bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ibandronate Reduces Osteolytic Lesions but not Tumor Burden in a Murine Model of Myeloma Bone Disease
Authors: Dallas Sarah L. , Garrett I. Ross , Oyajobi Babatunde O. , Dallas Mark R. , Boyce Brendan F. , Bauss Frieder , Radl Jiri , Mundy Gregory R. 
Published: October 2019

AbstractWe determined the effects of the potent bisphosphonate ibandronate in a murine model of human myeloma bone disease. In this model, bone lesions typical of the human disease develop in mice following inoculation of myeloma cells via the tail vein. Treatment with ibandronate (4 μg per mouse per day) significantly reduced the occurrence of osteolytic bone lesions in myeloma-bearing mice. However, ibandronate did not prevent the mice from developing hindlimb paralysis and did not produce a detectable effect on survival. There was no significant effect of ibandronate on total myeloma cell burden, as assessed by morphometric measurements of myeloma cells in the bone marrow, liver, and spleen, or by measurement of serum IgG2b levels. These results support clinical findings that bisphosphonates may be useful for the treatment of myeloma-associated bone destruction, but suggest that other therapies are also required to reduce tumor growth.
Increased Risk of Chronic Graft-Versus-Host Disease, Obstructive Bronchiolitis, and Alopecia With Busulfan Versus Total Body Irradiation: Long-Term Results of a Randomized Trial in Allogeneic Marrow Recipients With Leukemia
Authors: Ringdén O. , Remberger M. , Ruutu T. , Nikoskelainen J. , Volin L. , Vindeløv L. , Parkkali T. , Lenhoff S. , Sallerfors B. , Mellander L. , Ljungman P. , Jacobsen N. 
Published: October 2019

Abstract
Leukemic patients receiving marrow from HLA-identical sibling donors were randomized to treatment with either busulfan 16 mg/kg (n = 88) or total body irradiation ([TBI] n = 79) in addition to cyclophosphamide 120 mg/kg. The patients were observed for a period of 5 to 9 years. Busulfan-treated patients had an increased risk of veno-occlusive disease (VOD) of the liver (12% v 1%,P = .01) and hemorrhagic cystitis (32% v 10%,P = .003). Acute graft-versus-host disease (GVHD) was similar in the two groups, but the 7-year cumulative incidence of chronic GVHD was 59% in the busulfan-treated group versus 47% in the TBI group (P = .05). Death from GVHD was more common in the busulfan group (22% v 3%, P &lt; .001). Obstructive bronchiolitis occurred in 26% of the busulfan patients but in only 5% of the TBI patients (P &lt; .01). Complete alopecia developed in 8 busulfan patients and partial alopecia in 17, versus five with partial alopecia in the TBI group (P &lt; .001). Cataracts occurred in 5 busulfan-treated patients and 16 TBI patients (P = .02). The incidence of relapse after 7 years was 29% in both groups. Seven-year transplant-related mortality (TRM) in patients with early disease was 21% in the busulfan group and 12% in the TBI group. In patients with more advanced disease, the corresponding figures were 64% and 22%, respectively (P = .004). Leukemia-free survival (LFS) in patients with early disease was 68% in busulfan-treated patients and 66% in TBI patients. However, 7-year LFS in patients with more advanced disease was 17% in the busulfan group versus 49% in the TBI group (P &lt; .01). In patients with chronic myeloid leukemia (CML) in first chronic phase, 7-year LFS was 72% and 83% in the two groups, respectively.
Association of the Platelet Glycoprotein Ia C807T Gene Polymorphism With Nonfatal Myocardial Infarction in Younger Patients
Authors: Santoso S. , Kunicki T.J. , Kroll H. , Haberbosch W. , Gardemann A. 
Published: October 2019

Abstract
Recently, we have shown that two alleles of the glycoprotein (GP) Ia gene, designated C807 and T807, are associated with low or high platelet GPIa-IIa density and consequently with slower or faster rate of platelet adhesion to type I collagen, respectively. This polymorphism could therefore present a genetic predisposition for the development of thrombotic disease and hemostasis. We investigated the relationship of the GPIa C807T dimorphism to the risk of coronary artery disease (CAD) and myocardial infarction (MI). An allele-specific polymerase chain reaction (PCR) was developed for genotyping of C807T polymorphism. DNA samples from 2237 male patients who underwent coronary angiography on account of coronary heart disease as verified illness or presumptive diagnosis were genotyped. The odds ratio was calculated as an estimate of the relative risk by multiple logistic regression. We found a strong association between the T allele and nonfatal MI among individuals younger than the mean age of 62 years (n = 1,057; odds ratio, 1.57; P = .004). The odds ratio of MI increased for T807 carriers with decreasing age. The highest odds ratio was detected within the youngest 10% of the study sample (&lt;49 years; n = 223; odds ratio, 2.61; P = .009). In contrast, no evidence of an association between C807T dimorphism with CAD was found. Our findings suggest that inherited platelet GP variations might have an important impact on acute thrombotic disease.
Optimal Proliferation of a Hematopoietic Progenitor Cell Line Requires Either Costimulation With Stem Cell Factor or Increase of Receptor Expression That Can Be Replaced by Overexpression of Bcl-2
Authors: Huang Huei-Mei , Li Jian-Chiuan , Hsieh Yueh-Chun , Yang-Yen Hsin-Fang , Yen Jeffrey Jong-Young 
Published: October 2019

AbstractIn vitro proliferation of hematopoietic stem cells requires costimulation by multiple regulatory factors whereas expansion of lineage-committed progenitor cells generated by stem cells usually requires only a single factor. The distinct requirement of factors for proliferation coincides with the differential temporal expression of the subunits of cytokine receptors during early stem cell differentiation. In this study, we explored the underlying mechanism of the requirement of costimulation in a hematopoietic progenitor cell line TF-1. We found that granulocyte-macrophage colony-stimulating factor (GM-CSF) optimally activated proliferation of TF-1 cells regardless of the presence or absence of stem cell factor (SCF). However, interleukin-5 (IL-5) alone sustained survival of TF-1 cells and required costimulation of SCF for optimal proliferation. The synergistic effect of SCF was partly due to its anti-apoptosis activity. Overexpression of the IL-5 receptor  subunit (IL5R) in TF-1 cells by genetic selection or retroviral infection also resumed optimal proliferation due to correction of the defect in apoptosis suppression. Exogenous expression of an oncogenic anti-apoptosis protein, Bcl-2, conferred on TF-1 cells an IL-5–dependent phenotype. In summary, our data suggested SCF costimulation is only necessary when the expression level of IL5R is low and apoptosis suppression is defective in the signal transduction of IL-5. Expression of Bcl-2 proteins released the growth restriction of the progenitor cells and may be implicated in leukemia formation.
Altered Development and Cytokine Responses of Myeloid Progenitors in the Absence of Transcription Factor, Interferon Consensus Sequence Binding Protein
Authors: Scheller Marina , Foerster John , Heyworth Clare M. , Waring Jeffrey F. , Löhler Jürgen , Gilmore Gary L. , Shadduck Richard K. , Dexter T. Mike , Horak Ivan 
Published: October 2019

Abstract
Mice deficient for the transcription factor, interferon consensus sequence binding protein (ICSBP), are immunodeficient and develop disease symptoms similar to human chronic myeloid leukemia (CML). To elucidate the hematopoietic disorder of ICSBP−/− mice, we investigated the growth, differentiation, and leukemogenic potential of ICSBP−/−myeloid progenitor cells in vitro, as well as by cell-transfers in vivo. We report that adult bone marrow, as well as fetal liver of ICSBP-deficient mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte macrophage colony-stimulating factor (GM-CSF) and G-CSF in vitro. In contrast, their response to M-CSF is strongly reduced and, surprisingly, ICSBP−/− colonies formed in the presence of M-CSF are mostly of granulocytic morphology. This disproportional differentiation toward cells of the granulocytic lineage in vitro parallels the expansion of granulocytes in ICSBP−/− mice and correlates with a 4-fold reduction of M-CSF receptor expressing cells in bone marrow. Cell transfer studies showed an intrinsic leukemogenic potential and long-term reconstitution capability of ICSBP−/− progenitors. Further experiments demonstrated strongly reduced adhesion of colony-forming cells from ICSBP−/− bone marrow to fibronectin. In summary, ICSBP−/− myeloid progenitor cells share several abnormal features with CML progenitors, suggesting that the distal parts of signaling pathways of these two disorders are overlapping.
Lymphoid-Restricted Development From Multipotent Candidate Murine Stem Cells: Distinct and Complimentary Functions of the c-kit and flt3-Ligands
Authors: Borge Ole Johan , Adolfsson Jörgen , Jacobsen Annica Mårtensson, Inga-Lill Mårtensson, and Sten E.W. 
Published: October 2019

AbstractThe two tyrosine kinase receptors, c-kit and flt3, and their respective ligands KL and FL, have been demonstrated to play key and nonredundant roles in regulating the earliest events in hematopoiesis. However, their precise roles and potential interactions in promoting early lymphoid commitment and development remain unclear. Here we show that most if not all murine Lin−/loSca1+c-kit+ bone marrow (BM) cells generating B220+CD19+proB-cells in response to FL and interleukin-7 (IL-7) also have a myeloid potential. In contrast to FL + IL-7, KL + IL-7 could not promote proB-cell formation from Lin−/loSca1+c-kit+ cells. However, KL potently enhanced FL + IL-7–stimulated proB-cell formation, in part through enhanced recruitment of FL + IL-7–unresponsive Lin−/loSca1+c-kit+progenitors, and in part by enhancing the growth of proB-cells. The enhanced recruitment (4-fold) in response to KL occurred exclusively from the Lin−/loSca1+c-kit+flt3−long-term repopulating stem cell population, whereas KL had no effect on FL + IL-7–stimulated recruitment of Lin−/loSca1+c-kit+flt3+short-term repopulating cells. The progeny of FL + IL-7–stimulated Lin−/loSca1+c-kit+ cells lacked in vitro and in vivo myeloid potential, but efficiently reconstituted both B and T lymphopoiesis. In agreement with this FL, but not KL, efficiently induced expression of B220 and IL-7 receptor- on Lin−/loSca1+c-kit+flt3+cells. Thus, whereas KL appears crucial for recruitment of FL + IL-7–unresponsive candidate (c-kit+flt3−) murine stem cells, FL is essential and sufficient for development toward lymphoid restricted progenitors from a population of (c-kit+flt3+) multipotent short-term reconstituting progenitors.
Granulocyte-Macrophage Colony-Stimulating Factor Upregulates Reduced 5-Lipoxygenase Metabolism in Peripheral Blood Monocytes and Neutrophils in Acquired Immunodeficiency Syndrome
Authors: Coffey Michael J. , Phare Susan M. , Cinti Sandro , Peters-Golden Marc , Kazanjian Powel H. 
Published: October 2019

AbstractLeukotrienes (LT) are mediators derived from the 5-lipoxygenase (5-LO) pathway, which play a role in host defense, and are synthesized by both monocytes (peripheral blood monocyte [PBM]) and neutrophils (PMN). Because 5-LO metabolism is reduced in alveolar macrophages and PMN from acquired immunodeficiency syndrome (AIDS) subjects, we investigated the synthesis of LT by PBM and PMN from these subjects. There was a reduction (74.2% ± 8.8% of control) in LT synthesis in PBM from human immunodeficiency virus (HIV)-infected compared with normal subjects. Expression of 5-LO (51.2% ± 8.8% of control), and 5-LO activating protein (FLAP) (48.5% ± 8.0% of control) was reduced in parallel. We hypothesized that this reduction in LT synthetic capacity in PBM and PMN was due to reduced cytokine production by CD4 T cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We treated 10 AIDS subjects with GM-CSF for 5 days. PBM 5-LO metabolism ex vivo was selectively increased after GM-CSF therapy and was associated with increased 5-LO and FLAP expression. PMN leukotriene B4(LTB4) synthesis was also augmented and associated with increased 5-LO, FLAP, and cytosolic phospholipase A2 expression. In conclusion, as previously demonstrated for PMN, PBM from AIDS subjects also demonstrate reduced 5-LO metabolism. GM-CSF therapy reversed this defect in both PBM and PMN. In view of the role of LT in antimicrobial function, cytokine administration in AIDS may play a role as adjunct therapy for infections.
HFE Downregulates Iron Uptake From Transferrin and Induces Iron-Regulatory Protein Activity in Stably Transfected Cells
Authors: Riedel H.D. , Muckenthaler M.U. , Gehrke S.G. , Mohr I. , Brennan K. , Herrmann T. , Fitscher B.A. , Hentze M.W. , Stremmel W. 
Published: October 2019

AbstractHereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular “labile iron pool.” The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.
Recipient Tumor Necrosis Factor- and Interleukin-10 Gene Polymorphisms Associate With Early Mortality and Acute Graft-Versus-Host Disease Severity in HLA-Matched Sibling Bone Marrow Transplants
Authors: Cavet James , Middleton Peter G. , Segall Miriam , Noreen Harriet , Davies Stella M. , Dickinson Anne M. 
Published: October 2019

AbstractThe proinflammatory cytokine tumor necrosis factor- (TNF-) is strongly implicated in graft-versus-host disease (GVHD) and other acute bone marrow transplant (BMT) complications. The antiinflammatory interleukin-10 (IL-10) antagonizes TNF- and reduces GVHD. We previously showed association of recipient TNF (TNFd) and IL-10 (IL-10−1064) gene polymorphisms with acute GVHD severity in matched sibling BMT using only cyclosporin A monotherapy. The current study tested association of GVHD with TNFd and IL-10−1064/-1082 polymorphisms in a large cohort (144 matched sibling donor/recipient pairs) given both cyclosporine A (CyA) and methotrexate (MTX) prophylaxis. Genotype results were correlated with acute and chronic GVHD and mortality. Patients homozygous for the TNFd microsatellite allele 3 had higher early mortality: 23.7% of TNFd3/d3 homozygotes died before day 30, compared with 6.80% of non-d3/d3 recipients (P = .013). Recipients possessing longer IL-10−1064 microsatellite alleles developed more severe acute GVHD: 22.3% of recipients possessing alleles 12 to 15 developed grade III to IV GVHD, versus 3.92% of those with smaller alleles (P &lt; .01). Other recipient or donor genotypes tested did not significantly affect GVHD or mortality. We conclude that recipient TNFd and IL-10−1064 polymorphisms associate with early mortality and severe acute GVHD in matched sibling BMT with dual prophyaxis. This supports the hypothesis of genetic predisposition towards GVHD and other BMT complications other than histocompatibility antigen disparity.
Vaccines With Interleukin-12–Transduced Acute Myeloid Leukemia Cells Elicit Very Potent Therapeutic and Long-Lasting Protective Immunity
Authors: Dunussi-Joannopoulos Kyriaki , Runyon Kathlene , Erickson Jamie , Schaub Robert G. , Hawley Robert G. , Leonard John P. 
Published: October 2019

AbstractInterleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay between T cells and antigen-presenting cells (APCs). Preclinical studies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor immunity mediated by T cells in several types of tumors. However, the in vivo antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been previously reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is incapable of rescuing mice from lethal leukemia. In contrast, AML cells genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon-γ (IFN-γ), or CD8+ T cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of IFN-γ on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules and induction of the costimulatory molecules B7.1 and B7.2, but no significant direct antiproliferative effect. 51Cr release assays show that rejection of live IL12-AML cells supports the development of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.
Interferon Consensus Sequence Binding Protein and Interferon Regulatory Factor-4/Pip Form a Complex That Represses the Expression of the Interferon-Stimulated Gene-15 in Macrophages
Authors: Rosenbauer Frank , Waring Jeffrey F. , Foerster John , Wietstruk Marcus , Philipp Dieter , Horak Ivan 
Published: October 2019

AbstractInterferon consensus sequence binding protein (ICSBP), a transcription factor of the interferon (IFN) regulatory factor (IRF) family, binds to the IFN-stimulated response element (ISRE) in the regulatory region of IFNs and IFN-stimulated genes (ISG). To identify target genes, which are deregulated by an ICSBP null-mutation in mice (ICSBP−/−), we have analyzed transcription of an ISRE-bearing gene, ISG15. We have found that although ISG15 expression is unchanged in B cells, it is upregulated in macrophages from ICSBP−/− mice. Three factors, ICSBP, IRF-2, and IRF-4/Pip interact with the ISRE in B cells, however only ICSBP and IRF-4/Pip were found to bind this sequence in macrophages of wild-type mice. Although IRF-4 was considered to be a lymphoid-specific factor, we provide evidence for its role in macrophage gene regulation. Our results suggest that the formation of cell-type–specific heteromeric complexes between individual IRFs plays a crucial role in regulating IFN responses.
Reed-Sternberg Cell Genome Expression Supports a B-Cell Lineage
Authors: Cossman Jeffrey , Annunziata Christina M. , Barash Steven , Staudt Louis , Dillon Patrick , He Wei-Wu , Ricciardi-Castagnoli Paola , Rosen Craig A. , Carter Kenneth C. 
Published: October 2019

AbstractThe malignant Reed-Sternberg cell of Hodgkin’s disease, first described a century ago, has resisted in-depth analysis due to its extreme rarity in lymphomatous tissue. To directly study its genome-wide gene expression, approximately 11,000,000 bases (27,518 cDNA sequences) of expressed gene sequence was determined from living single Reed-Sternberg cells, Hodgkin’s tissue, and cell lines. This approach increased the number of genes known to be expressed in Hodgkin’s disease by 20-fold to 2,666 named genes. The data here indicate that Reed-Sternberg cells from both nodular sclerosing and lymphocyte predominant Hodgkin’s disease were derived from an unusual B-cell lineage based on a comparison of their gene expression to approximately 40,000,000 bases (105 sequences) of expressed gene sequence from germinal center B cells (GCB) and dendritic cells. The data set of expressed genes, reported here and on the World Wide Web, forms a basis to understand the genes responsible for Hodgkin’s disease and develop novel diagnostic markers and therapies. This study of the rare Reed-Sternberg cell, concealed in its heterogenous cellular context, also provides a formidable test case to advance the limit of analysis of differential gene expression to the single disease cell.
The Thrombocytopenia of Wiskott Aldrich Syndrome Is Not Related to a Defect in Proplatelet Formation
Authors: Haddad Elie , Cramer Elisabeth , Rivière Christel , Rameau Philippe , Louache Fawzia , Guichard Josette , Nelson David L. , Fischer Alain , Vainchenker William , Debili Najet 
Published: October 2019

AbstractThe Wiskott-Aldrich syndrome (WAS) is an X-linked hereditary disease characterized by thrombocytopenia with small platelet size, eczema, and increased susceptibility to infections. The gene responsible for WAS was recently cloned. Although the precise function of WAS protein (WASP) is unknown, it appears to play a critical role in the regulation of cytoskeletal organization. The platelet defect, resulting in thombocytopenia and small platelet size, is a consistent finding in patients with mutations in the WASP gene. However, its exact mechanism is unknown. Regarding WASP function in cytoskeletal organization, we investigated whether these platelet abnormalities could be due to a defect in proplatelet formation or in megakaryocyte (MK) migration. CD34+ cells were isolated from blood and/or marrow of 14 WAS patients and five patients with hereditary X-linked thrombocytopenia (XLT) and cultured in serum-free liquid medium containing recombinant human Mpl-L (PEG-rHuMGDF) and stem-cell factor (SCF) to study in vitro megakaryocytopoiesis. In all cases, under an inverted microscope, normal MK differentiation and proplatelet formation were observed. At the ultrastructural level, there was also no abnormality in MK maturation, and normal filamentous MK were present. Moreover, the in vitro produced platelets had a normal size, while peripheral blood platelets of the same patients exhibited an abnormally small size. However, despite this normal platelet production, we observed that F-actin distribution was abnormal in MKs from WAS patients. Indeed, F-actin was regularly and linearly distributed under the cytoplasmic membrane in normal MKs, but it was found concentrated in the center of the WAS MKs. After adhesion, normal MKs extended very long filopodia in which WASP could be detected. In contrast, MKs from WAS patients showed shorter and less numerous filopodia. However, despite this abnormal filopodia formation, MKs from WAS patients normally migrated in response to stroma-derived factor-1 (SDF-1), and actin normally polymerized after SDF-1 or thrombin stimulation. These results suggest that the platelet defect in WAS patients is not due to abnormal platelet production, but instead to cytoskeletal changes occuring in platelets during circulation.