Browsing by Subject "bone marrow"

Now showing 1 - 5 of 5
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    Histoplasmosis: Fever of Unknown Origin Disseminated to Bone Marrow
    (2021-06-09) Lugo, Adrian; Adjapong, Andrews; Ahmad, Waseem
    Histoplasmosis capsulatum is a dimorphic fungus highly endemic to the Mississippi and Ohio River valleys of North America. Infection develops when Histoplasma microconidia are inhaled and transform into their yeast form inside the lungs. In this report, we highlight the importance of including histoplasmosis as a differential diagnosis for a fever of unknown origin. A 42-year-old female with a PMH of HIV presented to the ED in Southwest Indiana for a fever. Her last known CD4 count was 4 and viral load was 601,000. She was found to have pancytopenia. Her platelets were refractory to platelet transfusion and she had several episodes of epistaxis requiring packing. She failed IV antibiotics as her fever persisted. Blood cultures were initially negative, chest x-ray was insignificant, urinalysis was unremarkable, and a respiratory panel was negative, but a urine blastomyces antigen test came back positive and a month later the blood culture subsequently grew presumptive histoplasma capsulatum. She subsequently underwent a bone marrow biopsy as part of her pancytopenia workup which demonstrated histiocytes containing fungal organisms. Her pancytopenia was therefore declared to be secondary to disseminated mycosis. She was treated with IV amphotericin B per infectious disease with improvement. Extrapulmonary disease has been well reported in patients with blastomycosis and histoplasmosis, but bone marrow infiltration is rare. In fact, according to one epidemiological study, only 4% of cases have bone involvement. Our case report is unique as the patient had evidence of fungus in the bone, and it was only through inadvertently obtaining a bone marrow sample for hematologic testing that we were able to find the source for her fever. Although CT of the chest would later demonstrate lung involvement, the case of disseminated mycosis was made by both blood cultures and bone marrow aspirate, indicating osteomyelitis and, hence, disseminated disease that would have otherwise gone unnoticed. This case report highlights the importance of keeping histoplasmosis and other fungal infections on the list of differential diagnoses given the demographic and geographical region as it can potentially be the source for acute illness.
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    Physical, psychological, and social sequelae following hematopoietic stem cell transplantation: a review of the literature
    (Wiley, 2009) Mosher, Catherine E.; Redd, William H.; Rini, Christine M.; Burkhalter, Jack E.; DuHamel, Katherine N.
    Objective: This article reviews recent literature on adults' quality of life following hematopoietic stem cell transplantation (HSCT). Methods: We identified 22 prospective reports with at least 20 participants at baseline through a search of databases (Medline and PsycInfo) and handsearching of articles published from 2002 to October 2007. If longitudinal data were not available or were scarce for a particular topic or time point, cross-sectional studies were reviewed. Results: Although physical, psychological, and social aspects of quality of life tend to improve during the years following transplantation, a significant proportion of HSCT survivors experience persistent anxiety and depressive symptoms, fatigue, sexual dysfunction, and fertility concerns. Despite ongoing treatment side effects, the majority of HSCT survivors resume their work, school, or household activities. Conclusion: We conclude that theory-driven research with larger samples is needed to identify subgroups of HSCT survivors with adjustment difficulties. Such research would examine survivors' evolving standards and definitions of quality of life to improve the accuracy and meaningfulness of assessment and incorporate biological, psychological, and contextual factors that may contribute to positive adjustment. Copyright © 2008 John Wiley & Sons, Ltd.
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    ROLE OF CD166 IN MULTIPLE MYELOMA CELL HOMING TO THE BONE MARROW MICROENVIRONMENT AND DISEASE PROGRESSION
    (Office of the Vice Chancellor for Research, 2014-04-11) Xu, Linlin; Machal, Christophe; Wu, Hao; Poteat, Bradley; Crean, Colin; Cardoso, Angelo A; Chirgwin, John M; Hanenberg, Helmut; Mohammad, Khalid S; Suvannasankha, Attaya; Srour, Edward F
    Multiple myeloma (MM) is a plasma cell malignancy characterized by multiple lytic lesions throughout the skeleton, suggesting that trafficking of MM cells from the bone marrow (BM) and lodgment of these cells at secondary sites is important in disease progression. CD38+CD138- MM cells were previously characterized as putative MM stem cells (MMSC, Cancer Res. 2008; 68(1):190-7.). We analyzed CD38+CD138- cells contained within the MM cell line H929 and determined that a fraction of these cells (29.9%±1.4%) expresses CD166. CD166 is a member of the immunoglobulin superfamily capable of mediating both homophilic and heterophilic (CD6) interactions and has been shown to enhance metastasis and invasion in several tumors including breast cancer and melanoma. Studies from our laboratory suggest that CD38+CD138-CD166+ MM cells possess many functional properties commonly associated with MMSC including cell cycle quiescence, maintenance and propagation of daughter cells on a stromal substrate and gene expression profile. We hypothesized that CD166 promotes MM cell trafficking to the BM and is critical for disease progression. To test this hypothesis, H929-GFP myeloma cells were injected intravenously into NSG mice and GFP cells were recovered from the BM 14hr later. While only 3.3%±1.5% of total H929-GFP cells express the CD38+CD138- phenotype, the frequency of CD38+CD138- cells contained in BM-homed H929-GFP cells was significantly higher (53.4%±3.7%, n=3, p<0.01), suggesting a preferential homing of MMSC to the marrow microenvironment. Interestingly, whereas only 29.9%±1.4% of CD38+CD138- cells expressed CD166 prior to injection, 84.1%±10.8% of BM-homed H929-GFP CD38+CD138- cells expressed CD166 (n=3, p<0.01), suggesting that CD166 plays a critical role in directing homing of MM cells to the BM. Next, CD166 expression on H929-GFP cells was knocked down (KD) with shRNA in order to examine if reduced CD166 expression inhibit the homing of MM cells to the BM. The number of BM-homed GFP cells was significantly decreased for CD166KD cells (5658±904, n=6) compared to mock control (8551±848, n=6; p<0.05). Interestingly, cells in which suppression of CD166 expression was not achieved with shRNA homed preferentially to the BM (4.3%±0.3% CD166+cells in CD166 KD H929-GFP before injection versus 29.3%±3.6% in BM-homed GFP cells). Then we compared the progression of MM in NSG mice initiated with mock control or CD166 KD H929-GFP cells. Disease progression in mice receiving control cells was more rapid compared to that in mice receiving CD166KD cells as evidenced by serum levels of human IgA (kappa) at 4 weeks posttransplantation (240.5±67.1ng/ml versus 45.1±33.0ng/ml, n=3; p<0.05). We next examined the potential role of CD166 in osteolytic lesions using a novel Ex Vivo Organ Culture Assay (EVOCA) in which MM cells are co-cultured over calvariae from 10d-old pups for 7 days creating an in vitro 3D system for the interaction of MM cells with bone microenvironment. Data from EVOCA with H929 cells showed that bone osteolytic lesions are substantially reduced when CD166 is absent on either MM (CD166- fraction) or osteoblast lineage cells (calvariae from CD166-/- mice). Furthermore, co-culturing CD166+ or CD166- H929 cells with bone marrow stromal cells (BMSC) from WT or CD166-/- mice revealed that mRNA levels of receptor activator of NF-κB ligand (RANKL) are decreased when CD166 is absent on either MM or stromal cells while mRNA levels of osteoprotegerin (OPG), an important inhibitor of osteoclastogenesis, are not altered. This resulted in decreased RANKL/OPG ratios in cultures containing a CD166- component suggesting reduced MM-induced osteoclastogenesis in the absence of CD166. Interestingly, levels of M-CSF and IL-6 were similar in all these cultures suggesting that loss of CD166 may mediate suppression of osteolytic lesions through the downregulation of RANKL. Together, these results suggest that CD166 plays an important role in homing and retention of MM cells in the BM and promotes MM disease progression as well as bone-lytic disease and that CD166 may serve as a therapeutic target in the treatment of MM.
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    A Single Radioprotective Dose of Prostaglandin E2 Blocks Irradiation-Induced Apoptotic Signaling and Early Cycling of Hematopoietic Stem Cells
    (Elsevier, 2020-07-30) Patterson, Andrea M.; Liu, Liqiong; Sampson, Carol H.; Plett, P. Artur; Li, Hongge; Singh, Pratibha; Mohammad, Khalid S.; Hoggatt, Jonathan; Capitano, Maegan L.; Orschell, Christie M.; Pelus, Louis M.; Medicine, School of Medicine
    Ionizing radiation exposure results in acute and delayed bone marrow suppression. Treatment of mice with 16,16-dimethyl prostaglandin E2 (dmPGE2) prior to lethal ionizing radiation (IR) facilitates survival, but the cellular and molecular mechanisms are unclear. In this study we show that dmPGE2 attenuates loss and enhances recovery of bone marrow cellularity, corresponding to a less severe hematopoietic stem cell nadir, and significantly preserves long-term repopulation capacity and progenitor cell function. Mechanistically, dmPGE2 suppressed hematopoietic stem cell (HSC) proliferation through 24 h post IR, which correlated with fewer DNA double-strand breaks and attenuation of apoptosis, mitochondrial compromise, oxidative stress, and senescence. RNA sequencing of HSCs at 1 h and 24 h post IR identified a predominant interference with IR-induced p53-downstream gene expression at 1 h, and confirmed the suppression of IR-induced cell-cycle genes at 24 h. These data identify mechanisms of dmPGE2 radioprotection and its potential role as a medical countermeasure against radiation exposure.
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    Survivin is Required for Mouse and Human Bone Marrow Mesenchymal Stromal Cell Function
    (Wiley, 2017) Singh, Pratibha; Fukuda, Seiji; Liu, Liqiong; Chitteti, Brahmananda Reddy; Pelus, Louis M.; Microbiology and Immunology, School of Medicine
    Although mesenchymal stromal cells (MSCs) have significant potential in cell-based therapies, little is known about the factors that regulate their functions. While exploring regulatory molecules potentially involved in MSC activities, we found that the endogenous multifunctional factor Survivin is essential for MSC survival, expansion, lineage commitment, and migration. Pharmacological or genetic blockade of Survivin expression in mouse and human bone marrow MSC enhances caspase 3 and 7 expression and reduces proliferation resulting in fewer MSC and clonogenic colony-forming unit-fibroblasts (CFU-F), whereas ectopic Survivin overexpression in MSC results in their expansion. Survivin is also required for the MSC proliferative responses to basic fibroblast growth factor and platelet derived growth factor. In a wound healing model, Survivin inhibition results in suppression of MSC migration to the wound site. In addition, loss of Survivin in MSCs compromises their hematopoiesis-supporting capacity. These results demonstrate that Survivin is a key regulator of mouse and human MSC function, and suggest that targeted modulation of Survivin in MSCs may have clinical utility to enhance MSC recovery and activity following insult or stress.