Browsing by Subject "Bone Marrow"
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Item Open Access Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans.(PloS one, 2017-01) Yan, Qin; Ahn, Sun Hee; Medie, Felix Mba; Sharma-Kuinkel, Batu K; Park, Lawrence P; Scott, William K; Deshmukh, Hitesh; Tsalik, Ephraim L; Cyr, Derek D; Woods, Christopher W; Yu, Chen-Hsin Albert; Adams, Carlton; Qi, Robert; Hansen, Brenda; Fowler, Vance GWe previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.Item Open Access Characterizing the role of the immune microenvironment in multiple myeloma progression at a single-cell level.(Blood advances, 2022-11) Schinke, Carolina; Poos, Alexandra M; Bauer, Michael; John, Lukas; Johnson, Sarah; Deshpande, Shayu; Carrillo, Luis; Alapat, Daisy; Rasche, Leo; Thanendrarajan, Sharmilan; Zangari, Maurizio; Al Hadidi, Samer; van Rhee, Frits; Davies, Faith; Raab, Marc S; Morgan, Gareth; Weinhold, NielsEarly alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could be the key to identifying novel therapeutic approaches. However, the intrinsic variability in cellular populations between patients and the differences in sample processing and analysis methods have made it difficult to identify consistent changes between data sets. Here, we used single-cell RNA sequencing of bone marrow cells from precursor stages, monoclonal gammopathy of unknown significance, smoldering MM, and newly diagnosed MM and analyzed our data in combination with a previously published data set that used a similar patient population and sample processing. Despite the vast interpatient heterogeneity, some alterations were consistently observed in both data sets. We identified changes in immune cell populations as the disease progressed, which were characterized by a substantial decrease in memory and naïve CD4 T cells, and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of nonclonal memory B cells and an increase in CD14 and CD16 monocytes in MM compared with its precursor stages. These results provide crucial information on the immune changes associated with the progression to clinical MM and can help to develop immune-based strategies for patient stratification and early therapeutic intervention.Item Open Access Early hematopoiesis inhibition under chronic radiation exposure in humans.(Radiat Environ Biophys, 2010-05) Akleyev, Alexander V; Akushevich, Igor V; Dimov, Georgy P; Veremeyeva, Galina A; Varfolomeyeva, Tatyana A; Ukraintseva, Svetlana V; Yashin, Anatoly IThe major goal of this study was to identify and quantitatively describe the association between the characteristics of chronic (low-dose rate) exposure to (low LET) ionizing radiation and cellularity of peripheral blood cell lines. About 3,200 hemograms (i.e., spectra of blood counts) obtained over the years of maximal exposure to ionizing radiation (1950-1956) for inhabitants of the Techa River were used in analyses. The mean cumulative red bone marrow dose (with standard errors), calculated using Techa River Dosimetry System-2000, was 333.6 +/- 4.6 mGy (SD = 259.9 mGy, max = 1151 mGy) to the year 1956. The statistical approach included both empirical methods for estimating frequencies of cytopenic states of the investigated blood cell lines (e.g. neutrophile, platelets, erythrocyte, etc.), and regression methods, including generalized linear models and logistic regressions which allowed taking into account confounding factors (e.g., attained age, age at maximal exposure, presence of concomitant diseases, and demographic characteristics). The results of the analyses demonstrated hematopoiesis inhibition manifested by a decrease in peripheral blood cellularity and an increase in the frequency of cytopenia in all blood cell lines (leukocytes, including lymphocytes, monocytes, neutrophiles, as well as platelets and erythrocytes). The intensity of hematopoiesis inhibition in the period of maximal exposures is determined by the combined influence of the dose rate and cumulative dose. The contribution of specific confounding factors was quantified and shown to be much less important than dose characteristics. The best predictor among dose characteristics was identified for each blood cell line. A 2-fold increase in dose rate is assumed to be a characteristic of radiosensitivity and a quantitative characteristic of the effect.Item Open Access Early hematopoietic effects of chronic radiation exposure in humans.(Health Phys, 2010-09) Akleyev, Alexander V; Akushevich, Igor V; Dimov, Georgy P; Veremeyeva, Galina A; Varfolomeyeva, Tatyana A; Ukraintseva, Svetlana V; Yashin, Anatoly IThe major goal of this study is to investigate and quantitatively describe the nature of the relationship between the characteristics of chronic exposure to ionizing radiation and specific patterns of hematopoiesis reduction. The study is based on about 3,200 hemograms taken for inhabitants of the Techa riverside villages over the years 1951-1956, i.e., the period characterized by a gradual decrease in dose rates. The mean cumulative red bone marrow dose was 333.6 + or - 4.6 mGy. The approach to statistical analyses involved both empirical methods and modeling (generalized linear models and logistic regressions). The results of the analyses highlighted a gradual increase in the frequency of cytopenias with dose rate. The impact of exposure on hematopoiesis reduction patterns was found to be more substantial than that of age and health status. Dose rates resulting in a two-fold increase in the frequency of cytopenias have been estimated.Item Open Access Epidermal growth factor regulates hematopoietic regeneration after radiation injury.(Nat Med, 2013-03) Doan, Phuong L; Himburg, Heather A; Helms, Katherine; Russell, J Lauren; Fixsen, Emma; Quarmyne, Mamle; Harris, Jeffrey R; Deoliviera, Divino; Sullivan, Julie M; Chao, Nelson J; Kirsch, David G; Chute, John PThe mechanisms that regulate hematopoietic stem cell (HSC) regeneration after myelosuppressive injury are not well understood. We identified epidermal growth factor (EGF) to be highly enriched in the bone marrow serum of mice bearing deletion of Bak and Bax in TIE2-expressing cells in Tie2Cre; Bak1(-/-); Bax(flox/-) mice. These mice showed radioprotection of the HSC pool and 100% survival after a lethal dose of total-body irradiation (TBI). Bone marrow HSCs from wild-type mice expressed functional EGF receptor (EGFR), and systemic administration of EGF promoted the recovery of the HSC pool in vivo and improved the survival of mice after TBI. Conversely, administration of erlotinib, an EGFR antagonist, decreased both HSC regeneration and the survival of mice after TBI. Mice with EGFR deficiency in VAV-expressing hematopoietic cells also had delayed recovery of bone marrow stem and progenitor cells after TBI. Mechanistically, EGF reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the proapoptotic protein PUMA. Our findings show that EGFR signaling regulates HSC regeneration after myelosuppressive injury.Item Open Access Polyethylene Glycol-conjugated L-asparaginase versus native L-asparaginase in combination with standard agents for children with acute lymphoblastic leukemia in second bone marrow relapse: a Children's Oncology Group Study (POG 8866).(Journal of pediatric hematology/oncology, 2011-12) Kurtzberg, Joanne; Asselin, Barbara; Bernstein, Mark; Buchanan, George R; Pollock, Brad H; Camitta, Bruce MBackground
Administration of L-asparaginase is limited by hypersensitivity reactions mediated by anti-asparaginase antibodies. To overcome this problem, native Escherichia coli L-asparaginase was conjugated to polyethylene glycol (PEG) to formulate PEG-L-asparaginase, a preparation with decreased immunogenicity and increased circulating half-life. In early trials, PEG-L-asparaginase was tolerated by patients known to be hypersensitive to the native E. coli product.Methods
The Pediatric Oncology Group conducted a phase II, randomized trial to compare the efficacy and toxicity of PEG-L-asparaginase compared with native E. coli asparaginase in children with acute lymphoblastic leukemia in second bone marrow relapse. All patients (n=76) received standard doses of vincristine and prednisone. Nonhypersensitive patients (n=34) were randomized to receive either PEG-L-asparaginase of 2500 IU/m/dose intramuscularly on days 1 and 15 (treatment I) or native E. coli asparaginase of 10,000 IU/m/dose intramuscularly on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 (treatment II). Patients with a clinical history of an allergic reaction to unmodified asparaginase were directly assigned to treatment with PEG-L-asparaginase (n=42). Asparaginase levels and anti-asparaginase antibody titers were monitored in all patients. Response and toxicity were scored using conventional criteria.Results
The complete response rate for the total study population was 41%. There was no difference in complete response between patients randomized to PEG (47%) and native asparaginase (41%). PEG was well tolerated even in patients with prior allergic reactions to native asparaginase. PEG half-life was shorter in patients with prior allergy.Conclusions
PEG asparaginase is a useful agent in patients with allergic reactions to native asparaginase.Item Open Access Semi-quantitative MRI biomarkers of knee osteoarthritis progression in the FNIH biomarkers consortium cohort - Methodologic aspects and definition of change.(BMC musculoskeletal disorders, 2016-11-10) Roemer, Frank W; Guermazi, Ali; Collins, Jamie E; Losina, Elena; Nevitt, Michael C; Lynch, John A; Katz, Jeffrey N; Kwoh, C Kent; Kraus, Virginia B; Hunter, David JTo describe the scoring methodology and MRI assessments used to evaluate the cross-sectional features observed in cases and controls, to define change over time for different MRI features, and to report the extent of changes over a 24-month period in the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium study nested within the larger Osteoarthritis Initiative (OAI) Study.We conducted a nested case-control study. Cases (n = 406) were knees having both radiographic and pain progression. Controls (n = 194) were knee osteoarthritis subjects who did not meet the case definition. Groups were matched for Kellgren-Lawrence grade and body mass index. MRIs were acquired using 3 T MRI systems and assessed using the semi-quantitative MOAKS system. MRIs were read at baseline and 24 months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. We provide the definition and distribution of change in these biomarkers over time.Seventy-three percent of the cases had subregions with BML worsening (vs. 66 % in controls) (p = 0.102). Little change in osteophytes was seen over 24 months. Twenty-eight percent of cases and 10 % of controls had worsening in meniscal scores in at least one subregion (p < 0.001). Seventy-three percent of cases and 53 % of controls had at least one area with worsening in cartilage surface area (p < 0.001). More cases experienced worsening in Hoffa- and effusion synovitis than controls (17 % vs. 6 % (p < 0.001); 41 % vs. 18 % (p < 0.001), respectively).A wide range of MRI-detected structural pathologies was present in the FNIH cohort. More severe changes, especially for BMLs, cartilage and meniscal damage, were detected primarily among the case group suggesting that early changes in multiple structural domains are associated with radiographic worsening and symptomatic progression.