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Cell Cycle Related Differentiation of Bone Marrow Cells into Lung Cells

Description: Green-fluorescent protein (GFP) labeled marrow cells transplanted into lethally irradiated mice can be detected in the lungs of transplanted mice and have been shown to express lung specific proteins while lacking the expression of hematopoietic markers. We have studied marrow cells induced to transit cell cycle by exposure to IL-3, IL-6, IL-11 and steel factor at different times of culture corresponding to different phases of cell cycle. We have found that marrow cells at the G1/S interface have a 3-fold increase in cells which assume a lung phenotype and that this increase is no longer seen in late S/G2. These cells have been characterized as GFP{sup +} CD45{sup -} and GFP{sup +} cytokeratin{sup +}. Thus marrow cells with the capacity to convert into cells with a lung phenotype after transplantation show a reversible increase with cytokine induced cell cycle transit. Previous studies have shown the phenotype of bone marrow stem cells fluctuates reversibly as these cells traverse cell cycle, leading to a continuum model of stem cell regulation. The present studies indicate that marrow stem cell production of nonhematopoietic cells also fluctuates on a continuum.
Date: December 31, 2007
Creator: Dooner, Mark; Aliotta, Jason M.; Pimental, Jeffrey; Dooner, Gerri J.; Abedi, Mehrdad; Colvin, Gerald et al.
Partner: UNT Libraries Government Documents Department

Targeted Gene Deletion Demonstrates that Cell Adhesion MoleculeICAM-4 is Critical for Erythroblastic Island Formation

Description: Erythroid progenitors differentiate in erythroblastic islands, bone marrow niches composed of erythroblasts surrounding a central macrophage. Evidence suggests that within islands adhesive interactions regulate erythropoiesis and apoptosis. We are exploring whether erythroid intercellular adhesion molecule-4 (ICAM-4), animmunoglobulin superfamily member, participates in island formation. Earlier, we identified alpha V integrins as ICAM-4 counter receptors. Since macrophages express alpha V, ICAM-4 potentially mediates island attachments. To test this, we generated ICAM-4 knockout mice and developed quantitative, live cell techniques for harvesting intact islands and for reforming islands in vitro. We observed a 47 percent decrease in islands reconstituted from ICAM-4 null marrow compared to wild type. We also found a striking decrease in islands formed in vivo in knockout mice. Further, peptides that block ICAM-4 alpha V adhesion produced a 53-57 percent decrease in reconstituted islands, strongly suggesting that ICAM-4 binding to macrophage alpha V functions in island integrity. Importantly, we documented that alpha V integrin is expressed in macrophages isolated from erythro blastic islands. Collectively, these data provide convincing evidence that ICAM-4 is critical in erythroblastic island formation via ICAM-4/alpha V adhesion and also demonstrate that the novel experimental strategies we developed will be valuable in exploring molecular mechanisms of erythroblastic island formation and their functional role in regulating erythropoiesis.
Date: February 15, 2006
Creator: Lee, Gloria; Lo, Annie; Short, Sarah A.; Mankelow, Tosti J.; Spring, Frances; Parsons, Stephen F. et al.
Partner: UNT Libraries Government Documents Department

Hereditary Spherocytosis and Hereditary Elliptocytosis: Aberrant Protein Sorting during Erythroblast Enucleation

Description: During erythroblast enucleation, membrane proteins distribute between extruded nuclei and reticulocytes. In hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), deficiencies of membrane proteins, in addition to those encoded by the mutant gene, occur. Elliptocytes, resulting from protein 4.1R gene mutations, lack not only 4.1R but also glycophorin C, which links the cytoskeleton and bilayer. In HS resulting from ankyrin-1 mutations, band 3, Rh-associated antigen, and glycophorin A are deficient. The current study was undertaken to explore whether aberrant protein sorting, during enucleation, creates these membrane-spanning protein deficiencies. We found that although glycophorin C sorts to reticulocytes normally, it distributes to nuclei in 4.1R-deficient HE cells. Further, glycophorin A and Rh-associated antigen, which normally partition predominantly to reticulocytes, distribute to both nuclei and reticulocytes in an ankyrin-1-deficient murine model of HS. We conclude that aberrant protein sorting is one mechanistic basis for protein deficiencies in HE and HS.
Date: February 8, 2010
Creator: Salomao, Marcela; Chen, Ke; Villalobos, Jonathan; Mohandas, Narla; An, Xiuli & Chasis, Joel Anne
Partner: UNT Libraries Government Documents Department

Studies with Colloids Containing Radioisotopes of Yttrium, Zirconium, Columbium, and Lanthanum: 1. The Chemical Principles and Methods Involved in Preparation of Colloids of Yttrium, Zirconium, Columbium, and Lanthanum

Description: For a number of investigations, including fundamental studies of radiation effects on living tissues and therapeutic utilization of radioisotopes, it is valuable to have methods for the selective localization of radioisotopes in certain tissues. Finely dispersed anhydrous chromic phosphate has been found useful by Jones, Wrobel, and Lyons in selectively irradiating the liver and spleen with p{sup 32} beta particles. The present studies, reported in this and the following communication, are concerned with methods for controlled selective localization of colloids (incorporating radioisotopes) in the liver, spleen, or bone marrow, and with an analysis of some of the factors involved in the phenomenon of localization.
Date: April 21, 1948
Creator: Gofman, John W.
Partner: UNT Libraries Government Documents Department

Erythroblastic Islands: Specialized Mircoenvironmental Niches forErythropoiesis

Description: This review focuses on current understanding of molecular mechanisms operating within erythroblastic islands including cell-cell adhesion, regulatory feedback, and central macrophage function. RECENT FINDINGS: Erythroblasts express a variety of adhesion molecules and recently two interactions have been identified that appear to be critical for island integrity. Erythroblast macrophage protein, expressed on erythroblasts and macrophages, mediates cell-cell attachments via homophilic binding. Erythroblast intercellular adhesion molecule-4 links erythroblasts to macrophages through interaction with macrophage alphav integrin. In intercellular adhesion molecule-4 knockout mice, erythroblastic islands are markedly reduced, whereas the erythroblast macrophage protein null phenotype is severely anemic and embryonic lethal. Retinoblastoma tumor suppressor (Rb) protein stimulates macrophage differentiation by counteracting inhibition of Id2 on PU.1, a transcription factor that is a crucial regulator of macrophage differentiation. Rb-deficient macrophages do not bind Rb null erythroblasts and the Rb null phenotype is anemic and embryonic lethal. Lastly, extruded nuclei rapidly expose phosphatidylserine on their surface, providing a recognition signal similar to apoptotic cells. SUMMARY: Although understanding of molecular mechanisms operating within islands is at an early stage, tantalizing evidence suggests that erythroblastic islands are specialized niches where intercellular interactions in concert with cytokines play critical roles in regulating erythropoiesis.
Date: January 6, 2006
Creator: Chasis, Joel Anne
Partner: UNT Libraries Government Documents Department

Alternative pre-mRNA splicing switches modulate gene expression in late erythropoiesis

Description: Differentiating erythroid cells execute a unique gene expression program that insures synthesis of the appropriate proteome at each stage of maturation. Standard expression microarrays provide important insight into erythroid gene expression but cannot detect qualitative changes in transcript structure, mediated by RNA processing, that alter structure and function of encoded proteins. We analyzed stage-specific changes in the late erythroid transcriptome via use of high-resolution microarrays that detect altered expression of individual exons. Ten differentiation-associated changes in erythroblast splicing patterns were identified, including the previously known activation of protein 4.1R exon 16 splicing. Six new alternative splicing switches involving enhanced inclusion of internal cassette exons were discovered, as well as 3 changes in use of alternative first exons. All of these erythroid stage-specific splicing events represent activated inclusion of authentic annotated exons, suggesting they represent an active regulatory process rather than a general loss of splicing fidelity. The observation that 3 of the regulated transcripts encode RNA binding proteins (SNRP70, HNRPLL, MBNL2) may indicate significant changes in the RNA processing machinery of late erythroblasts. Together, these results support the existence of a regulated alternative pre-mRNA splicing program that is critical for late erythroid differentiation.
Date: February 3, 2009
Creator: Yamamoto, Miki L.; Clark, Tyson A.; Gee, Sherry L.; Kang, Jeong-Ah; Schweitzer, Anthony C.; Wickrema, Amittha et al.
Partner: UNT Libraries Government Documents Department

The control of polycythemia by marrow inhibition

Description: Experimental use of sodium radiophosphate (P32)in treatment of polycythemia is described. Treatment history is 66 patients treated with P32 alone, 32 patients treated with P32 followed within 4 months by venesections, 21 patients treated with P32 followed more than 4 months later by venesections, 6 patients treated exclusively by venesections, and 9 patients treated and followed elsewhere.
Date: August 9, 1949
Creator: Lawrence, J.H.
Partner: UNT Libraries Government Documents Department

The Implications of Cost-Effectiveness Analysis of Medical Technology: Background Paper 2: Case Studies of Medical Technologies: Case Study 6: The Cost Effectiveness of Bone Marrow Transplant Therapy and Its Policy Implications

Description: A case study by the Office of Technology Assessment (OTA) that focuses on bone marrow transplantation "presents both a critical analysis of the technology itself and policy options that would strengthen control over the rate of technological diffusion" (p. 3).
Date: May 1981
Creator: United States. Congress. Office of Technology Assessment.
Partner: UNT Libraries Government Documents Department

Bone Marrow Transplants: Despite Recruitment Successes, National Program May Be Underutilized

Description: A letter report issued by the General Accounting Office with an abstract that begins "More than 30,000 people are diagnosed annually with leukemia or other blood, metabolic, or immune system disorders, many of whom may die without stem cell transplants, using stem cells from bone marrow or another source. When a patient needs a transplant of donated stem cells and no genetically compatible related donor is available, the National Bone Marrow Donor Registry may help the patient search for compatible stem cells from unrelated donors. The National Bone Marrow Registry Reauthorization Act of 1998 required, among other things, that the Registry carry out a donor recruitment program giving priority to minority and underrepresented donor populations, ensure efficiency of operations, and verify compliance with standards by organizations that participate in the Registry. From 1998, when the National Bone Marrow Registry Reauthorization Act was enacted, through 2001, the number of stem cell donors on the Registry increased for all racial and ethnic groups. Although the exact number of patients in need of transplants is not known, estimates suggest that about one-third of them use the Registry to search for donors. The organizations that are involved in transplantation and participate in the National Marrow Donor Program (NMDP) network generally adhere to NMDP's standards and procedures. In 2001, NMDP required 24 centers to take corrective actions because they did not meet its standards."
Date: October 18, 2002
Creator: United States. General Accounting Office.
Partner: UNT Libraries Government Documents Department

Studies of Liver Function in Experimental Animals With Special Reference to Radiation and Metal Exposure

Description: Report discussing experiments investigating the effects of radiation and metal toxicity on the function of the liver, kidneys, adrenals, and bone marrow of experimental animals.
Date: July 31, 1947
Creator: Schwartz, Samuel.; Schneider, Lorraine; Porter, Lillie Mae; Tinsley, Mary & Wallace, Jean
Partner: UNT Libraries Government Documents Department

Novel secreted isoform of adhesion molecule ICAM-4: Potential regulator of membrane-associated ICAM-4 interactions

Description: ICAM-4, a newly characterized adhesion molecule, is expressed early in human erythropoiesis and functions as a ligand for binding a4b1 and aV integrin-expressing cells. Within the bone marrow, erythroblasts surround central macrophages forming erythroblastic islands. Evidence suggests that these islands are highly specialized subcompartments where cell adhesion events, in concert with cytokines, play critical roles in regulating erythropoiesis and apoptosis. Since erythroblasts express a4b1 and ICAM-4 and macrophages exhibit aV, ICAM-4 is an attractive candidate for mediating cellular interactions within erythroblastic islands. To determine whether ICAM-4 binding properties are conserved across species, we first cloned and sequenced the murine homologue. The translated amino acid sequence showed 68 percent overall identity with human ICAM-4. Using recombinant murine ICAM-4 extracellular domains, we discovered that hematopoietic a4b1-expressing HEL cells and non-hematopoietic aV-expressing FLY cells adhered to mouse ICAM-4. Cell adhesion studies showed that FLY and HEL cells bound to mouse and human proteins with similar avidity. These data strongly suggest conservation of integrin-binding properties across species. Importantly, we characterized a novel second splice cDNA that would be predicted to encode an ICAM-4 isoform, lacking the membrane-spanning domain. Erythroblasts express both isoforms of ICAM-4. COS-7 cells transfected with GFP constructs of prototypic or novel ICAM-4 cDNA showed different cellular localization patterns. Moreover, analysis of tissue culture medium revealed that the novel ICAM-4 cDNA encodes a secreted protein. We postulate that secretion of this newly described isoform, ICAM-4S, may modulate binding of membrane-associated ICAM-4 and could thus play a critical regulatory role in erythroblast molecular attachments.
Date: February 18, 2003
Creator: Lee, Gloria; Spring, Frances A.; Parons, Stephen F.; Mankelow, Tosti J.; Peters, Luanne L.; Koury, Mark J. et al.
Partner: UNT Libraries Government Documents Department

Chromatin condensation in terminally differentiating mouse erythroblasts does not involve special architectural proteins but depends on histone deacetylation

Description: Terminal erythroid differentiation in vertebrates is characterized by progressive heterochromatin formation, chromatin condensation and, in mammals, culminates in nuclear extrusion. To date, although mechanisms regulating avian erythroid chromatin condensation have been identified, little is known regarding this process during mammalian erythropoiesis. To elucidate the molecular basis for mammalian erythroblast chromatin condensation, we used Friend virus-infected murine spleen erythroblasts that undergo terminal differentiation in vitro. Chromatin isolated from early and late stage erythroblasts had similar levels of linker and core histones, only a slight difference in nucleosome repeats, and no significant accumulation of known developmentally-regulated architectural chromatin proteins. However, histone H3(K9) dimethylation markedly increased while histone H4(K12) acetylation dramatically decreased and became segregated from the histone methylation as chromatin condensed. One histone deacetylase, HDAC5, was significantly upregulated during the terminal stages of Friend virus-infected erythroblast differentiation. Treatment with histone deacetylase inhibitor, trichostatin A, blocked both chromatin condensation and nuclear extrusion. Based on our data, we propose a model for a unique mechanism in which extensive histone deacetylation at pericentromeric heterochromatin mediates heterochromatin condensation in vertebrate erythroblasts that would otherwise be mediated by developmentally-regulated architectural proteins in nucleated blood cells.
Date: August 21, 2008
Creator: Popova, Evgenya Y.; Krauss, Sharon Wald; Short, Sarah A.; Lee, Gloria; Villalobos, Jonathan; Etzell, Joan et al.
Partner: UNT Libraries Government Documents Department

{sup 188}Rhenium-HEDP in the Treatment of Pain in Bone Metastases

Description: Systemic use of radiopharmaceuticals is a recognized alternative method for the treatment of pain in patients with multiple bone metastasis. A new option, {sup 188}Re-HEDP is proposed, using generator-obtained {sup 188}Rhenium ({beta} energy = 2.1 MeV, {gamma} energy = 155 keV, half-life = 16.9 hours). After establishing parameters of biodistribution, dosimetry and image acquisition in mice, rats and rabbits, Phase I and II studies were conducted on 12 patients with multiple metastasis from carcinomas, with pain surpassing other analgesic options. More than 50% pain relief was found in 91% of the patients, with total relief during a variable period in 41% of them allowing opiate and other analgesic drugs to be decreased or withdrawn, and showing a lower bone marrow contribution to total absorbed dose than that reported for other similar radiopharmaceuticals. Further study of this option is recommended in order to determine higher dose protocols without toxic bone marrow reaction possibilities.
Date: January 18, 1999
Creator: Gaudiano, J.; Savio, E.; Robles, A.; Muniz, S.; Leon, A.; Verdera, S. et al.
Partner: UNT Libraries Government Documents Department

Studies with Colloids Containing Radioisotopes of Yttrium, Zirconium, Columbium and Lanthaum: 2. The Controlled Selective Localization of Radioisotopes of Yttrium, Zirconium, Columbium in the Bone Marrow, Liver and Spleen

Description: Several workers have shown that certain colloidally dispered materials are removed from the blood stream by the liver and spleen. Jones, Wrobel, and Lyons have utilized suspensions of anhydrous chromic phosphate for the selective irradiation of the liver and spleen with p{sup 32} beta particles. Gersh demonstrated that colloidal calcium phosphate is taken up by the liver and spleen. He stressed the failure of bone marrow phagocytes to take up this colloid in rats and dogs (though he referred to possible uptake in the marrow of rabbits under special conditions), and commented on the relative 'refractoriness' in general of the bono marrow as compared with liver and spleen with respect to the uptake of colloidal dyes from the blood stream. Some histological data indicate that 'Thorotrast' (a colloidal thorium dioxide preparation) is deposited in the bone marrow as well as in the liver and spleen, but no quantitative data as to the relative distribution are available. In the preceding communication the methods for the preparation of colloids incorporating radioisotopes of yttrium, columbium, and zirconium were given. The present studies are concerned with the localization of such colloids primarily in the bone marrow or primarily in the spleen and liver, with an analysis of some of the factors which may be responsible for differences in localization.
Date: April 21, 1948
Creator: Dobson, E.L.; Gofman, J.W.; Jones, H.B.; Kelly, Lola S. & Walker, L.
Partner: UNT Libraries Government Documents Department

Is Increased Low-dose somatic Radiosensitivity Associated with Increased Transgenerational Germline Mutation

Description: Using single-molecule polymerase chain reaction, the frequency of spontaneous and radiation-induced mutation at an expanded simple tandem repeat (ESTR) locus was studied in DNA samples extracted from sperm and bone marrow of Atm knockout (Atm+/–) heterozygous male mice. The frequency of spontaneous mutation in sperm and bone marrow in Atm+/– males did not significantly differ from that in wild-type BALB/c mice. Acute gamma-ray exposure did not affect ESTR mutation frequency in bone marrow and resulted in similar increases in sperm samples taken from Atm+/– and BALB/c males. Taken together, these results suggest that the Atm haploinsufficiency analyzed in our study does not affect spontaneous and radiation-induced ESTR mutation frequency in mice.
Date: October 2, 2008
Creator: Brenner, David J.
Partner: UNT Libraries Government Documents Department

PATHOGENESIS AND REGENERATION OF RADIATION INDUCED BONE MARROW INJURY, AND THERAPEUTIC IMPLICATIONS

Description: The hematological data of patients of 4 radiation accidents, Rongelap 1954, Oak Ridge 1958, Vinca 1958, and Lockport 1960, are reviewed and compared. The blood cell curves appear to show three phases. An initial phase at about 8 to 10 days, a phase of transient or abortive regenerations, and a phase of final effective recovery were demonstrated. These phases in the blood are preceded and caused by particular events in the bone marrow. Evidence was brought forward that transient rises in leukocytes and reticulocytes associated with a delayed platelet disappearance curve are associated with a marrow capable of spontaneous recovery. In patients with inhomogenous total--body irradiation, the transient rise may iead directly to effective recovery. Immediate decline of all blood cell elements without evidence of further, even abortive attempts of marrow regeneration must be considered as evidence for a iethal bone marrow dose and extremeiy serious complications may be expected. The clinical implications of these analyses are outlined and the diagnostic possibilities described. (auth)
Date: January 1, 1962
Creator: Fliedner, T.M.; Cronkite, E.P. & Bond, V.P.
Partner: UNT Libraries Government Documents Department