19 results on '"Spaeth EL"'
Search Results
2. Lights, camera, active! Appreciation of active learning predicts positive attitudes towards lecture capture
- Author
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Nordmann, Emily, Clark, Anne, Spaeth, El, and MacKay, Jill R D
- Subjects
ComputingMilieux_COMPUTERSANDEDUCATION - Abstract
Much has been written about instructor attitudes towards lecture capture, particularly concerning political issues such as opt-out policies and the use of recordings by management. Additionally, the pedagogical concerns of lecturers have been extensively described and focus on the belief that recording lectures will impact on attendance and will reduce interactivity and active learning activities in lectures. However, little work has looked at the relationship between attitudes towards lecture capture and broader conceptions of learning and teaching. In this pre-registered study we administered the Conceptions of Learning and Teaching scale and a novel lecture capture attitude scale to 159 higher education teachers. We found that appreciation of active learning predicted more positive attitudes towards lecture recordings as an educational support tool, whilst higher teacher-centered scores predicted greater concern about the negative educational impact of recordings. The effects observed were small, however, they are strong evidence against the view that it is instructors who value participatory and active learning that are opposed to lecture capture. Exploratory analyses also suggested that those who did not view recordings as an essential educational resource record fewer of their lectures, highlighting the real-world impact that attitudes can have, and further strengthening the need for staff to be provided with evidence-based guidance upon which to base their teaching practice. All data, analysis code and the pre-registration are available at https://osf.io/uzs3t/
- Published
- 2021
3. Lights, camera, active! Appreciation of active learning predicts positive attitudes towards lecture capture
- Author
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Nordmann, Emily, primary, Clark, Anne, additional, Spaeth, El, additional, and MacKay, Jill R D, additional
- Published
- 2020
- Full Text
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4. On Feedback and Emotional Labour
- Author
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Spaeth, El, primary
- Published
- 2018
- Full Text
- View/download PDF
5. Validation of an Abridged Breast Cancer Risk Prediction Model for the General Population.
- Author
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Spaeth EL, Dite GS, Hopper JL, and Allman R
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- Humans, Female, Cohort Studies, Prospective Studies, Risk Assessment, Risk Factors, Breast Neoplasms diagnosis, Breast Neoplasms epidemiology, Breast Neoplasms prevention & control
- Abstract
Prevention Relevance: In this prospective population-based cohort study, we show the improved performance of a new risk assessment model compared with a gold-standard model (BCRAT). The classification of at-risk women using this new model highlights the opportunity to improve risk stratification and implement existing clinical risk-reduction interventions., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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6. Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.
- Author
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Allen JK, Armaiz-Pena GN, Nagaraja AS, Sadaoui NC, Ortiz T, Dood R, Ozcan M, Herder DM, Haemmerle M, Gharpure KM, Rupaimoole R, Previs RA, Wu SY, Pradeep S, Xu X, Han HD, Zand B, Dalton HJ, Taylor M, Hu W, Bottsford-Miller J, Moreno-Smith M, Kang Y, Mangala LS, Rodriguez-Aguayo C, Sehgal V, Spaeth EL, Ram PT, Wong STC, Marini FC, Lopez-Berestein G, Cole SW, Lutgendorf SK, De Biasi M, and Sood AK
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- Animals, Cell Line, Tumor, Cyclic AMP metabolism, Female, Guanine Nucleotide Exchange Factors metabolism, Humans, Membrane Glycoproteins metabolism, Mice, Neoplasms mortality, Peripheral Nerves metabolism, Peripheral Nerves pathology, Receptor, trkB metabolism, Signal Transduction, Tumor Microenvironment physiology, Xenograft Model Antitumor Assays, Brain-Derived Neurotrophic Factor metabolism, Feedback, Physiological, Neoplasms pathology, Norepinephrine metabolism, Receptors, Adrenergic, beta-3 metabolism
- Abstract
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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7. Role of neoplastic monocyte-derived fibrocytes in primary myelofibrosis.
- Author
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Verstovsek S, Manshouri T, Pilling D, Bueso-Ramos CE, Newberry KJ, Prijic S, Knez L, Bozinovic K, Harris DM, Spaeth EL, Post SM, Multani AS, Rampal RK, Ahn J, Levine RL, Creighton CJ, Kantarjian HM, and Estrov Z
- Subjects
- Animals, Bone Marrow pathology, Bone Marrow Transplantation, Cells, Cultured, Fibroblasts drug effects, Fibrosis, Homeodomain Proteins pharmacology, Humans, Mice, Mice, SCID, Nitriles, Primary Myelofibrosis pathology, Pyrazoles pharmacology, Pyrimidines, Recombinant Proteins pharmacology, Serum Amyloid P-Component pharmacology, Fibroblasts physiology, Monocytes cytology, Primary Myelofibrosis etiology
- Abstract
Primary myelofibrosis (PMF) is a fatal neoplastic disease characterized by clonal myeloproliferation and progressive bone marrow (BM) fibrosis thought to be induced by mesenchymal stromal cells stimulated by overproduced growth factors. However, tissue fibrosis in other diseases is associated with monocyte-derived fibrocytes. Therefore, we sought to determine whether fibrocytes play a role in the induction of BM fibrosis in PMF. In this study, we show that BM from patients with PMF harbors an abundance of clonal, neoplastic collagen- and fibronectin-producing fibrocytes. Immunodeficient mice transplanted with myelofibrosis patients' BM cells developed a lethal myelofibrosis-like phenotype. Treatment of the xenograft mice with the fibrocyte inhibitor serum amyloid P (SAP; pentraxin-2) significantly prolonged survival and slowed the development of BM fibrosis. Collectively, our data suggest that neoplastic fibrocytes contribute to the induction of BM fibrosis in PMF, and inhibiting fibrocyte differentiation with SAP may interfere with this process., (© 2016 Verstovsek et al.)
- Published
- 2016
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8. Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance.
- Author
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Jacamo R, Chen Y, Wang Z, Ma W, Zhang M, Spaeth EL, Wang Y, Battula VL, Mak PY, Schallmoser K, Ruvolo P, Schober WD, Shpall EJ, Nguyen MH, Strunk D, Bueso-Ramos CE, Konoplev S, Davis RE, Konopleva M, and Andreeff M
- Subjects
- Animals, Bone and Bones metabolism, Cell Adhesion, Cell Line, Transformed, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, Endothelial Cells cytology, Gene Expression Profiling, Humans, Mice, RNA, Messenger metabolism, Signal Transduction, Stromal Cells cytology, Drug Resistance, Neoplasm, Gene Expression Regulation, Leukemic, Integrin alpha4beta1 metabolism, NF-kappa B metabolism, Vascular Cell Adhesion Molecule-1 metabolism
- Abstract
Leukemia cells are protected from chemotherapy-induced apoptosis by their interactions with bone marrow mesenchymal stromal cells (BM-MSCs). Yet the underlying mechanisms associated with this protective effect remain unclear. Genome-wide gene expression profiling of BM-MSCs revealed that coculture with leukemia cells upregulated the transcription of genes associated with nuclear factor (NF)-κB signaling. Moreover, primary BM-MSCs from leukemia patients expressed NF-κB target genes at higher levels than their normal BM-MSC counterparts. The blockade of NF-κB activation via chemical agents or the overexpression of the mutant form of inhibitor κB-α (IκBα) in BM-MSCs markedly reduced the stromal-mediated drug resistance in leukemia cells in vitro and in vivo. In particular, our unique in vivo model of human leukemia BM microenvironment illustrated a direct link between NF-κB activation and stromal-associated chemoprotection. Mechanistic in vitro studies revealed that the interaction between vascular cell adhesion molecule 1 (VCAM-1) and very late antigen-4 (VLA-4) played an integral role in the activation of NF-κB in the stromal and tumor cell compartments. Together, these results suggest that reciprocal NF-κB activation in BM-MSCs and leukemia cells is essential for promoting chemoresistance in the transformed cells, and targeting NF-κB or VLA-4/VCAM-1 signaling could be a clinically relevant mechanism to overcome stroma-mediated chemoresistance in BM-resident leukemia cells.
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- 2014
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9. Quantitative multispectral analysis following fluorescent tissue transplant for visualization of cell origins, types, and interactions.
- Author
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Spaeth EL, Booth CM, and Marini FC
- Subjects
- Animals, Bone Marrow Cells metabolism, Bone Marrow Cells physiology, Female, Fluorescent Antibody Technique methods, Fluorescent Dyes chemistry, Green Fluorescent Proteins analysis, Indoles chemistry, Luminescent Proteins analysis, Luminescent Proteins metabolism, Mice, Mice, Transgenic, Neoplasm Transplantation, Red Fluorescent Protein, Bone Marrow Cells cytology, Bone Marrow Transplantation methods, Flow Cytometry methods, Green Fluorescent Proteins biosynthesis, Green Fluorescent Proteins genetics, Microscopy, Fluorescence methods, Ovarian Neoplasms pathology
- Abstract
With the desire to understand the contributions of multiple cellular elements to the development of a complex tissue; such as the numerous cell types that participate in regenerating tissue, tumor formation, or vasculogenesis, we devised a multi-colored cellular transplant model of tumor development in which cell populations originate from different fluorescently colored reporter gene mice and are transplanted, engrafted or injected in and around a developing tumor. These colored cells are then recruited and incorporated into the tumor stroma. In order to quantitatively assess bone marrow derived tumor stromal cells, we transplanted GFP expressing transgenic whole bone marrow into lethally irradiated RFP expressing mice as approved by IACUC. 0ovarian tumors that were orthotopically injected into the transplanted mice were excised 6-8 weeks post engraftment and analyzed for bone marrow marker of origin (GFP) as well as antibody markers to detect tumor associated stroma using multispectral imaging techniques. We then adapted a methodology we call MIMicc- Multispectral Interrogation of Multiplexed cellular compositions, using multispectral unmixing of fluoroprobes to quantitatively assess which labeled cell came from which starting populations (based on original reporter gene labels), and as our ability to unmix 4, 5, 6 or more spectra per slide increases, we've added additional immunohistochemistry associated with cell lineages or differentiation to increase precision. Utilizing software to detect co-localized multiplexed-fluorescent signals, tumor stromal populations can be traced, enumerated and characterized based on marker staining.
- Published
- 2013
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10. Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment.
- Author
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Spaeth EL, Labaff AM, Toole BP, Klopp A, Andreeff M, and Marini FC
- Subjects
- Animals, Apoptosis, Blotting, Western, Bone Marrow Cells metabolism, Bone Marrow Cells pathology, Cell Differentiation, Cell Movement, Cell Proliferation, Chromatin Immunoprecipitation, Culture Media, Conditioned pharmacology, Female, Fibroblasts metabolism, Humans, Immunoenzyme Techniques, Mammary Neoplasms, Animal genetics, Mammary Neoplasms, Animal metabolism, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Phenotype, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Twist-Related Protein 1 genetics, Fibroblasts pathology, Hyaluronan Receptors physiology, Mammary Neoplasms, Animal pathology, Mesenchymal Stem Cells pathology, Ovarian Neoplasms pathology, Tumor Microenvironment, Twist-Related Protein 1 metabolism
- Abstract
Tumor-stroma interactions play a crucial role in cancer progression by eliciting factors that promote proliferative, angiogenic, and invasive supports to the tumor microenvironment. Mesenchymal stromal/stem cells (MSC) contribute to stroma in part as cancer-associated fibroblasts (CAF), but a complete understanding of how MSC contribute to the tumor stroma is lacking. In this study, we show how CAF phenotypes rely upon MSC expression of the multifunctional cell surface glycoprotein CD44, a putative stem cell marker. Through bone marrow transplantation experiments in a transgenic mouse model of cancer, we determined that CD44 deficiency leads to a relative reduction in the contribution of bone marrow-derived cells to tumor stroma. CD44 attenuation in MSC limited their expression of CAF markers induced by tumor conditioning, and these MSC migrated poorly and provided weak angiogenic support compared with wild-type MSC. These defects were linked to deficiencies in the ability of CD44-attenuated MSC to transcriptionally upregulate Twist expression. Together, our results establish that CD44 expression contributes to critical functions in the tumor stroma.
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- 2013
- Full Text
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11. Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer.
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Dembinski JL, Wilson SM, Spaeth EL, Studeny M, Zompetta C, Samudio I, Roby K, Andreeff M, and Marini FC
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- Animals, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Female, Genetic Therapy methods, Humans, Immunohistochemistry, Interferon-beta therapeutic use, Male, Mice, Mice, Inbred C57BL, Xenograft Model Antitumor Assays, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells drug effects, Ovarian Neoplasms therapy
- Abstract
Background Aims: Many ovarian cancers originate from ovarian surface epithelium, where they develop from cysts intermixed with stroma. The stromal layer is critical to the progression and survival of the neoplasm and consequently is recruited into the tumor microenvironment., Methods: Using both syngeneic mouse tumors (ID8-R) and human xenograft (OVCAR3, SKOV3) tumor models, we first confirmed that intraperitoneally injected circulating mesenchymal stem cells (MSCs) could target, preferentially engraft and differentiate into α-smooth muscle actin-positive myofibroblasts, suggesting their role as "reactive stroma" in ovarian carcinoma development and confirming their potential as a targeted delivery vehicle for the intratumoral production of interferon-β (IFN-β). Mice with ovarian carcinomas then received weekly intraperitoneal injections of IFN-β expressing MSCs., Results: Intraperitoneal injections of IFN-β expressing MSCs resulted in complete eradication of tumors in 70% of treated OVCAR3 mice (P = 0.004) and an increased survival of treated SKOV3 mice compared with controls (P = 0.01). Similar tumor growth control was observed using murine IFN-β delivered by murine MSCs in ID8-R ovarian carcinoma. As a potential mechanism of tumor killing, MSCs produced IFN-β-induced caspase-dependent tumor cell apoptosis., Conclusions: Our results demonstrate that ovarian carcinoma engrafts MSCs to participate in myofibrovascular networks and that IFN-β produced by MSCs intratumorally modulates tumor kinetics, resulting in prolonged survival., (Published by Elsevier Inc.)
- Published
- 2013
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12. Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis.
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Battula VL, Shi Y, Evans KW, Wang RY, Spaeth EL, Jacamo RO, Guerra R, Sahin AA, Marini FC, Hortobagyi G, Mani SA, and Andreeff M
- Subjects
- Animals, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, CD24 Antigen genetics, CD24 Antigen metabolism, Cell Line, Transformed, Cell Line, Tumor, Epithelial-Mesenchymal Transition genetics, Female, Gangliosides genetics, Gene Expression Regulation, Enzymologic genetics, Gene Expression Regulation, Neoplastic genetics, Gene Knockdown Techniques, Humans, Hyaluronan Receptors genetics, Hyaluronan Receptors metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasm Transplantation, Neoplastic Stem Cells pathology, Neoplastic Stem Cells transplantation, Sialyltransferases biosynthesis, Sialyltransferases genetics, Transplantation, Heterologous, Biomarkers, Tumor biosynthesis, Breast Neoplasms metabolism, Gangliosides biosynthesis, Neoplastic Stem Cells metabolism
- Abstract
Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have increased resistance to conventional therapies and are capable of establishing metastasis. However, only a few biomarkers of CSCs have been identified. Here, we report that ganglioside GD2 (a glycosphingolipid) identifies a small fraction of cells in human breast cancer cell lines and patient samples that are capable of forming mammospheres and initiating tumors with as few as 10 GD2+ cells. In addition, the majority of GD2+ cells are also CD44hiCD24lo, the previously established CSC-associated cell surface phenotype. Gene expression analysis revealed that GD3 synthase (GD3S) is highly expressed in GD2+ as well as in CD44hiCD24lo cells and that interference with GD3S expression, either by shRNA or using a pharmacological inhibitor, reduced the CSC population and CSC-associated properties. GD3S knockdown completely abrogated tumor formation in vivo. Also, induction of epithelial-mesenchymal transition (EMT) in transformed human mammary epithelial cells (HMLER cells) dramatically increased GD2 as well as GD3S expression in these cells, suggesting a role of EMT in the origin of GD2+ breast CSCs. In summary, we identified GD2 as a new CSC-specific cell surface marker and GD3S as a potential therapeutic target for CSCs, with the possibility of improving survival and cure rates in patients with breast cancer.
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- 2012
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13. Tracking inflammation-induced mobilization of mesenchymal stem cells.
- Author
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Spaeth EL, Kidd S, and Marini FC
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- Adipocytes cytology, Animals, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cell Differentiation, Cell Line, Cell Separation methods, Chondrocytes cytology, Humans, Mesenchymal Stem Cell Transplantation methods, Mice, Osteocytes cytology, Tumor Microenvironment, Cell Movement physiology, Cell Tracking methods, Inflammation metabolism, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells metabolism
- Abstract
The act of migration is similar for many cell types. The migratory mechanism of mesenchymal stem cells (MSC) is not completely elucidated, yet many of the initial studies have been based on current understanding of the leukocyte migration. A normal function of MSC is the ability of the cell to migrate to and repair wounded tissue. This wound healing property of MSC originates with migration towards inflammatory signals produced by the wounded environment [1]. A tumor and its microenvironment are capable of eliciting a similar inflammatory response from the MSC, thus resulting in migration of the MSC towards the tumor microenvironment. We have shown MSC migration both in vitro and in vivo. In this chapter, we elucidate several in vivo methods to study MSC migration and mobilization to the tumor microenvironment. The first model is an exogenous model of MSC migration that can be performed in both xenograft and syngenic systems with in vitro expanded MSC. The second model utilizes transgenic-fluorescent--colored mice to follow endogenous bone marrow components including MSC. The third technique enables us to analyze data from the transgenic model through multispectral imaging. Furthermore, the migratory phenotype of MSC can be exploited for use in tumor-targeted gene delivery therapy has been efficacious in animal model studies and is an anticipated therapeutic device in clinical trials.
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- 2012
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14. Dissecting mesenchymal stem cell movement: migration assays for tracing and deducing cell migration.
- Author
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Spaeth EL and Marini FC
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- Adipocytes physiology, Animals, Cell Line, Tumor, Cell Separation, Gene Transfer Techniques, Humans, Immunohistochemistry, Luminescent Measurements, Luminescent Proteins analysis, Mesenchymal Stem Cells physiology, Mice, Neoplasms pathology, Osteoblasts physiology, Adipocytes cytology, Cell Differentiation physiology, Cell Migration Assays, Cell Movement, Mesenchymal Stem Cells cytology, Osteoblasts cytology
- Abstract
Targeted migration is a necessary attribute for any gene delivery vehicle. Mesenchymal stem cells (MSC) have been used as effective delivery vehicles for treatments against cancer, graft versus host disease, -arthritis, multiple sclerosis, and many other diseases. MSC migrate toward sites of inflammation, however, the true migratory mechanism has yet to be elucidated. There are several receptors and respective chemokines known to be involved in the migration of the MSC. Further insight to MSC migration will be revealed both in vivo and in vitro through the application of migration assays from the most simple, to the more technologically demanding.
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- 2011
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15. Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment.
- Author
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Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, Shi Y, Abbruzzese J, Konopleva M, Andreeff M, and Marini FC
- Subjects
- Animals, Antineoplastic Agents immunology, Antineoplastic Agents therapeutic use, Cell Growth Processes immunology, Cell Line, Tumor, Genetic Therapy, Growth Inhibitors immunology, Growth Inhibitors therapeutic use, Humans, Immunosuppression Therapy, Inflammation, Interferon-beta genetics, Interferon-beta immunology, Mesenchymal Stem Cells immunology, Mesenchymal Stem Cells pathology, Mice, Mice, SCID, Neoplasm Transplantation, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology, Stromal Cells pathology, Stromal Cells transplantation, Transgenes genetics, Interferon-beta metabolism, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells metabolism, Pancreatic Neoplasms therapy, Stromal Cells metabolism
- Abstract
Background Aims: Because of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression., Methods: Human pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-beta were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase., Results: MSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P=0.032). The production of IFN-beta within the tumor site by MSC-IFN-beta further suppressed tumor growth (P=0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFkappaB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC-IFN-beta injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC-IFN-beta alone (P=0.041)., Conclusions: These results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-beta for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents.
- Published
- 2010
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16. Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells.
- Author
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Dembinski JL, Spaeth EL, Fueyo J, Gomez-Manzano C, Studeny M, Andreeff M, and Marini FC
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- Animals, Breast Neoplasms genetics, Breast Neoplasms therapy, Breast Neoplasms virology, Cell Line, Tumor, Female, Humans, Immunoenzyme Techniques, Melanoma, Experimental genetics, Melanoma, Experimental therapy, Melanoma, Experimental virology, Mice, Ovarian Neoplasms genetics, Ovarian Neoplasms therapy, Ovarian Neoplasms virology, Survival Rate, Xenograft Model Antitumor Assays, Adenoviridae genetics, Genetic Vectors therapeutic use, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells virology, Oncolytic Virotherapy, Virus Replication
- Abstract
The fiber-modified adenoviral vector Delta-24-RGD (D24RGD) offers vast therapeutic potential. Direct injection of D24RGD has been used to successfully target ovarian tumors in mice. However, systemic toxicity, especially in the liver, profoundly limits the efficacy of direct viral vector delivery. Mesenchymal stem cells (MSC) have the ability to function as a vector for targeted gene therapy because of their preferential engraftment into solid tumors and participation in tumor stroma formation. We show that MSC-guided delivery of D24RGD is specific and efficient and reduces the overall systemic toxicity in mice to negligible levels compared with D24RGD alone. In our model, we found efficient targeted delivery of MSC-D24RGD to both breast and ovarian cell lines. Furthermore, immunohistochemical staining for adenoviral hexon protein confirmed negligible levels of systemic toxicity in mice that were administered MSC-D24RGD compared with those that were administered D24RGD. These data suggest that delivery of D24RGD through MSC not only increases the targeted delivery efficiency, but also reduces the systemic exposure of the virus, thereby reducing overall systemic toxicity to the host and ultimately enhancing its value as an anti-tumor therapeutic candidate.
- Published
- 2010
- Full Text
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17. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression.
- Author
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Spaeth EL, Dembinski JL, Sasser AK, Watson K, Klopp A, Hall B, Andreeff M, and Marini F
- Subjects
- Animals, Cell Division, Disease Progression, Female, Humans, Transplantation, Heterologous, Cell Lineage, Fibroblasts cytology, Mesenchymal Stem Cells cytology, Ovarian Neoplasms pathology
- Abstract
Background: Tumor associated fibroblasts (TAF), are essential for tumor progression providing both a functional and structural supportive environment. TAF, known as activated fibroblasts, have an established biological impact on tumorigenesis as matrix synthesizing or matrix degrading cells, contractile cells, and even blood vessel associated cells. The production of growth factors, cytokines, chemokines, matrix-degrading enzymes, and immunomodulatory mechanisms by these cells augment tumor progression by providing a suitable environment. There are several suggested origins of the TAF including tissue-resident, circulating, and epithelial-to-mesenchymal-transitioned cells., Methodology/principal Findings: We provide evidence that TAF are derived from mesenchymal stem cells (MSC) that acquire a TAF phenotype following exposure to or systemic recruitment into adenocarcinoma xenograft models including breast, pancreatic, and ovarian. We define the MSC derived TAF in a xenograft ovarian carcinoma model by the immunohistochemical presence of 1) fibroblast specific protein and fibroblast activated protein; 2) markers phenotypically associated with aggressiveness, including tenascin-c, thrombospondin-1, and stromelysin-1; 3) production of pro-tumorigenic growth factors including hepatocyte growth factor, epidermal growth factor, and interleukin-6; and 4) factors indicative of vascularization, including alpha-smooth muscle actin, desmin, and vascular endothelial growth factor. We demonstrate that under long-term tumor conditioning in vitro, MSC express TAF-like proteins. Additionally, human MSC but not murine MSC stimulated tumor growth primarily through the paracrine production of secreted IL6., Conclusions/significance: Our results suggest the dependence of in vitro Skov-3 tumor cell proliferation is due to the presence of tumor-stimulated MSC secreted IL6. The subsequent TAF phenotype arises from the MSC which ultimately promotes tumor growth through the contribution of microvascularization, stromal networks, and the production of tumor-stimulating paracrine factors.
- Published
- 2009
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18. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment.
- Author
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Klopp AH, Spaeth EL, Dembinski JL, Woodward WA, Munshi A, Meyn RE, Cox JD, Andreeff M, and Marini FC
- Subjects
- Adenoviridae genetics, Animals, Cell Line, Tumor, Genetic Engineering, Luciferases analysis, Luciferases genetics, Mammary Neoplasms, Animal pathology, Mammary Neoplasms, Animal radiotherapy, Mesoderm radiation effects, Mice, Mice, Inbred BALB C, Neoplasms pathology, Stem Cell Transplantation, Stem Cells pathology, Stem Cells radiation effects, Transfection, Mammary Neoplasms, Animal therapy, Mesoderm physiology, Neoplasms radiotherapy, Stem Cells physiology
- Abstract
Mesenchymal stem cells (MSC) migrate to and proliferate within sites of inflammation and tumors as part of the tissue remodeling process. Radiation increases the expression of inflammatory mediators that could enhance the recruitment of MSC into the tumor microenvironment. To investigate this, bilateral murine 4T1 breast carcinomas (expressing renilla luciferase) were irradiated unilaterally (1 or 2 Gy). Twenty-four hours later, 2 x 10(5) MSC-expressing firefly luciferase were injected i.v. Mice were then monitored with bioluminescent imaging for expression of both renilla (tumor) and firefly (MSC) luciferase. Forty-eight hours postirradiation, levels of MSC engraftment were 34% higher in tumors receiving 2 Gy (P = 0.004) than in the contralateral unirradiated limb. Immunohistochemical staining of tumor sections from mice treated unilaterally with 2 Gy revealed higher levels of MSC in the parenchyma of radiated tumors, whereas a higher proportion of MSC remained vasculature-associated in unirradiated tumors. To discern the potential mediators involved in MSC attraction, in vitro migration assays showed a 50% to 80% increase in MSC migration towards conditioned media from 1 to 5 Gy-irradiated 4T1 cells compared with unirradiated 4T1 cells. Irradiated 4T1 cells had increased expression of the cytokines, transforming growth factor-beta1, vascular endothelial growth factor, and platelet-derived growth factor-BB, and this up-regulation was confirmed by immunohistochemistry in tumors irradiated in vivo. Interestingly, the chemokine receptor CCR2 was found to be up-regulated in MSC exposed to irradiated tumor cells and inhibition of CCR2 led to a marked decrease of MSC migration in vitro. In conclusion, clinically relevant low doses of irradiation increase the tropism for and engraftment of MSC in the tumor microenvironment.
- Published
- 2007
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19. Coinfection of Chlamydia trachomatis, Ureaplasma urealyticum and human papillomavirus among patients attending STD clinics in Estonia.
- Author
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Denks K, Spaeth EL, Jõers K, Randoja R, Talpsep T, Ustav M, and Kurg R
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- Adolescent, Adult, Aged, Ambulatory Care Facilities, Chlamydia Infections complications, Chlamydia trachomatis, Estonia epidemiology, Female, Humans, Middle Aged, Papillomavirus Infections complications, Prevalence, Ureaplasma Infections complications, Ureaplasma urealyticum, Alphapapillomavirus genetics, Chlamydia Infections epidemiology, Female Urogenital Diseases epidemiology, Papillomavirus Infections epidemiology, Ureaplasma Infections epidemiology
- Abstract
Women visiting Estonian STD clinics were subjected to PCR assay for human papillomavirus (HPV), Chlamydia trachomatis and Ureaplasma urealyticum biovar 2. The overall prevalence of coinfection was 8%. The chlamydial infection was found to be associated with HPV, especially with high-risk HPV (OR=2.5, p<0.005) and most significantly in women over 41 y of age. C. trachomatis infection also occurred more frequently in U. urealyticum-infected than in U. urealyticum-free patients (OR=2.6, p=0.02). U. urealyticum infection did not associate with HPV status. The clinical significance of the association between C. trachomatis and U. urelyticum infection remains to be elucidated.
- Published
- 2007
- Full Text
- View/download PDF
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