bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Hepatitis C Virus Infections in Leukemia Survivors: Prevalence, Viral Load, and Severity of Liver Disease
Authors: Paul Ian M. , Sanders Jeffrey , Ruggiero Francesca , Andrews Thomas , Ungar David , Eyster M. Elaine 
Published: October 2019

AbstractThe natural history of chronic hepatitis C (HCV) infections in long-term leukemia survivors has not been well characterized. We studied the prevalence of HCV infections, measured HCV RNA levels, and evaluated the severity of liver disease in patients with leukemia who achieved long-term remissions after intensive chemotherapy or bone marrow transplantation (BMT). HCV antibody tests were performed by the enzyme-linked immunosorbent assay (ELISA) and positive tests confirmed by the recombinant immunoblot assay (RIBA). HCV RNA levels were measured by the branched DNA (bDNA) assay. Seventy-five leukemia survivors with 25 or more blood donor exposures were identified. Nine (12%) were anti-HCV positive. All were infected before 1992 when second generation HCV screening tests were implemented. Mean HCV RNA levels were 10.3 ×106 eq/mL versus 3.2 × 106 eq/mL (P = .056) in a control group of 20 anti-HCV positive immunocompetent individuals of comparable age who were infected twice as long (17.8 ± 6.5 years v 9.0 ± 4.4 years in leukemia survivors, P = .001). Liver biopsies were performed on six of the nine anti-HCV positive leukemia survivors. All showed at least moderate portal inflammation and half had evidence of bridging fibrosis. We conclude that viral loads in anti-HCV positive leukemia survivors are markedly higher than in immunocompetent controls. Our results suggest that long-term leukemia survivors with chronic HCV may have more rapidly progressive liver disease than has been previously recognized.
Thrombopoietin Augments Stem Cell Factor–Dependent Growth of Human Mast Cells From Bone Marrow Multipotential Hematopoietic Progenitors
Authors: Sawai Nobukuni , Koike Kenichi , Mwamtemi Hadija Hemed , Kinoshita Tatsuya , Kurokawa Yumi , Sakashita Kazuo , Higuchi Tsukasa , Takeuchi Kouichi , Shiohara Masaaki , Kamijo Takehiko , Ito Susumu , Kato Takashi , Miyazaki Hiroshi , Yamashita Tetsuji , Komiyama Atsushi 
Published: October 2019

AbstractThe effects of thrombopoietin (TPO) and/or stem cell factor (SCF) on the development of human mast cells from CD34+ bone marrow (BM) cells were investigated using a serum-deprived liquid culture system. Mast cells were identified by measurement of intracellular histamine content, immunocytochemical staining, and flow cytometric analysis. Whereas SCF alone generated only a small number of tryptase+ cells, the addition of TPO to the culture containing SCF resulted in an apparent production of mast cells from 3 weeks until at least 15 weeks. Some of the cells reacted with an antichymase monoclonal antibody as well. Based on the effects of growth factor(s) on a later phase of the mast cell growth, TPO may stimulate an early stage of mast cell development in combination with SCF, whereas subsequent growth seems to be supported by SCF alone. Single-cell culture studies indicated that the CD34+CD38−c-kit+ cells and CD34+CD38+c-kit+ cells were responsible for the SCF + TPO–dependent mast cell production. Two-step culture assays clearly showed that mast cells originated from multilineage colony-forming cells that had potential to differentiate into neutrophil/mast cell lineages, neutrophil/macrophage/mast cell lineages, or neutrophil/macrophage/mast cell/erythroid lineages. These results suggest that TPO plays an important role in the development of human mast cells from CD34+ BM cells in concert with SCF, and provide direct evidence of the differentiation into the mast cell lineage of human multipotential BM-derived progenitors.
von Willebrand Factor Proteolysis Is Deficient in Classic, but not in Bone Marrow Transplantation–Associated, Thrombotic Thrombocytopenic Purpura
Authors: van der Plas R. Martijn , Schiphorst Marion E. , Huizinga Eric G. , Hené Ronald J. , Verdonck Leo F. , Sixma Jan J. , Fijnheer Rob 
Published: October 2019

Abstract
Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) differs from classic TTP in its clinical course and therapy. A characteristic of classic TTP is the inhibition of a plasma protease that specifically cleaves von Willebrand factor (vWF), thus reducing its multimeric size. We investigated whether this protease was also inhibited in BMT-associated TTP. Plasma from patients with classic or BMT-associated TTP was incubated with recombinant vWF R834Q, a vWF mutant with enhanced sensitivity to the protease. The proteolysis of vWF multimers was analyzed and quantified on Western blot. Metalloprotease activity was strongly inhibited in the classic TTP patient group. However, metalloprotease activity was normal in the BMT-associated TTP patient group. The difference in activity between the two patient groups was highly significant (P = .0016). The results indicate that the etiologies of classic and BMT-associated TTP are indeed different and provide an explanation for the lack of success of plasma exchange in BMT-associated TTP.
Familial Overexpression of β Antithrombin Caused by an Asn135Thr Substitution
Authors: Bayston T.A. , Tripodi A. , Mannucci P.M. , Thompson E. , Ireland H. , Fitches A.C. , Hananeia L. , Olds R.J. , Lane D.A. 
Published: October 2019

AbstractWe have investigated the basis of antithrombin deficiency in an asymptomatic individual (and family) with borderline levels (≈70% antigen and activity) of antithrombin. Direct sequencing of amplified DNA showed a mutation in codon 135, AAC to ACC, predicting a heterozygous Asn135Thr substitution. This substitution alters the predicted consensus sequence for glycosylation, Asn-X-Ser, adjacent to the heparin interaction site of antithrombin. The antithrombin isolated from plasma of the proband by heparin-Sepharose chromatography contained amounts of β antithrombin (the very high affinity fraction) greatly increased (≈20% to 30% of total) above the trace levels found in normals. Expression of the residue 135 variant in both a cell-free system and COS-7 cells confirmed altered glycosylation arising as a consequence of the mutation. Wild-type and variant protein were translated and exported from COS-7 cells with apparently equal efficiency, in contrast to the reduced level of variant observed in plasma of the affected individual. This case represents a novel cause of antithrombin deficiency, removal of glycosylation concensus sequence, and highlights the potentially important role of β antithrombin in regulating coagulation.
Selective Expansion of Alveolar Macrophages In Vivo by Adenovirus-Mediated Transfer of the Murine Granulocyte-Macrophage Colony-Stimulating Factor cDNA
Authors: Worgall Stefan , Singh Ravi , Leopold Philip L. , Kaner Robert J. , Hackett Neil R. , Topf Norbert , Moore Malcolm A.S. , Crystal Ronald G. 
Published: October 2019

AbstractBased on the hypothesis that genetic modification of freshly isolated alveolar macrophages (AM) with the granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA would induce AM to proliferate, this study focuses on the ability of adenoviral (Ad) vectors to transfer and efficiently express the murine (m) GM-CSF cDNA in murine AM with consequent expansion in the number of AM in vitro and in vivo. To demonstrate that an Ad vector can effectively transfer and express genes in AM, murine AM recovered by bronchoalveolar lavage from the lung of Balb/c mice were infected with an Ad vector coding for green fluorescent protein (GFP) in vitro and expressed GFP in a dose-dependent fashion. Infection of AM with an Ad vector containing an expression cassette coding for mGM-CSF led to GM-CSF expression and to AM proliferation in vitro. When AM infected with AdGFP were returned to the respiratory tract of syngeneic recipient mice, GFP-expressing cells could still be recovered by bronchoalveolar lavage 2 weeks later. In vitro infection of AM with AdmGM-CSF and subsequent transplantation of the genetically modified AM to the lungs of syngeneic recipients led to GM-CSF expression in vivo. Strikingly, the AM recovered by lavage 5 weeks after transplantation demonstrated an increased rate of proliferation, and the total number of alveolar macrophages was 1.9-fold greater than controls. Importantly, the increase in the numbers of AM was selective (ie, other inflammatory cell numbers were unchanged), and there was no modification to the lung architecture. Thus, it is feasible to genetically modify AM with Ad vectors and to use this strategy to modify the behavior of AM in vivo. Based on the importance of AM in the primary defense of the respiratory epithelial surface, this strategy may be useful in enhancing pulmonary defenses in immunodeficiency states.
Augmented Proliferation of Human Alveolar Macrophages After Allogeneic Bone Marrow Transplantation
Authors: Nakata Koh , Gotoh Hajime , Watanabe Junichi , Uetake Takeshi , Komuro Iwao , Yuasa Kazumi , Watanabe Shinya , Ieki Ryuji , Sakamaki Hisashi , Akiyama Hideki , Kudoh Shohji , Naitoh Makoto , Satoh Hitoshi , Shimada Kaoru 
Published: October 2019

AbstractAfter allogeneic bone marrow transplantation (allo-BMT), recipient alveolar macrophages (AM) are gradually replaced by AM of the donor origin. An influx of mononuclear phagocytes of donor origin to the lung is responsible for the repopulation, but the detailed kinetics remain unclear. We therefore studied 24 BMT recipients who underwent bronchoalveolar lavage (BAL) from 24 to 83 days after BMT. AM cell number, size, morphology, proliferating ability, and genotype of AM were measured. Before day 50, the number and size of AM in BAL fluid were similar to those of normal nonsmokers. However, after day 50, the mean number of AM increased threefold and the mean cell size decreased due to the increase of small AM. These small cells are presumably of donor origin based on DNA fingerprinting analysis and based on fluorescence in situ hybridization for the Y chromosome in a sex-mismatched case. Immunohistochemistry and cell cycle analysis demonstrated that the increase in AM number coincided with a remarkable increase of AM expressing proliferating cell nuclear antigen, suggesting that small AM are proliferating. This is the first report representing that augmented proliferation of donor AM in situ may contribute to the reconstitution of AM population after BMT.
Persistence and Clinical Outcome of Hepatitis G Virus Infection in Pediatric Bone Marrow Transplant Recipients and Children Treated for Hematological Malignancy
Authors: Yamada-Osaki Maki , Sumazaki Ryo , Tsuchida Masahiro , Koike Kazutoshi , Fukushima Takashi , Matsui Akira 
Published: October 2019

Abstract
The natural course and the clinical significance of hepatitis G virus (HGV) infection were investigated in 106 pediatric patients who received chemotherapy for hematological malignancy or underwent bone marrow transplantation (BMT) using HGV-RNA and antibodies to the HGV-E2 protein (anti-E2). HGV markers were detected in 21 patients (19.8%; HGV-RNA in 19 and anti-E2 in 2). Longitudinal analysis of these HGV-infected patients showed that 1 had anti-E2 before the initial blood transfusion, 14 had persistent viremia, and 6 became clear of circulating HGV-RNA after completion of therapy, although 5 of the 6 HGV-cleared patients never developed anti-E2. Reactivation of HGV infection during chemotherapy was observed in two anti-E2–positive, HGV-RNA–negative patients; the reappearance of the same HGV strain was confirmed by phylogenetic analysis. Among BMT survivors without other known causes of liver dysfunction, HGV-RNA–positive patients had a higher peak serum alanine amino transferase (ALT) value than negative patients. Contrary to previous reports, immunosuppressed patients can apparently recover from HGV infection without detectable anti-E2 and some patients who supposedly recovered from HGV infection can nonetheless suffer exacerbation when subsequently immunosuppressed.
Direct Alloreactivity by Human Cytotoxic T Lymphocytes Can Be Inhibited by Altered Peptide Ligand Antagonism
Authors: Burrows Scott R. , Khanna Rajiv , Moss Denis J. 
Published: October 2019

AbstractAlloreactive T lymphocytes that respond directly to foreign major histocompatibility complex (MHC) molecules and bound peptide are known to be central mediators of graft-versus-host disease (GVHD) and allograft rejection. We have recently identified a peptide from the human protein, cytochrome P450 (isotypes IIC9, 10, or 18), that is recognized in association with human leukocyte antigen (HLA) B*3501 by alloreactive cytotoxic T lymphocytes (CTLs). These CTLs with this specificity were isolated from several unrelated individuals and were found to express a common T-cell receptor (TCR). Synthetic analogs of the cytochrome P450 peptide were generated by introducing single amino acid substitutions at putative TCR contact positions. Four altered peptide ligands were powerful competitive antagonists of these CTL clones, reducing lysis levels of target cells expressing the alloantigen HLA B*3501 by over 80%. This first demonstration that it is possible to suppress CTL alloreactivity with structural variants of allodeterminants raises the prospect that such TCR antagonists could be exploited within the clinical arena to specifically modulate GVHD and allograft rejection.
Reconstitution of the Functional Mouse Oncostatin M (OSM) Receptor: Molecular Cloning of the Mouse OSM Receptor β Subunit
Authors: Tanaka Minoru , Hara Takahiko , Copeland Neal G. , Gilbert Debra J. , Jenkins Nancy A. , Miyajima Atsushi 
Published: October 2019

AbstractOncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines that share the gp130 receptor subunit. Of these family members, leukemia inhibitory factor (LIF) is most closely related to OSM, and various overlapping biologic activities have been described between human LIF and OSM (hLIF and hOSM). Two types of functional hOSM receptors are known: the type I OSM receptor is identical to the LIF receptor that consists of gp130 and the LIF receptor β subunit (LIFRβ), and the type II OSM receptor consists of gp130 and the OSM receptor β subunit (OSMRβ). It is thus conceivable that common biologic activities between hLIF and hOSM are mediated by the shared type I receptor and OSM-specific activities are mediated by the type II receptor. However, in contrast to the human receptors, recent studies have demonstrated that mouse OSM (mOSM) does not activate the type I receptor and exhibits unique biologic activity. To elucidate the molecular structure of the functional mOSM receptor, we cloned a cDNA encoding mOSMRβ, which is 55.5% identical to the hOSMRβ at the amino acid level. mOSM-responsive cell lines express high-affinity mOSM receptors, as well as mOSMRβ, whereas embryonic stem cells, which are responsive to LIF but not to mOSM, do not express mOSMRβ. mOSMRβ alone binds mOSM with low affinity (kd = 13.0 nmol/L) and forms a high-affinity receptor (kd = 606 pmol/L) with gp130. Ba/F3 transfectants expressing both mOSMRβ and gp130 proliferated in response to mOSM, but failed to respond to LIF and human OSM. Thus, the cloned mOSMRβ constitutes an essential and species-specific receptor component of the functional mOSM receptor. Reminiscent of the colocalization of the mOSM and mLIF genes, the mOSMRβ gene was found to be located in the vicinity of the LIFRβ locus in the proximal end of chromosome 15.
Combined Genotypes of CCR5, CCR2, SDF1, and HLA Genes Can Predict the Long-Term Nonprogressor Status in Human Immunodeficiency Virus-1–Infected Individuals
Authors: Magierowska Magdalena , Theodorou Ioannis , Debré Patrice , Sanson Françoise , Autran Brigitte , Rivière Yves , Charron Dominique , ALT French , Groups IMMUNOCO Study , Costagliola Dominique 
Published: October 2019

Abstract
Human immunodeficiency virus (HIV)-1–infected long-term nonprogressors (LT-NP) represent less than 5% of HIV-1–infected patients. In this work, we tried to understand whether combined genotypes of CCR5-▵32, CCR2-64I, SDF1-3′A and HLA alleles can predict the LT-NP status. Among the chemokine receptor genotypes, only the frequency of the CCR5-▵32 allele was significantly higher in LT-NP compared with the group of standard progressors. The predominant HLA alleles in LT-NP were HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7. A combination of both HLA and chemokine receptor genotypes integrated in a multivariate logistic regression model showed that if a subject is heterozygous for CCR5-▵32 and homozygous for SDF1 wild type, his odds of being LT-NP are increased by 16-fold, by 47-fold when a HLA-B27 allele is present with HLA-DR6 absent, and by 47-fold also if at least three of the following alleles are present: HLA-A3, HLA-B14, HLA-B17, HLA-DR7. This model allowed a correct classification of 70% of LT-NPs and 81% of progressors, suggesting that the host’s genetic background plays an important role in the evolution of HIV-1. The chemokine receptor and chemokine genes along with the HLA genotype can serve as predictors of HIV-1 outcome for classification of HIV-1–infected subjects as LT-NPs or progressors.
Bone Marrow Transplantation in Adult Thalassemic Patients
Authors: Lucarelli G. , Clift R.A. , Galimberti M. , Angelucci E. , Giardini C. , Baronciani D. , Polchi P. , Andreani M. , Gaziev D. , Erer B. , Ciaroni A. , D’Adamo F. , Albertini F. , Muretto P. 
Published: October 2019

Abstract
One hundred seven adult patients with thalassemia aged from 17 through 35 years and transplanted from HLA-identical siblings between November 1988 and September 1996 were evaluated on December 31, 1997. The outcome experience of 20 consecutive patients transplanted between November 13, 1988 and January 10, 1991 and reported in September 1992 is updated after 5 additional years. The experience on 87 patients transplanted between May 1991 and September 1996 is described and evaluated as of the end of December 1997. Of 107 patients, 69 survive between 1.5 and 9 years after transplantation. Sixty-six of these patients do not have thalassemia and are identified as ex-thalassemic after bone marrow transplantation. The youngest survivor is 20 years old, 6 are older than 30 years, and the oldest is 37 years of age. Patients with chronic active hepatitis at the time of transplant were significantly more likely to die than patients without (P = .05; relative risk, 2.05). Marrow transplantation is a valid treatment option for older patients with thalassemia who have suitable donors and show deterioration with conventional therapy.
The Nuclear Topography of ABL, BCR, PML, and RAR Genes: Evidence for Gene Proximity in Specific Phases of the Cell Cycle and Stages of Hematopoietic Differentiation
Authors: Neves Hélia , Ramos Carlos , da Silva Maria Gomes , Parreira António , Parreira Leonor 
Published: October 2019

AbstractThe mechanisms whereby chromosomal translocations are consistently associated with specific tumor types are largely unknown. A generally accepted hypothesis is that the physical proximity of the involved chromosomal regions may be one important factor in the genesis of these phenomena. Accordingly, a likely possibility is that such a proximity may occur in a cell-lineage and cell-differentiation stage-specific manner. In this work, we have addressed this issue using as models the ABL and BCR genes of t(9;22) and the PML and RAR genes of t(15;17). By using in situ hybridization and confocal microscopy, we have measured the distances between these two pairs of genes in three-dimensionally preserved hematopoietic cells belonging to different cell lineages, at various stages of differentiation, and at various stages of the cell cycle, with the following results. (1) Intergenic distances vary periodically during the cell cycle and a significant association of ABL with BCR and of PML with RAR is seen at the transition between S and G2, which persists during G2 and prophase (such a behavior is not observed for distances between ABL or PML and the β-globin genes, used as a control). (2) The proportion of cells in which PML and RAR or ABL and BCR are closely associated is higher in hematopoietic precursors than in B-lymphoid cells (whereas the distances between ABL or PML and the β-globin genes are not affected by cell type). (3) When intergenic distances in unstimulated bone marrow CD34+ cells were compared with those in CD34+ cells treated with interleukin-3 (IL-3), a trend towards a higher proximity of the ABL and BCR genes in the former and of the PML and RAR genes in the latter is observed. (4) Analysis of B-lymphoid cells during mitosis shows that intergenic distances at metaphase are strongly influenced by physical constraints imposed by the chromosomal location of the gene, by the size of the respective chromosome, and by the geometry of the metaphase plate. These findings suggest that intrinsic spatial dynamics, established early in hematopoiesis and perpetuated differentially in distinct cell lineages, may facilitate the collision of individual genes and thus reciprocal recombination between them at subsequent stages of hematopoietic differentiation.
Characterization of Two Naturally Occurring Mutations in the Second Epidermal Growth Factor-Like Domain of Factor VII
Authors: Hunault Mathilde , Arbini Arnaldo A. , Carew Josephine A. , Peyvandi Flora , Bauer Kenneth A. 
Published: October 2019

AbstractWe investigated the mechanisms responsible for severe factor VII (FVII) deficiency in homozygous Italian patients with either Gly97Cys or Gln100Arg mutations in the second epidermal growth factor domain of FVII. Transient expression of complementary DNA coding for the mutations in COS-1 cells showed impaired secretion of the mutant molecules. Using stably transfected Chinese hamster ovary (CHO) cells, we performed pulse-chase labeling studies, immunohistochemistry, and experiments with inhibitors of protein degradation, showing that FVII-Cys97 did not accumulate intracellularly but was degraded in a pre-Golgi, nonlysosomal compartment by a cysteine protease. In stably transfected CHO cells expressing FVII-Arg100, the level of intracellular FVII was not increased by several inhibitors of protein degradation, but FVII-Arg100 was retained in the endoplasmic reticulum for a longer period of time than wild-type FVII. FVII-Arg100 had a lower apparent molecular weight than did wild-type FVII under nondenaturing conditions, which is attributable to misfolding due to abnormal disulfide bond formation.
Downregulation of Interleukin-12 (IL-12) Responsiveness in Human T Cells by Transforming Growth Factor-β: Relationship With IL-12 Signaling
Authors: Pardoux Cécile , Ma Xiaojing , Gobert Stéphanie , Pellegrini Sandra , Mayeux Patrick , Gay Françoise , Trinchieri Giorgio , Chouaib Salem 
Published: October 2019

AbstractInterleukin-12 (IL-12) is a cytokine that plays a central role in the control of cell-mediated immunity. We have previously shown that transforming growth factor-β1 (TGF-β) inhibitory effects on human primary allogeneic cytotoxicity and proliferative responses interfere with IL-12 pathway. The present study was undertaken to further elucidate the biochemical basis of the functional interaction between these two cytokines and to define the site of TGF-β action on the signaling pathway activated by IL-12. Our data indicate that TGF-β induced an inhibition of interferon-γ (IFN-γ) production without affecting the IL-12Rβ1 and IL-12Rβ2 subunits mRNA expression by activated T cells. We further show that TGF-β has a significant inhibitory effect on the early signal transduction events following interaction of IL-12 with its receptor on activated T cells, resulting in the inhibition of both JAK2 and Tyk2 phosphorylation. In addition, TGF-β was found to significantly inhibit IL-12–induced phosphorylation of the STAT4 transcription factor. Electrophoretic mobility shift assay indicated that TGF-β induced a decrease in IL-12–induced STAT4 DNA binding activity in T lymphocytes. This study suggests that TGF-β influences IL-12 responsiveness at least in part by inhibiting early signaling events essential to gene induction in IL-12–activated T cells.