bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factor XIIIa supports microvascular endothelial cell adhesion and inhibits capillary tube formation in fibrin
Authors: Dallabrida Susan M. , Falls Lisa A. , Farrell David H. 
Published: October 2019

AbstractCoagulation factor XIIIa is a transglutaminase that catalyzes covalent cross-link formation in fibrin clots. In this report, we demonstrate that factor XIIIa also mediates adhesion of endothelial cells and inhibits capillary tube formation in fibrin. The adhesive activity of factor XIIIa was not dependent on the transglutaminase activity, and did not involve the factor XIIIb-subunits. The adhesion was inhibited by 99% using a combination of monoclonal antibodies directed against integrin vβ3 and β1-containing integrins, and was dependent on Mg2+ or Mn2+. Soluble factor XIIIa also bound to endothelial cells in solution, as detected by flow cytometry. In addition, factor XIIIa inhibited endothelial cell capillary tube formation in fibrin in a dose-dependent manner. Furthermore, the extent of inhibition differed in 2 types of fibrin. The addition of 10 to 100 μg/mL factor XIIIa produced a dose-dependent reduction in capillary tube formation of 60% to 100% in γA/γA fibrin, but only a 10% to 37% decrease in γA/γ′ fibrin. These results show that factor XIIIa supports endothelial cell adhesion in an integrin-dependent manner and inhibits capillary tube formation.
Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia
Authors: Padró Teresa , Ruiz Sandra , Bieker Ralf , Bürger Horst , Steins Martin , Kienast Joachim , Büchner Thomas , Berdel Wolfgang E. , Mesters Rolf M. 
Published: October 2019

AbstractThe importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P &lt; .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P &lt; .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P &lt; .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.
Autosomal dominant thrombocytopenia: incomplete megakaryocyte differentiation and linkage to human chromosome 10
Authors: Drachman Jonathan G. , Jarvik Gail P. , Mehaffey Michele G. 
Published: October 2019

AbstractWe studied a large kindred with nonsyndromic autosomal dominant thrombocytopenia to define the phenotype and used genomic linkage analysis to determine the locus of the abnormal gene. Affected family members are characterized by lifelong moderate thrombocytopenia (mean = 42.7 × 109/L) with moderate propensity toward easy bruising and minor bleeding. Megakaryocytes are present in bone marrow with reduced frequency, and there are no apparent abnormalities of myeloid or erythroid cells. This type of inherited thrombocytopenia has no evident association with hematopoietic malignancy or progression to aplastic anemia. In the past, members of this family have failed therapeutic trials of immunosuppression and splenectomy. In our investigation, we found that affected individuals had normal platelet size compared with unaffected family members and modestly increased thrombopoietin levels. Hematopoietic colony assays from bone marrow and peripheral blood demonstrated that megakaryocyte precursors (CFU-Mk) were dramatically increased in both number and size in affected individuals. Bone marrow cells grown in liquid culture with thrombopoietin failed to develop polyploid cells greater than 8N. Also, electron microscopy demonstrated that megakaryocytes from an affected individual had markedly delayed nuclear and cytoplasmic differentiation. Genome-wide linkage analysis established a single locus for the disease gene on the short arm of chromosome 10 with a maximum 2-point lod score of 5.68 (at θ = 0). By recruiting additional family members, the genomic region was narrowed to 17 centimorgans. We conclude that a gene in this locus plays an important role in megakaryocyte endomitosis and terminal maturation.
N-terminal truncated human RAG1 proteins can direct T-cell receptor but not immunoglobulin gene rearrangements
Authors: Noordzij Jeroen G. , Verkaik Nicole S. , Hartwig Nico G. , de Groot Ronald , van Gent Dik C. , van Dongen Jacques J. M. 
Published: October 2019

Abstract
The proteins encoded by RAG1 and RAG2 can initiate gene recombination by site-specific cleavage of DNA in immunoglobulin and T-cell receptor (TCR) loci. We identified a new homozygous RAG1 gene mutation (631delT) that leads to a premature stop codon in the 5′ part of the RAG1 gene. The patient carrying this 631delT RAG1 gene mutation died at the age of 5 weeks from an Omenn syndrome-like T+/B−severe combined immunodeficiency disease. The high number of blood T-lymphocytes (55 × 106/mL) showed an almost polyclonal TCR gene rearrangement repertoire not of maternal origin. In contrast, B-lymphocytes and immunoglobulin gene rearrangements were hardly detectable. We showed that the 631delT RAG1 gene can give rise to an N-terminal truncated RAG1 protein, using an internal AUG codon as the translation start site. Consistent with the V(D)J recombination in T cells, this N-terminal truncated RAG1 protein was active in a plasmid V(D)J recombination assay. Apparently, the N-terminal truncated RAG1 protein can recombine TCR genes but not immunoglobulin genes. We conclude that the N-terminus of the RAG1 protein is specifically involved in immunoglobulin gene rearrangements.
HIV protease inhibitors restore impaired T-cell proliferative response in vivo and in vitro: a viral-suppression–independent mechanism
Authors: Lu Wei , Andrieu Jean-Marie 
Published: October 2019

Abstract
In 99 adults infected with human immunodeficiency virus type 1 (HIV-1) who received highly active antiretroviral therapy (HAART) (including 2 nucleoside analogues and 1 or 2 protease inhibitors) for 1 year, CD4+ and CD8+ T cells (including memory and naive subsets) increased similarly among patients with sustained plasma viral load decrease, transient decrease, or no decrease. A linear correlation was observed between the decrease in serum β2-microglobulin concentration (an independent surrogate marker of HIV disease) and the increase in peripheral blood T-cells (CD4+ and CD8+) counts. In vitro, HIV protease inhibitors indinavir and saquinavir (but not nucleoside analogues) enhanced the survival of patients' peripheral blood T cells at doses that are at least 30-fold lower than those required for achieving 90% viral inhibition in the same cultures. This enhanced T-cell survival (which is similar for CD4 and CD8 cells) was associated with a restoration of T-cell proliferative response to immune stimuli. However, neither TCR/CD3-ligation– nor Fas-ligation–triggered apoptosis was affected by either of the 2 protease inhibitors. A reduction in apoptosis observed after prolonged culture of patient T cells in the presence of the protease inhibitors could result from restored T-cell proliferation. These findings explain the discrepancies between virologic and immunologic responses that are increasingly reported in patients receiving HAART, and may provide insights into the pathogenesis of HIV infection.
AML1-MTG8 leukemic protein induces the expression of granulocyte colony-stimulating factor (G-CSF) receptor through the up-regulation of CCAAT/enhancer binding protein epsilon
Authors: Shimizu Kimiko , Kitabayashi Issay , Kamada Nanao , Abe Tatsuo , Maseki Nobuo , Suzukawa Kazumi , Ohki Misao 
Published: October 2019

AbstractThe t(8;21) translocation is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). In this translocation, the AML1 (CBFA2/PEBP2aB) gene is disrupted and fused to the MTG8 (ETO) gene. The ectopic expression of the resulting AML1-MTG8 fusion gene product in L-G and 32Dcl3 murine myeloid precursor cells stimulates cell proliferation without inducing morphologic terminal differentiation into mature granulocytes in response to granulocyte-colony stimulating factor (G-CSF). This study found that the ectopic expression of AML1-MTG8 elevates the expression of the G-CSF receptor (G-CSFR). Analysis of the promoter region of the G-CSFR gene revealed that up-regulation of G-CSFR expression by AML1-MTG8 does not depend on the AML1-binding sequence, but on the C/EBP (CCAAT/enhancer binding protein) binding site. The results suggest that the overproduction of G-CSFR is at least partly mediated by C/EBPɛ, whose expression is activated by AML1-MTG8. The ectopic expression of G-CSFR in L-G cells induced cell proliferation in response to G-CSF, but did not inhibit cell differentiation into mature neutrophils. Overexpression of C/EBPɛ in L-G cells also stimulated G-CSF–dependent cell proliferation. High expression levels of G-CSFR were also found in the leukemic cells of AML patients with t(8;21). Therefore, G-CSF–dependent cell proliferation of myeloid precursor cells may be implicated in leukemogenesis.
Molecular monitoring of minimal residual disease in patients in long-term complete remission after allogeneic stem cell transplantation for multiple myeloma
Authors: Cavo Michele , Terragna Carolina , Martinelli Giovanni , Ronconi Sonia , Zamagni Elena , Tosi Patrizia , Lemoli Roberto M. , Benni Monica , Pagliani Giorgio , Bandini Giuseppe , Tura Sante 
Published: October 2019

Abstract
In the present study, we used a polymerase chain reaction–based (PCR-based) strategy to retrospectively analyze the presence of residual myeloma cells in serial posttransplant bone marrow samples obtained from 13 patients in remission after allogeneic hemopoietic stem cell transplantation (allo SCT). For this purpose, patient-specific primers were generated from complementarity determining regions 2 and 3 of the rearranged IgH gene. The level of sensitivity of the PCR-based assay ranged from 1 in 105 to 1 in 106 normal marrow cells. Following transplantation, 9 of 12 patients who attained stringently defined complete remission (CR) remained persistently PCR− for a median of 36 months, and 4 of the patients remained PCR− up to the latest analysis, which was performed at 48, 72, 72, and 120 months, respectively, after allo SCT. None of the patients in the PCR− subgroup experienced a disease relapse, and only 1 of 4 PCR+ patients experienced a relapse. It is concluded that allo SCT has the potential ability to induce sustained serological and molecular CR in selected patients with multiple myeloma.
Traumatic lumbar puncture at diagnosis adversely affects outcome in childhood acute lymphoblastic leukemia
Authors: Gajjar Amar , Harrison Patricia L. , Sandlund John T. , Rivera Gaston K. , Ribeiro Raul C. , Rubnitz Jeffrey E. , Razzouk Bassem , Relling Mary V. , Evans William E. , Boyett James M. , Pui Ching-Hon 
Published: October 2019

AbstractThe effect of traumatic lumbar puncture at the time of initial diagnostic workup on treatment outcome in children with newly diagnosed acute lymphoblastic leukemia (ALL) was investigated. The findings of the first 2 lumbar punctures performed on 546 patients with newly diagnosed ALL treated on 2 consecutive front-line studies (1984-1991) at St Jude Children's Research Hospital were retrospectively reviewed. Lumbar punctures were performed at the time of diagnosis and again for the instillation of first intrathecal chemotherapy. The event-free survival (EFS) experience for patients with 1 cerebrospinal fluid (CSF) sample contaminated with blast cells was worse than that for patients with no contaminated CSF samples (P = .026); that of patients with 2 consecutive contaminated CSF samples was particularly poor (5-year EFS = 46 ± 9%). In a Cox multiple regression analysis, the strongest prognostic indicator was 2 consecutive contaminated CSF samples, with a hazard ratio of 2.39 (95% confidence interval, 1.36-4.20). These data indicate that contamination of CSF with circulating leukemic blast cells during diagnostic lumbar puncture can adversely affect the treatment outcome of children with ALL and is an indication to intensify intrathecal therapy.
Sphingosine 1-phosphate as a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells
Authors: Yatomi Yutaka , Ohmori Tsukasa , Rile Ge , Kazama Fuminori , Okamoto Hirotaka , Sano Takamitsu , Satoh Kaneo , Kume Shoji , Tigyi Gabor , Igarashi Yasuyuki , Ozaki Yukio 
Published: October 2019

AbstractThe serum-borne lysophospholipid mediators sphingosine 1-phosphate (Sph-1-P) and lysophosphatidic acid (LPA) have been shown to be released from activated platelets and to act on endothelial cells. In this study, we employed the repeated lipid extraction (under alkaline and acidic conditions), capable of detecting Sph-1-P, LPA, and possibly structurally similar lysophospholipids, whereby a marked formation of [32P]Sph-1-P, but not [32P]LPA, was observed in [32P]orthophosphate-labeled platelets. Platelet Sph-1-P release, possibly mediated by protein kinase C, was greatly enhanced in the presence of albumin, which formed a complex with Sph-1-P. This finding suggests that platelet Sph-1-P may become accessible to depletion by albumin when its transbilayer movement (flipping) across the plasma membrane is enhanced by protein kinase C. Although human umbilical vein endothelial cells expressed receptors for both Sph-1-P and LPA, Sph-1-P acted much more potently than LPA on the cells in terms of intracellular Ca++ mobilization, cytoskeletal reorganization, and migration. The results suggest that Sph-1-P, rather than LPA, is a major bioactive lysophospholipid that is released from platelets and interacts with endothelial cells, under the conditions in which critical platelet-endothelial interactions (including thrombosis, angiogenesis, and atherosclerosis) occur. Furthermore, albumin-bound Sph-1-P may account for at least some of the serum biological activities on endothelial cells, which have been ascribed to the effects of albumin-bound LPA, based on the similarities between LPA and serum effects.
Interleukin 1β inhibits interleukin 6–mediated rat γ fibrinogen gene expression
Authors: Zhang Zhixin , Fuller Gerald M. 
Published: October 2019

AbstractInterleukin (IL)-1β and IL-6 are the 2 major inducers of a group of hepatic genes during acute inflammation; however, each cytokine uses different intracellular signaling molecules. In most instances, the 2 cytokines interact positively to enhance hepatic gene expression, but in one class of acute-phase reactants, which includes fibrinogen, IL-1β exerts a transient inhibitory effect over the IL-6 stimulatory signal. This study explored the effects of IL-1β/nuclear factor κB (NF-κB) and IL-6/signal transducer and activator of transcription 3 (STAT3) combinatory signaling on the transcriptional regulation of the rat γ fibrinogen gene. Northern blot and functional analyses employing luciferase reporter constructs driven by the rat γ fibrinogen promoter demonstrated that IL-1β inhibited the IL-6-mediated transcription of this gene. Exposing primary rat hepatocytes to IL-1β had no effect on IL-6-mediated STAT3 activation; instead, IL-1β-activated NF-κB associated with 2 IL-6 responsive elements (STAT3 binding site) on the rat γ fibrinogen promoter and blocked STAT3 binding to these regions. The competitive binding of NF-κB and STAT3 on the overlapping binding site provides a mechanism for the inhibition by IL-1β of the IL-6-mediated transactivation of rat γ fibrinogen.
Efficient priming of protein antigen–specific human CD4+ T cells by monocyte-derived dendritic cells
Authors: Schlienger Katia , Craighead Nancy , Lee Kelvin P. , Levine Bruce L. , June Carl H. 
Published: October 2019

AbstractDendritic cells (DCs) have the unique ability to initiate an immune response in vivo by capturing antigens (Ags) in peripheral tissues and migrating to secondary lymphoid organs, where they sensitize naive CD4+ T cells. To mimic this process in vitro, previous studies have shown that DCs directly isolated from peripheral blood can be used to elicit primary responses to neoantigens (neoAgs). In other studies, when monocyte-derived DCs have been utilized to sensitize total CD4+ T cells in vitro, only secondary proliferation to neoAgs could be elicited. In the present study, the relative abilities of CD40 ligation, protein kinase C activation, and culture in tumor necrosis factor α (TNF-α) to induce functional and phenotypic maturation of human DCs from monocyte precursors were compared. Optimal TNF-α–induced maturation of DCs required a prolonged 4-day culture. It was then found that loading immature DCs with the neoAgs keyhole limpet hemocyanin or human immunodeficiency virus-1 p24 gag prior to TNF-α–induced maturation, rather than after maturation, was crucial to sensitize CD4+ T cells to new Ags. This primary proliferation to neoAgs was initiated from the CD4+ CD45RA+naive T-cell population. Finally, it was found that monocyte-derived DCs acquired the ability to secrete interleukin-12 p70, after contact with Ag-specific T cells. The ability to prime and expand Ag-specific CD4+ T cells ex vivo to neoAgs in serum-free conditions has potential application for cellular vaccination and adoptive immunotherapy.
Presentation of proteins encapsulated in sterically stabilized liposomes by dendritic cells initiates CD8+ T-cell responses in vivo
Authors: Ignatius Ralf , Mahnke Karsten , Rivera Miguel , Hong Keelung , Isdell Frank , Steinman Ralph M. , Pope Melissa , Stamatatos Leonidas 
Published: October 2019

AbstractLiposomes have been proposed as a vehicle to deliver proteins to antigen-presenting cells (APC), such as dendritic cells (DC), to stimulate strong T cell–mediated immune responses. Unfortunately, because of their instability in vivo and their rapid uptake by cells of the mononuclear phagocyte system on intravenous administration, most types of conventional liposomes lack clinical applicability. In contrast, sterically stabilized liposomes (SL) have increased in vivo stability. It is shown that both immature and mature DC take up SL into neutral or mildly acidic compartments distinct from endocytic vacuoles. These DC presented SL-encapsulated protein to both CD4+ and CD8+ T cells in vitro. Although CD4+ T-cell responses were comparable to those induced by soluble protein, CD8+ T-cell proliferation was up to 300-fold stronger when DC had been pulsed with SL-encapsulated ovalbumin. DC processed SL-encapsulated antigen through a TAP-dependent mechanism. Immunization of mice with SL-encapsulated ovalbumin led to antigen presentation by DC in vivo and stimulated greater CD8+ T-cell responses than immunization with soluble protein or with conventional or positively charged liposomes carrying ovalbumin. Therefore, the application of SL-encapsulated antigens offers a novel effective, safe vaccine approach if a combination of CD8+and CD4+ T-cell responses is desired (ie, in anti-viral or anti-tumor immunity).
Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites
Authors: Riemersma Sietske A. , Jordanova Ekaterina S. , Schop Roelandt F. J. , Philippo Katja , Looijenga Leendert H. J. , Schuuring Ed , Kluin Philip M. 
Published: October 2019

AbstractIn B-cell lymphomas, loss of human leukocyte antigen (HLA) class I and II molecules might contribute to immune escape from CD8+ and CD4+ cytotoxic T cells, especially because B cells can present their own idiotype. Loss of HLA expression and the possible underlying genomic alterations were studied in 28 testicular, 11 central nervous system, and 21 nodal diffuse large B-cell lymphomas (DLCLs), the first two sites are considered as immune-privileged sites. The analysis included immunohistochemistry, loss of heterozygosity analysis, and fluorescent in situ hybridization (FISH) on interphase cells and isolated DNA fibers. Total loss of HLA-A expression was found in 60% of the extranodal cases and in 10% of the nodal cases (P &lt; .01), whereas loss of HLA-DR expression was found in 56% and 5%, respectively (P &lt; .01). This was accompanied by extensive loss of heterozygosity within the HLA region in the extranodal DLCLs. In 3 cases, retention of heterozygosity for D6S1666 in the class II region suggested a homozygous deletion. This finding was confirmed by interphase FISH that showed homozygous deletions in the class II genes in 11 of the 18 extranodal lymphomas but in none of the 7 nodal DLCLs (P &lt; .001). Mapping by fiber FISH showed variable deletions that always included HLA-DQ and HLA-DR genes. Hemizygous deletions and mitotic recombinations often involving all HLA genes were found in 13 of 18 extranodal and 2 of 7 nodal lymphomas. In conclusion, a structural loss of HLA class I and II expression might help the B-cell lymphoma cells to escape from immune attack.
Hereditary hemochromatosis in a patient with congenital dyserythropoietic anemia
Authors: Fargion Silvia , Valenti Luca , Fracanzani Anna Ludovica , Sampietro Maurizio , Cappellini Maria Domenica , Scaccabarozzi Anna , Soligo Davide , Mariani Chiara , Fiorelli Gemino 
Published: October 2019

Abstract
Herein is described the case of a young woman presenting with iron overload and macrocytosis. The initial diagnosis was hereditary hemochromatosis. Severe anemia developed after a few phlebotomies, and she was also found to have congenital dyserythropoietic anemia that, though not completely typical, resembled type II. Only genetic testing allowed the definition of the coexistence of the 2 diseases, both responsible for the iron overload. This report points out the need to consider congenital dyserythropoietic anemia in patients with hemochromatosis and unexplained macrocytosis and, conversely, to check for the presence of hereditary hemochromatosis in patients with congenital dyserythropoietic anemia and severe iron overload. To the authors' knowledge, this is the first report of homozygosity for the C282Y mutation of the HFE gene in a patient affected by congenital dyserythropoietic anemia.