoto, M. Kawano, and A. Kuramoto. "Effect of glucocorticoids on the biologic activities of myeloma cells: inhibition of interleukin-1 beta osteoclast activating factor-induced bone resorption." Blood 75, no. 3 (February 1, 1990): 715–20. http://dx.doi.org/10.1182/blood.v75.3.715.bloodjournal753715.
Full textAbstract:
Regulatory effects of glucocorticoids (dexamethasone) on myeloma cells as well as bone resorption in multiple myeloma were investigated. Glucocorticoids significantly inhibited proliferation of myeloma cells, and decreased the messenger RNA (mRNA) expressions of interleukin-6 (IL- 6) and secretory type immunoglobulin G (IgG). The inhibitory effects of glucocorticoids on myeloma cell proliferation could be due to the decreased expression of IL-6 mRNA, decreased IL-6 production, and thus suppression of autocrine growth by IL-6, which is an autocrine growth factor for myeloma cells as reported previously (Nature 332:83, 1988). Glucocorticoids also inhibited M-protein secretion by decreasing the levels of secretory type Ig mRNA. On the other hand, because IL-1 beta rather than lymphotoxin is considered to be a major osteoclast activating factor (OAF) produced by myeloma cells, and glucocorticoids decreased the expression of IL-1 beta mRNA and markedly suppressed the bone resorbing activity induced by IL-1 beta OAF in 45Ca-release bone resorption assay, it is suggestive that glucocorticoids could inhibit bone resorption induced by IL-1 beta OAF in multiple myeloma. Therefore, from these data it is concluded that glucocorticoids could be more effective chemotherapeutic agents in multiple myeloma than we expected, especially with regards to the inhibitory effects on proliferation and M-protein secretion from myeloma cells, as well as bone resorption by myeloma cells.
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Portier, M., XG Zhang, E. Caron, ZY Lu, R. Bataille, and B. Klein. "gamma-Interferon in multiple myeloma: inhibition of interleukin-6 (IL- 6)-dependent myeloma cell growth and downregulation of IL-6-receptor expression in vitro." Blood 81, no. 11 (June 1, 1993): 3076–82. http://dx.doi.org/10.1182/blood.v81.11.3076.3076.
Full textAbstract:
Abstract In multiple myeloma, malignant plasma cells from most patients with active disease proliferate spontaneously when cultured for 5 days in vitro. This spontaneous proliferation is related to the endogenous production of interleukin-6 (IL-6), the major myeloma-cell growth factor. A 50% inhibitory dose (100 U/mL) of human recombinant gamma- interferon (hr gamma-IFN) blocked the proliferation of myeloma cells almost completely in all 19 patients analyzed. This inhibition was not caused by suppression of endogenous IL-6 production and was also observed in the presence of an excess of hrIL-6. hr gamma-IFN was also completely inhibitory in four human myeloma cell lines (HMCL) whose growth is totally dependent on the addition of exogenous hrIL-6. This inhibition was associated with a 47% to 73% decrease in membrane IL-6- binding gp80 protein as well as with a 90% decrease in the amount of gp80 mRNA in HMCL. These results are in line with recent reports indicating that gamma-IFN inhibited several IL-6-dependent biologic processes. They suggest a need to reconsider why previous preliminary clinical trials failed to demonstrate a beneficial effect of gamma-IFN in multiple myeloma.
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Portier, M., XG Zhang, E. Caron, ZY Lu, R. Bataille, and B. Klein. "gamma-Interferon in multiple myeloma: inhibition of interleukin-6 (IL- 6)-dependent myeloma cell growth and downregulation of IL-6-receptor expression in vitro." Blood 81, no. 11 (June 1, 1993): 3076–82. http://dx.doi.org/10.1182/blood.v81.11.3076.bloodjournal81113076.
Full textAbstract:
In multiple myeloma, malignant plasma cells from most patients with active disease proliferate spontaneously when cultured for 5 days in vitro. This spontaneous proliferation is related to the endogenous production of interleukin-6 (IL-6), the major myeloma-cell growth factor. A 50% inhibitory dose (100 U/mL) of human recombinant gamma- interferon (hr gamma-IFN) blocked the proliferation of myeloma cells almost completely in all 19 patients analyzed. This inhibition was not caused by suppression of endogenous IL-6 production and was also observed in the presence of an excess of hrIL-6. hr gamma-IFN was also completely inhibitory in four human myeloma cell lines (HMCL) whose growth is totally dependent on the addition of exogenous hrIL-6. This inhibition was associated with a 47% to 73% decrease in membrane IL-6- binding gp80 protein as well as with a 90% decrease in the amount of gp80 mRNA in HMCL. These results are in line with recent reports indicating that gamma-IFN inhibited several IL-6-dependent biologic processes. They suggest a need to reconsider why previous preliminary clinical trials failed to demonstrate a beneficial effect of gamma-IFN in multiple myeloma.
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Haque, Md Azizul, Mohammad Nayeem, Rizoana Ahamad, and Kaniz Fatema Muna. "A Case Report on Small Cell Carcinoma with Bilateral Vocal Cord Palsy and Superior Vena Cava Syndrome." Bangladesh Journal of Medical Science 19, no. 4 (April 12, 2020): 769–71. http://dx.doi.org/10.3329/bjms.v19i4.46640.
Full textAbstract:
Small cell lung cancer (SCLC), previously known as oat cell carcinoma, is considered distinct from other lung cancers, which are called non-small cell lung cancers (NSCLC) because of their clinical and biologic characteristics. Small cell lung cancer is a neuroendocrine carcinoma that exhibits aggressive behavior, rapid growth, early spread to distant sites, excuisite sensitivity to chemotherapy and frequent association with distinct paraneoplastic syndromes, including syndrome of inappropriate secretion of antidiuretic hormone (SIADH), ectopic adrenocorticotropic hormone (ACTH) production and many others. Approximately 98% of patients with small cell lung cancer have a smoking history. Here, we report a case of small cell lung cancer in a 70-year-old male presenting to us with bilateral vocal cord palsy and superior vena cava syndrome.
Bangladesh Journal of Medical Science Vol.19(4) 2020 p.769-771
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Barba, Anna Angela, Sabrina Bochicchio, Annalisa Dalmoro, and Gaetano Lamberti. "Lipid Delivery Systems for Nucleic-Acid-Based-Drugs: From Production to Clinical Applications." Pharmaceutics 11, no. 8 (July 24, 2019): 360. http://dx.doi.org/10.3390/pharmaceutics11080360.
Full textAbstract:
In the last years the rapid development of Nucleic Acid Based Drugs (NABDs) to be used in gene therapy has had a great impact in the medical field, holding enormous promise, becoming “the latest generation medicine” with the first ever siRNA-lipid based formulation approved by the United States Food and Drug Administration (FDA) for human use, and currently on the market under the trade name Onpattro™. The growth of such powerful biologic therapeutics has gone hand in hand with the progress in delivery systems technology, which is absolutely required to improve their safety and effectiveness. Lipid carrier systems, particularly liposomes, have been proven to be the most suitable vehicles meeting NABDs requirements in the medical healthcare framework, limiting their toxicity, and ensuring their delivery and expression into the target tissues. In this review, after a description of the several kinds of liposomes structures and formulations used for in vitro or in vivo NABDs delivery, the broad range of siRNA-liposomes production techniques are discussed in the light of the latest technological progresses. Then, the current status of siRNA-lipid delivery systems in clinical trials is addressed, offering an updated overview on the clinical goals and the next challenges of this new class of therapeutics which will soon replace traditional drugs.
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Penrose, Harrison, Eman Toraih, Emmanuelle Ruiz, Rida Iftikhar, Morgan Collins, Emad Kandil, and Suzana Savkovic. "DIFFERENTIALLY EXPRESSED GENE SIGNATURES OF ULCERATIVE COLITIS DETERMINE NOVEL REGULATORS AND PREDICT RESPONSE TO BIOLOGIC THERAPY." Inflammatory Bowel Diseases 27, Supplement_1 (January 1, 2021): S28—S29. http://dx.doi.org/10.1093/ibd/izaa347.067.
Full textAbstract:
Abstract Disease heterogenicity among Ulcerative colitis (UC) patients and their variable responses to therapy is not well understood. Previously, using publicly available transcriptomes from colonic tissue of UC patients, we demonstrated the immune cell landscape and pathways that are common and distinct among patients and for non-responders to biologic therapy. Here, we AIM to determine differentially expressed gene signatures specific to inflamed UC tissue and for non-responders to biologic anti-TNFa and anti-a4b7 therapy in large patient cohorts. Methods: Transcriptomes from 210 UC patient samples from inflamed and matched uninflamed tissue (GSE4183, GSE14580, GSE38713, GSE107593) and from UC patients prior to and while receiving anti-TNFa (infliximab) and anti-a4b7 integrin (vedolizumab) (GSE12251, GSE73661) treatment were analyzed. Generating and analyzing differentially expressed genes (DEGs), transcriptional signatures, and hierarchical clustering were performed using the limma Bioconductor R package and Cluster3/JavaTree software. Disease/function analysis was performed by Ingenuity Pathway Analysis (IPA) and predicting outcomes to therapy by receiver operating characteristic (ROC) curve analysis and area under the curve (AUC). Transcripts were validated in primary UC tissue samples using qPCR. Results: In three UC cohorts, we identified a specific transcriptional signature of 100 DEGs (UC100) common among patients (Figure 1A-D). The UC100 signature was validated in an independent cohort, demonstrating the ability to distinctly separate inflamed from matched uninflamed transcriptomes (p=4.65e-08). The UC100 DEGs encode protein involved in inflammation, immunity, antimicrobial response, growth, cellular movement, metabolism (lipid, amino acid), and energy production. Among them are many DEGs with unexamined roles in UC, including PCK1, HMGCS2, ACAT1, HCAR3, LPCAT1, and LIPG. Their differential expression was further validated in primary UC tissue by qPCR. Moreover, we identified twenty DEGs in UC patients resistant to anti-TNFa and anti-a4b7 therapy (UCR20) (Figure 2A-C). The UC20R DEGs encode protein involved in inflammation, immune cell trafficking, antimicrobial responses, lipid metabolism, and mitochondrial dysfunction. Four of the top DEGs predicted resistance to both therapies with a sensitivity of 73.3% and specificity 85.7%; AUC for IGFBP5: 0.86±0.008, p=0.008; STC1: 0.83±0.09, p=0.015; VNN2: 0.81±0,10, p=0.022; and SELE: 0.77±0.11, p=0.045. Conclusion: This study demonstrates differentially expressed genes in UC common across cohorts and those with predictive power to biologic therapy outcome. This provides a platform for development of more precise diagnostic tools and personally tailored therapeutic regimens for UC patients.
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Gill, Saar, Adrianne E. Vasey, Alysha De Souza, Jeanette Baker, Aaron T. Smith, Holbrook E. Kohrt, Mareike Florek, et al. "Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells." Blood 119, no. 24 (June 14, 2012): 5758–68. http://dx.doi.org/10.1182/blood-2012-03-415364.
Full textAbstract:
Abstract Natural killer (NK) cells are potent anti-viral and antitumor “first responders” endowed with natural cytotoxicity and cytokine production capabilities. To date, attempts to translate these promising biologic functions through the adoptive transfer of NK cells for the treatment of cancer have been of limited benefit. Here we trace the fate of adoptively transferred murine NK cells and make the surprising observation that NK cells traffic to tumor sites yet fail to control tumor growth or improve survival. This dysfunction is related to a rapid down-regulation of activating receptor expression and loss of important effector functions. Loss of interferon (IFN)γ production occurs early after transfer, whereas loss of cytotoxicity progresses with homeostatic proliferation and tumor exposure. The dysfunctional phenotype is accompanied by down-regulation of the transcription factors Eomesodermin and T-bet, and can be partially reversed by the forced overexpression of Eomesodermin. These results provide the first demonstration of NK-cell exhaustion and suggest that the NK-cell first-response capability is intrinsically limited. Further, novel approaches may be required to circumvent the described dysfunctional phenotype.
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Bagnara, GP, G. Zauli, L. Vitale, P. Rosito, V. Vecchi, G. Paolucci, GC Avanzi, U. Ramenghi, F. Timeus, and V. Gabutti. "In vitro growth and regulation of bone marrow enriched CD34+ hematopoietic progenitors in Diamond-Blackfan anemia." Blood 78, no. 9 (November 1, 1991): 2203–10. http://dx.doi.org/10.1182/blood.v78.9.2203.2203.
Full textAbstract:
Abstract Diamond-Blackfan anemia (DBA) is a congenital red blood cell aplasia. No clear explanation has been given of its defective erythropoiesis, although different humoral or cellular inhibitory factors have been proposed. To clarify the nature of this defect we studied the effect of several human recombinant growth factors on an enriched CD34+ population obtained from the bone marrow of 10 DBA patients. We observed a defect underlying the early erythroid progenitors, which were unresponsive to several growth factors (erythropoietin, interleukin-3 [IL-3], IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], erythroid potentiating activity), either alone or in association. The production of cytokines was not impaired, and high levels of IL-3 and GM-CSF were found in phytohemagglutinin-leukocyte- conditioned medium (PHA-LCM) when tested with a sensitive biologic assay on the M-07E cell line. Hematopoietic stem cells in DBA patients may be induced to differentiate to the granulocyte megakaryocyte, but not the erythroid compartment, as shown after CD34+ cell preincubation with IL-3. Addition of the stem cell factor to IL-3 and erythropoietin induces a dramatic in vitro increase in both the number and the size of BFU-E, which also display a normal morphologic terminal differentiation.
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Bagnara, GP, G. Zauli, L. Vitale, P. Rosito, V. Vecchi, G. Paolucci, GC Avanzi, U. Ramenghi, F. Timeus, and V. Gabutti. "In vitro growth and regulation of bone marrow enriched CD34+ hematopoietic progenitors in Diamond-Blackfan anemia." Blood 78, no. 9 (November 1, 1991): 2203–10. http://dx.doi.org/10.1182/blood.v78.9.2203.bloodjournal7892203.
Full textAbstract:
Diamond-Blackfan anemia (DBA) is a congenital red blood cell aplasia. No clear explanation has been given of its defective erythropoiesis, although different humoral or cellular inhibitory factors have been proposed. To clarify the nature of this defect we studied the effect of several human recombinant growth factors on an enriched CD34+ population obtained from the bone marrow of 10 DBA patients. We observed a defect underlying the early erythroid progenitors, which were unresponsive to several growth factors (erythropoietin, interleukin-3 [IL-3], IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF], erythroid potentiating activity), either alone or in association. The production of cytokines was not impaired, and high levels of IL-3 and GM-CSF were found in phytohemagglutinin-leukocyte- conditioned medium (PHA-LCM) when tested with a sensitive biologic assay on the M-07E cell line. Hematopoietic stem cells in DBA patients may be induced to differentiate to the granulocyte megakaryocyte, but not the erythroid compartment, as shown after CD34+ cell preincubation with IL-3. Addition of the stem cell factor to IL-3 and erythropoietin induces a dramatic in vitro increase in both the number and the size of BFU-E, which also display a normal morphologic terminal differentiation.
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McNAB, W. BRUCE. "A General Framework Illustrating an Approach to Quantitative Microbial Food Safety Risk Assessment." Journal of Food Protection 61, no. 9 (September 1, 1998): 1216–28. http://dx.doi.org/10.4315/0362-028x-61.9.1216.
Full textAbstract:
Hazard analysis critical control point (HACCP), risk assessment, predictive microbiology, and dose-response modeling have been recognized as important tools for the assessment and management of health risks posed by food-borne pathogens. Unfortunately, the biology of both the food chain and food poisoning is complex and dynamic. Therefore, mathematical modeling of microbial risk from food production through to consumption and illness is difficult. Nevertheless, previous authors have made impressive progress in modeling specific pathogen-food-consumer combinations. In this study a framework for a Monte Carlo model of a generic food system was developed. It links together food ingredients, batch processing, cross contamination, microbial growth, cooking, recontamination, consumption, human exposure to pathogens, the dose-response relationship, and the biologic and economic impact components of such risks. This framework is presented to illustrate one potential approach to quantitative risk assessment for microbial food safety. It requires refinement with appropriate distributions and mathematical relationships before it can be applied to a specific pathogen-food-consumer situation.
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Nussler, A. K., M. Di Silvio, T. R. Billiar, R. A. Hoffman, D. A. Geller, R. Selby, J. Madariaga, and R. L. Simmons. "Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin." Journal of Experimental Medicine 176, no. 1 (July 1, 1992): 261–64. http://dx.doi.org/10.1084/jem.176.1.261.
Full textAbstract:
Nitric oxide (NO) is a short-lived biologic mediator that is shown to be induced in various cell types and to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of the inducible type of the NO synthase (NOS). However, there is limited evidence for the existence of such inducible NOS in a human cell type. We show here the induction of NO biosynthesis in freshly isolated human hepatocytes (HC) after stimulation with interleukin 1, tumor necrosis factor (TNF), IFN-gamma, and endotoxin. Increased levels of nitrite (NO2-) and nitrate (NO3-) in culture supernatants were associated with NADPH-dependent NOS activity in the cell lysates. The production of NO2- and NO3- was inhibited by NG-monomethyl L-arginine and was associated with an increase in cyclic guanylate monophosphate release. The data presented here provide evidence for the existence of typical inducible NO biosynthesis in a human cell type.
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Armanious, Hanan, Pascal Gelebart, Mona Anand, Andrew Belch, and Raymond Lai. "Constitutive activation of metalloproteinase ADAM10 in mantle cell lymphoma promotes cell growth and activates the TNFα/NFκB pathway." Blood 117, no. 23 (June 9, 2011): 6237–46. http://dx.doi.org/10.1182/blood-2010-10-313940.
Full textAbstract:
Abstract One of the main functions of A Disintegrin and Metalloproteinase 10 (ADAM10) is to regulate the bioavailability of adhesion molecules and ligands to various cellular-signaling receptors. Constitutive activation of ADAM10 has been implicated in the pathogenesis of several types of solid tumors. In this study, we found that mantle cell lymphoma (MCL) cell lines and all 12 patient samples examined expressed the active/mature form of ADAM10. In contrast, PBMCs from healthy donors (n = 5) were negative. Using immunohistochemistry, ADAM10 was readily detectable in 20 of 23 (87%) MCL tumors, but absent in 5 reactive tonsils. Knockdown of ADAM10 using short interfering RNA (siRNA) in MCL cells significantly induced growth inhibition and cell-cycle arrest, and these changes were correlated with down-regulation of cyclin D1, up-regulation of p21waf1, and significant reductions in the TNFα production/transcriptional activity of NFκBp65. The addition of recombinant ADAM10 to MCL cells led to the opposite biologic effects. Lastly, down-regulation of ADAM10 using siRNA enhanced the growth-suppressing effects mediated by the proteasome inhibitors MG132 and bortezomib. We conclude that constitutive activation of ADAM10 contributes to the growth of MCL and therefore inhibition of ADAM10 may be a useful strategy to enhance the response of MCL to other therapeutic agents.
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Tsai, Shu-Chun, Sue-Jane Lin, Po-Wen Chen, Wen-Yi Luo, Te-Huei Yeh, Hsei-Wei Wang, Chi-Ju Chen, and Ching-Hwa Tsai. "EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines." Blood 114, no. 1 (July 2, 2009): 109–18. http://dx.doi.org/10.1182/blood-2008-12-193375.
Full textAbstract:
AbstractEpstein-Barr virus (EBV) infection can modify the cytokine expression profiles of host cells and determine the fate of those cells. Of note, expression of interleukin-13 (IL-13) may be detected in EBV-associated Hodgkin lymphoma and the natural killer (NK) cells of chronic active EBV-infected patients, but its biologic role and regulatory mechanisms are not understood. Using cytokine antibody arrays, we found that IL-13 production is induced in B cells early during EBV infection. Furthermore, the EBV lytic protein, Zta (also known as the BZLF-1 product), which is a transcriptional activator, was found to induce IL-13 expression following transfection. Mechanistically, induction of IL-13 expression by Zta is mediated directly through its binding to the IL-13 promoter, via a consensus AP-1 binding site. Blockade of IL-13 by antibody neutralization showed that IL-13 is required at an early stage of EBV-induced proliferation and for long-term maintenance of the growth of EBV immortalized lymphoblastoid cell lines (LCLs). Thus, Zta-induced IL-13 production facilitates B-cell proliferation and may contribute to the pathogenesis of EBV-associated lymphoproliferative disorders, such as posttransplantation lymphoproliferative disease (PTLD) and Hodgkin lymphoma.
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Shi, Hoi-Ping, and Chi-Mei Lee. "Phosphate removal under denitrifying conditions byBrachymonassp. strain P12 andParacoccus denitrificansPP15." Canadian Journal of Microbiology 53, no. 6 (June 2007): 727–37. http://dx.doi.org/10.1139/w07-026.
Full textAbstract:
In this study, we used the denitrifying phosphorus-removing bacterium Brachymonas sp. strain P12 to investigate the enhanced biologic phosphorus-removal (EBPR) mechanism involved with polyhydroxybutyrate (PHB), glycogen, and phosphorus uptake in the presence of acetate under anoxic or aerobic conditions. The results showed that excess acetate concentration and aerobic cultivation can enhance PHB formation efficiency and that PHB formation might be stimulated by glycogenolysis of the cellular glycogen. The efficiency of the uptake of anoxic phosphorus was greater when PHB production was lower. The EBPR mechanism of Brachymonas sp. strain P12 for PHB, phosphorus, and glycogen was similar to the conventional anaerobic–aerobic (or anaerobic–anoxic) EBPR models, but these models were developed under anoxic or aerobic conditions only, without an anaerobic stage. The anoxic or aerobic log phase of growth is divided into two main phases: the early log phase, in which acetate and glycogen are consumed to supply enough energy and reducing power for PHB formation and cell growth (phosphorus assimilation), and the late log phase, which ends the simultaneous degradation of PHB and remaining acetate for polyphosphate accumulation. Glycogenolysis plays a significant role in the alternate responses between PHB formation and phosphorus uptake under anoxic or aerobic conditions. After the application of the denitrifying phosphorus-removing bacterium Brachymonas sp. strain P12, aerobic cultivation increases the level of PHB production, and anoxic cultivation further increases phosphorus uptake.
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Piérard-Franchimont, Claudine, and Gérald E. Piérard. "Alterations in Hair Follicle Dynamics in Women." BioMed Research International 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/957432.
Full textAbstract:
Endocrine changes supervening after parturition and menopause participate in the control of sebum production and hair growth modulation. The ensuing conditions include some peculiar aspects of hair loss (effluvium), alopecia, and facial hirsutism. The hair cycling is of major clinical relevance because most hair growth disorders result from disturbances in this chronobiological feature. Of note, any correlation between a biologic abnormality and hair cycling disturbance does not prove a relationship of causality. The proportion of postmenopausal women is rising in the overall population. Therefore, the prevalence of these hair follicle disturbances is globally on the rise. Current therapies aim at correcting the underlying hormonal imbalances, and at improving the overall cosmetic appearance. However, in absence of pathogenic diagnosis and causality criteria, chances are low that a treatment given by the whims of fate will adequately control hair effluvium. The risk and frequency of therapeutic inertia are further increased. When the hair loss is not controlled and/or compensated by growth of new hairs, several clinical aspects of alopecia inexorably develop. Currently, there is little evidence supporting any specific treatment for these endocrine hair disorders in post-partum and postmenopausal women. Current hair treatment strategies are symptomatic and nonspecific so current researchers aim at developing new, targeted methods.
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Woodward, TA, IK McNiece, PL Witte, P. Bender, R. Crittenden, DS Temeles, BE Robinson, GB Baber, DH Deacon, and PC Isakson. "Further studies on growth factor production by the TC-1 stromal cell line: pre-B stimulating activity." Blood 75, no. 11 (June 1, 1990): 2130–36. http://dx.doi.org/10.1182/blood.v75.11.2130.2130.
Full textAbstract:
Abstract Adherent murine stromal cells support long-term in vitro lymphopoiesis or myelopoiesis dependent on the culture conditions used. A cell line, TC-1, isolated from long-term liquid murine marrow cultures under conditions approaching those permissive for lymphoid growth, has been found to produce an activity that acts synergistically with interleukin- 3 (IL-3) or colony-stimulating factor-1 (CSF-1) to stimulate in vitro myeloid colonies, but which has no intrinsic colony-stimulating activity. We report here the presence of multiple growth factors in conditioned medium (CM) from the TC-1 line, including granulocyte- macrophage colony-stimulating factor (GM-CSF) (bioassay with antibody blocking and messenger RNA [mRNA] analysis), granulocyte CSF (G-CSF) and IL-4 (factor-dependent cell line bioassay), and CSF-1 (radioimmunoassay, mRNA) along with a pre-B cell inducing activity, which appears separate from these CSFs and segregates with the myeloid synergizing activity through anion exchange, sizing, and Conconavalin A chromatography. Because these activities are not yet purified to homogeneity, their identity or lack of identity remains an open question. Assays of TC-1 CM or cellular mRNA analysis have given negative results for IL-1, IL-2, IL-3, IL-6, and IL-7, and IL-6 does not stimulate pre-B cells in this assay. However, IL-4 and G-CSF do stimulate in vitro induction of pre-B cells from pre-B and B-cell- depleted Balb/C marrow and are present in CM by selective cell line assay. A monoclonal antibody to IL-4 that inhibited its pre-B inducing activity did not inhibit pre-B inducing activity of TC-1 CM. These data suggest the existence of a unique synergizing and pre-B inducing factor(s) in TC-1 CM. Given the known capacity of subliminal levels of growth factors to act synergistically, an alternate possibility is that these biologic phenomena represent the actions of low concentrations of growth factors acting synergistically and possibly associated with some core protein.
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Woodward, TA, IK McNiece, PL Witte, P. Bender, R. Crittenden, DS Temeles, BE Robinson, GB Baber, DH Deacon, and PC Isakson. "Further studies on growth factor production by the TC-1 stromal cell line: pre-B stimulating activity." Blood 75, no. 11 (June 1, 1990): 2130–36. http://dx.doi.org/10.1182/blood.v75.11.2130.bloodjournal75112130.
Full textAbstract:
Adherent murine stromal cells support long-term in vitro lymphopoiesis or myelopoiesis dependent on the culture conditions used. A cell line, TC-1, isolated from long-term liquid murine marrow cultures under conditions approaching those permissive for lymphoid growth, has been found to produce an activity that acts synergistically with interleukin- 3 (IL-3) or colony-stimulating factor-1 (CSF-1) to stimulate in vitro myeloid colonies, but which has no intrinsic colony-stimulating activity. We report here the presence of multiple growth factors in conditioned medium (CM) from the TC-1 line, including granulocyte- macrophage colony-stimulating factor (GM-CSF) (bioassay with antibody blocking and messenger RNA [mRNA] analysis), granulocyte CSF (G-CSF) and IL-4 (factor-dependent cell line bioassay), and CSF-1 (radioimmunoassay, mRNA) along with a pre-B cell inducing activity, which appears separate from these CSFs and segregates with the myeloid synergizing activity through anion exchange, sizing, and Conconavalin A chromatography. Because these activities are not yet purified to homogeneity, their identity or lack of identity remains an open question. Assays of TC-1 CM or cellular mRNA analysis have given negative results for IL-1, IL-2, IL-3, IL-6, and IL-7, and IL-6 does not stimulate pre-B cells in this assay. However, IL-4 and G-CSF do stimulate in vitro induction of pre-B cells from pre-B and B-cell- depleted Balb/C marrow and are present in CM by selective cell line assay. A monoclonal antibody to IL-4 that inhibited its pre-B inducing activity did not inhibit pre-B inducing activity of TC-1 CM. These data suggest the existence of a unique synergizing and pre-B inducing factor(s) in TC-1 CM. Given the known capacity of subliminal levels of growth factors to act synergistically, an alternate possibility is that these biologic phenomena represent the actions of low concentrations of growth factors acting synergistically and possibly associated with some core protein.
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Deneen, Benjamin, Scott M. Welford, Thu Ho, Felicia Hernandez, Irwin Kurland, and Christopher T. Denny. "PIM3 Proto-Oncogene Kinase Is a Common Transcriptional Target of Divergent EWS/ETS Oncoproteins." Molecular and Cellular Biology 23, no. 11 (June 1, 2003): 3897–908. http://dx.doi.org/10.1128/mcb.23.11.3897-3908.2003.
Full textAbstract:
ABSTRACT Despite significant structural diversity, present evidence suggests that EWS/ETS fusion proteins promote oncogenesis by transcriptionally modulating a common set of target genes. In order to identify these genes, microarray expression analyses were performed on NIH 3T3 polyclonal populations expressing one of three EWS/ETS fusion genes. The majority of these genes can be grouped into seven functional categories, including cellular metabolism and signal transduction. The biologic significance of these target genes was pursued. The effects of modulating genes involved in metabolism were assessed by flux studies and demonstrated shifts in glucose utilization and lactate production as a result of EWS/FLI1 expression. The proto-oncogene coding for serine/threonine kinase PIM3 was found to one of several genes encoding signal transduction proteins that were up-regulated by EWS/ETS fusions. PIM3 was found to be expressed in a panel of human Ewing's family tumor cell lines. Forced expression of PIM3 promoted anchorage-independent growth. Coexpression of a kinase-deficient PIM3 mutant attenuated EWS/FLI1-mediated NIH 3T3 tumorigenesis in immunodeficent mice.
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Hayashi, Toshiaki, Teru Hideshima, Klaus Podar, Paul Richardson, Olivier Munoz, Makoto Hamasaki, Kenji Ishitsuka, et al. "TGF-β Receptor I Kinase Inhibitor Downregulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment." Blood 104, no. 11 (November 16, 2004): 2355. http://dx.doi.org/10.1182/blood.v104.11.2355.2355.
Full textAbstract:
Abstract Transforming growth factors (TGFs) have pleiotropic biologic effects on tumor cells and their environment. In multiple myeloma (MM), we have reported that bone marrow stromal cells (BMSCs) from MM patients produce more TGF-β1 than BMSCs from healthy donors, which in turn induces interleukin-6 (IL-6) secretion. In this study, we delineate the functional squelae of TGF-β1 in MM, and importantly, show that the TGF-β receptor I kinase inhibitor SD-208 significantly decreases secretion of both IL-6 and vascular endothelial growth factor (VEGF) from BMSCs, as well as tumor cell growth triggered by MM cell adhesion to BMSCs. Cytokine production and MM cell proliferation triggered by TGF-β1 or adhesion to BMSCs were examined in the presence or absence of SD-208 using ELISA and 3H thymidine incorporation assay, respectively. Effects of SD-208 on TGF-β1-induced signaling pathways triggering IL-6 and VEGF transcription in BMSCs were delineated using immunofluorescence staining, immunoblotting and DNA-binding assay. We here show that adhesion of MM cells to BMSCs triggers secretion of TGF-β1, which further upregulates IL-6 and VEGF secretion in BMSCs. These cytokines in turn mediate MM cell growth, survival, drug resistance, and migration. Importantly, SD-208 significantly inhibits not only transcription but also secretion of both IL-6 and VEGF from BMSCs triggered by either TGF-β1 or adhesion of MM cells to BMSCs. Moreover, SD-208 decreased tumor cell growth triggered by MM cell adhesion to BMSCs. SD-208 works, at least in part, by blocking TGF-β1-triggered nuclear accumulation of Smad2/3 and hypoxia-inducible factor 1α, as well as related production of IL-6 and VEGF, respectively. These studies indicate that SD-208 inhibits production of cytokines mediating MM cell growth, survival, drug resistance, and migration in the BM milieu, thereby providing the preclinical rationale for clinical evaluation of SD-208 to improve patient outcome in MM.