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Brandy Edenfield

Bio: Brandy Edenfield is an academic researcher from Mayo Clinic. The author has contributed to research in topics: Pancreatic cancer & Pancreatic Intraepithelial Neoplasia. The author has an hindex of 10, co-authored 16 publications receiving 473 citations.

Papers
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Journal ArticleDOI
15 Mar 2008-Blood
TL;DR: The gene expression signature discovered in this study may represent a true "CNS signature" because it contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

154 citations

Journal ArticleDOI
TL;DR: It is demonstrated that pancreatic acinar cells expressing mutant KRAS can expedite their transformation to a duct-like phenotype by inducing local inflammation and a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer.
Abstract: Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can crosstalk with immune cells and how this contributes to the development of pancreatic lesions. Here we demonstrate that pancreatic acinar cells expressing mutant Kras can expedite their transformation to a duct-like phenotype by inducing local inflammation. Specifically, we show that KrasG12D induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KrasG12D-caused abnormal pancreatic structures by re-modulating the extracellular matrix and providing cytokines such as tumor necrosis factor (TNF). Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell-specific promoter both resulted in a decreased formation of abnormal structures and decreased progression of ADM to PanIN lesions.

146 citations

Journal ArticleDOI
TL;DR: Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly decreased the accumulation of alternatively activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

79 citations

Journal ArticleDOI
05 Aug 2013-PLOS ONE
TL;DR: POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment.
Abstract: Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS lymphoma. POM should be further evaluated in clinical trials.

74 citations

Journal ArticleDOI
TL;DR: It is discovered that trypsin inhibition, in combination with anti-coagulation therapy, synergistically prevented the progression to CP in PRSS1R122H mice, and these animal models help to better understand the complex nature of this disease.
Abstract: Currently, an effective targeted therapy for pancreatitis is lacking. Hereditary pancreatitis (HP) is a heritable, autosomal-dominant disorder with recurrent acute pancreatitis (AP) progressing to chronic pancreatitis (CP) and a markedly increased risk of pancreatic cancer. In 1996, mutations in PRSS1 were linked to the development of HP. Here, we developed a mouse model by inserting a full-length human PRSS1R122H gene, the most commonly mutated gene in human HP, into mice. Expression of PRSS1R122H protein in the pancreas markedly increased stress signaling pathways and exacerbated AP. After the attack of AP, all PRSS1R122H mice had disease progression to CP, with similar histologic features as those observed in human HP. By comparing PRSS1R122H mice with PRSS1WT mice, as well as enzymatically inactivated Dead-PRSS1R122H mice, we unraveled that increased trypsin activity is the mechanism for R122H mutation to sensitize mice to the development of pancreatitis. We further discovered that trypsin inhibition, in combination with anticoagulation therapy, synergistically prevented progression to CP in PRSS1R122H mice. These animal models help us better understand the complex nature of this disease and provide powerful tools for developing and testing novel therapeutics for human pancreatitis.

40 citations


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Journal ArticleDOI
12 May 2011-Blood
TL;DR: The criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly are addressed, and the issue of borderline categories having overlapping features with large B-cell lymphomas is reviewed.

1,735 citations

Journal ArticleDOI
TL;DR: Macrophage plasticity, an essential component of chronic inflammation, and its involvement in diverse human diseases, most notably cancer, is discussed here as a paradigm.
Abstract: Macrophages are a diverse set of cells present in all body compartments. This diversity is imprinted by their ontogenetic origin (embryonal versus adult bone marrow-derived cells); the organ context; by their activation or deactivation by various signals in the contexts of microbial invasion, tissue damage, and metabolic derangement; and by polarization of adaptive T cell responses. Classic adaptive responses of macrophages include tolerance, priming, and a wide spectrum of activation states, including M1, M2, or M2-like. Moreover, macrophages can retain long-term imprinting of microbial encounters (trained innate immunity). Single-cell analysis of mononuclear phagocytes in health and disease has added a new dimension to our understanding of the diversity of macrophage differentiation and activation. Epigenetic landscapes, transcription factors, and microRNA networks underlie the adaptability of macrophages to different environmental cues. Macrophage plasticity, an essential component of chronic inflammation, and its involvement in diverse human diseases, most notably cancer, is discussed here as a paradigm.

681 citations

Journal ArticleDOI
TL;DR: The 4(th) edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues published in 2008 builds upon the success of the 2001 3(rd) edition; new entities are defined, and solutions for problematic categories are sought.
Abstract: The 4(th) edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues published in 2008 builds upon the success of the 2001 3(rd) edition; new entities are defined, and solutions for problematic categories are sought. Recent studies have drawn attention to the biological overlap between classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphomas (DLBCL). Similarly, there is a greater appreciation of the borderlands between Burkitt lymphoma and DLBCL. Strategies for the management of these borderline lesions are proposed. Additionally, age-specific and site-specific factors play an important role in the definition of several new entities, which also have biological underpinnings. Among the peripheral T-cell lymphomas (PTCL), more precise definitions were introduced for several entities, including anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Several new variants of primary cutaneous T-cell lymphomas are proposed. Finally, the subclassification and categorization of the most common lymphoma subtypes, follicular lymphoma (FL) and DLBCL, were altered to enhance diagnostic accuracy and aid in clinical management. The 2008 WHO classification also draws attention to early events in lymphomagenesis. These lesions help delineate the earliest steps in neoplastic transformation and generally mandate a conservative therapeutic approach. The 2001 classification was rapidly adopted for clinical trials and successfully served as a common language for scientists comparing genetic and functional data. The modifications made in the 2008 classification are the result of this successful partnership among pathologists, clinicians, and biologists, but are only a stepping stone to the future.

580 citations

Journal ArticleDOI
TL;DR: Signs of biological convergence, such as stromal–immune crosstalk, including glutamine metabolism, focal adhesion kinase and transforming growth factor-β signalling, are promising targets for remodelling the TME into an antitumour milieu.
Abstract: Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC.

447 citations

Journal ArticleDOI
TL;DR: The body of work on CAFs is summarized, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity and functions, and the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states are highlighted.
Abstract: Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.

394 citations