bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viral and cellular cytokines in AIDS-related malignant lymphomatous effusions
Authors: Aoki Yoshiyasu , Yarchoan Robert , Braun James , Iwamoto Aikichi , Tosato Giovanna 
Published: October 2019

Abstract
Kaposi sarcoma-associated herpesvirus encodes viral IL-6 (vIL-6). To investigate the potential role of vIL-6 in the pathogenesis of human immunodeficiency virus (HIV)- related primary effusion lymphomas (PEL), a sensitive enzyme-linked immunosorbent assay was developed for vIL-6 and applied to the study of PEL. Whereas vIL-6 was detectable in 6 of 8 PEL effusions (range, 1390-66 630 pg/mL), it was not detectable in any of the control effusions. As expected, all PEL effusions contained human IL-6 (range, 957-37 494 pg/mL), and 7 of 8 contained detectable human IL-10 (range, 66-2,521,297 pg/mL). Human and vIL-6 have previously been shown to induce vascular endothelial growth factor, which in turn can increase vascular permeability. The results of the current study suggest that these cytokines play a central role in the pathogenesis and manifestations of PEL.
Immune response to the ALK oncogenic tyrosine kinase in patients with anaplastic large-cell lymphoma
Authors: Pulford Karen , Falini Brunangelo , Banham Alison H. , Codrington Diana , Roberton Helen , Hatton Christopher , Mason David Y. 
Published: October 2019

Abstract
Oncogenic anaplastic lymphoma kinase (ALK) fusion proteins (nucleophosmin–ALK [NPM-ALK] and other variants) are expressed in many cases of anaplastic large-cell lymphoma (ALCL) but are absent from normal tissues. The possibility that ALK proteins are immunogenic was investigated with the use of an immunocytochemical technique to screen plasma from ALK-positive ALCL on transfectants expressing ALK proteins and by an in vitro kinase assay. Circulating antibodies against NPM-ALK protein were present in all ALK-positive ALCL patients (11 out of 11 cases) studied while 10 patients also had antibodies recognizing normal ALK protein. Weak antibodies reactive with NPM-ALK (which may represent anti-NPM autoantibodies) were detected by the in vitro kinase assay in 3 of the 10 control samples (but not by immunocytochemistry). The presence of anti-ALK antibodies may be relevant to the relatively good prognosis of ALK-positive ALCL. The immunocytochemical technique for detecting anti-ALK activity is simple and semiquantative and may provide a means of detecting B-cell responses to other tumor-associated molecules.
Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper
Authors: Colowick Alan B. , Bohn Rhonda L. , Avorn Jerry , Ewenstein Bruce M. 
Published: October 2019

Abstract
The development of inhibitory antibodies to factor VIII (FVIII) occurs in approximately 30% to 40% of patients with severe hemophilia A. Management options for patients with inhibitor include eradicating it via immune tolerance induction (ITI) or treating bleeding episodes with large quantities of hemostatic agents. ITI is costly, approaching $1 million for the average 5-year-old, but if successful results in improved clinical outcomes. We constructed a decision analysis using the Markov process to model expected clinical outcomes and costs over a lifetime for a typical 5-year-old hemophiliac with high inhibitor levels. Estimates of relevant variables were based on a thorough review of the medical literature. Outcomes modeled included total lifetime costs as well as life expectancy. The decision analytic model revealed that the ITI strategy was associated with an increase in projected life expectancy of 4.6 years. Total estimated lifetime costs for the ITI strategy were approximately $1.7 million less per patient. Sensitivity analyses over clinically and economically reasonable ranges did not change these findings. The insight that ITI can achieve an improved clinical outcome while being cost-saving is not reflected in many current treatment regimens. This example also illustrates that expensive therapy for patients with a chronic disease may be cost effective when analyzed from a societal perspective over the patient's lifetime. This finding has important policy implications for medical decision makers at many levels and reinforces the need to undertake pharmacoeconomic analyses and choose therapies from a long-term, societal perspective.
Urokinase mediates fibrinolysis in the pulmonary microvasculature
Authors: Bdeir Khalil , Murciano Juan-Carlos , Tomaszewski John , Koniaris Lauren , Martinez Jose , Cines Douglas B. , Muzykantov Vladimir R. , Higazi Abd Al-Roof 
Published: October 2019

AbstractThe role of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) in fibrinolysis remains unsettled. The contribution of uPA may depend on the vascular location, the physical properties of the clot, and its impact on tissue function. To study the contribution of urokinase within the pulmonary microvasculature, a model of pulmonary microembolism in the mouse was developed. Iodine 125 (125I)–labeled fibrin microparticles injected intravenously through the tail vein lodged preferentially in the lung, distributing homogeneously throughout the lobes. Clearance of125I-microemboli in wild type mice was rapid and essentially complete by 5 hours. In contrast, uPA−/− and tissue-type plasminogen activator tPA−/− mice, but not uPAR−/− mice, showed a marked impairment in pulmonary fibrinolysis throughout the experimental period. The phenotype in the uPA−/− mouse was rescued completely by infusion of single chain uPA (scuPA). The increment in clot lysis was 4-fold greater in uPA−/− mice infused with the same concentration of scuPA complexed with soluble recombinant uPAR. These data indicate that uPA contributes to endogenous fibrinolysis in the pulmonary vasculature to the same extent as tPA in this model system. Binding of scuPA to its receptor promotes fibrinolytic activity in vivo as well as in vitro. The physical properties of fibrin clots, including size, age, and cellular composition, as well as heterogeneity in endothelial cell function, may modify the participation of uPA in endogenous fibrinolysis.
Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy
Authors: Mudry Ryan E. , Fortney James E. , York Teresa , Hall Brett M. , Gibson Laura F. 
Published: October 2019

AbstractApproximately 20% of B-lineage acute lymphoblastic leukemias are not cured by traditional chemotherapy. The possibility was examined that residual leukemic cells that potentially contribute to relapse are harbored in association with fibroblastic stromal cells in the bone marrow. Modulation of cytarabine (Ara-C) and etoposide (VP-16) efficacy by bone marrow stromal cells in vitro was investigated. Stromal cell coculture was shown to sustain the proliferation of B-lineage leukemic cells and to reduce leukemic cell apoptosis when exposed to Ara-C or VP-16. Direct contact with stromal cells was essential for the protection of leukemic cells during chemotherapy, whereas soluble factors had negligible effect. Specifically, signaling mediated through interaction with the stromal cell adhesion molecule VCAM-1 was required to maintain the maximum viability of leukemic cells during Ara-C and VP-16 exposure. In contrast, the interaction of leukemic cells with fibronectin did not confer significant resistance to either chemotherapeutic agent. These observations suggest a role for the bone marrow microenvironment in modulating the response of B-lineage leukemic cells to Ara-C or VP-16, and they indicate specific molecular interactions that may be important in determining the sensitivity of leukemic cells to treatment.
V(D)J recombinase-mediated transposition of the BCL2gene to the IGH locus in follicular lymphoma
Authors: Vaandrager Jan-Willem , Schuuring Ed , Philippo Katja , Kluin Philip M. 
Published: October 2019

AbstractUsing DNA fiber fluorescence in-situ hybridization (FISH) and 3-color interphase FISH, 2 cases of follicular lymphoma were identified in which the BCL2 gene was excised from 18q21 and inserted into the immunoglobulin heavy chain (IGH) locus at 14q32. Both the insertion breakpoint at 14q32 and the deletion breakpoint at 18q21 were cloned using inverse polymerase chain reaction. Sequence analysis showed that the JH sequences were juxtaposed to the 5′-side of BCL2, and the DH sequences were juxtaposed to the 3′-side of BCL2. There were breakpoints at both the JH and DH recombination signal sequences, and N-nucleotides were present at all breakpoint junctions. At theBCL2 locus, the 3′-breakpoints in both cases were localized at exactly the same nucleotide position, 6.2 kilobase downstream of the major breakpoint region, directly adjacent to a complete cryptic recombination signal sequence (RSS) consisting of a heptamer, a nonamer, and a 23–base pair (bp) spacer. The BCL25′-breakpoints were approximately 600 bp upstream of the gene, within the CA repeats. Although less evident than for the BCL23′-breakpoints, cryptic RSSs were also identified at these breakpoints, with a 12-bp spacer. On the basis of structural characteristics of these rearrangements, a model is proposed in which the BCL2 gene is deleted from its locus by recombination activation gene-1/-2 (RAG-1/-2)–mediated excision. The gene is subsequently inserted into the recombiningIGH locus, a process involving the formation of hybrid joints between the IGH coding ends and theBCL2 signal ends.
CD34 expression by murine hematopoietic stem cells mobilized by granulocyte colony-stimulating factor
Authors: Tajima Fumihito , Sato Takashi , Laver Joseph H. , Ogawa Makio 
Published: October 2019

Abstract
Controversy has existed about CD34 expression by hematopoietic stem cells. We recently reported that CD34 expression reflects the activation state of stem cells by using a murine transplantation model. It has been generally held that mobilized blood stem cells express CD34.However, it has also been reported that mobilized stem cells and progenitors are in G0/G1 phases of the cell cycle. To address the state of CD34 expression by the mobilized stem cells, we again used the mouse transplantation model. We prepared CD34− and CD34+ populations of nucleated blood cells from granulocyte colony-stimulating factor–treated Ly-5.1 mice and assayed each population for long-term engrafting cells in lethally irradiated Ly-5.2 mice. The majority of the stem cells were in the CD34+population. The CD34 expression by mobilized stem cells was reversible because re-transplantation of Ly-5.1 CD34− marrow cells harvested from the Ly-5.2 recipients of CD34+-mobilized stem cells 8 months posttransplantation revealed long-term engraftment. These results may support the use of total CD34+ cells in mobilized blood as a predictor for engraftment and CD34 selection for enrichment of human stem cells.
Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level
Authors: Nilsson Lars , Åstrand-Grundström Ingbritt , Arvidsson Ingrid , Jacobsson Björn , Hellström-Lindberg Eva , Hast Robert , Jacobsen Sten E. W. 
Published: October 2019

AbstractMyelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. Within MDS, 5q− syndrome constitutes a distinct clinical entity characterized by an isolated deletion of the long arm of chromosome 5 (5q−), a relatively good prognosis, and infrequent transformation to acute leukemia. The cell of origin in 5q− syndrome as well as in other 5q-deleted MDS patients has not been established, but evidence for involvement of multiple myeloid (but not lymphoid) lineages has suggested that a myeloid-restricted progenitor rather than a pluripotent (lympho-myeloid) stem cell might be the primary target in most patients. Although in 9 patients no evidence of peripheral blood T-cell and only 1 case of B-cell involvement was found, the data herein support that 5q deletions occur in hematopoietic stem cells (HSCs) with a combined lympho-myeloid potential. First, in all investigated patients a minimum of 94% of cells in the minor CD34+CD38− HSC compartment were 5q deleted as determined by fluorescence in situ hybridization. Second, in 3 of 5 patients 5q aberrations were detected in a large fraction (25% to 90%) of purified CD34+CD19+ pro-B cells. Furthermore, extensive functional characterization with regard to responsiveness to early-acting cytokines, long-term culture-initiating cells, and nonobese diabetic/severe combined immunodeficiency repopulating cells supported that MDS HSCs in 5q-deleted patients are CD34+CD38−, but inefficient at reconstituting hematopoiesis.
Soluble CD40 ligand induces selective proliferation of lymphoma cells in primary mantle cell lymphoma cell cultures
Authors: Andersen Niels S. , Larsen Jørgen K. , Christiansen Jette , Pedersen Lone B. , Christophersen Nicolaj S. , Geisler Christian H. , Jurlander Jesper 
Published: October 2019

AbstractInteraction between CD40 and the CD40 ligand (CD40L) is critical for the survival and proliferation of B cells during immunopoiesis. However, the role of CD40L in the pathogenesis of malignant lymphomas is ambiguous. Primary mantle cell lymphoma (MCL) cells were cultured in the presence of recombinant human CD40L trimer (huCD40LT), and a significant time- and dose-dependent induction of DNA synthesis was observed in thymidine incorporation assays (n = 7,P &lt; .04). The maximal rate of DNA synthesis was reached at huCD40LT doses of 100 ng/mL and above after 4 days of culture, but a significant increase of DNA synthesis was detected already at doses of 1 ng/mL (P = .03). HuCD40LT never inhibited the basal level of DNA synthesis. These findings established 400 ng/mL of huCD40LT for 4 days as standard conditions in the system. Under these conditions, huCD40LT significantly increased the proportion of cells in the S/G2/M phases of the cell cycle in 4 of 7 studied cases, while the fraction of apoptotic cells remained unchanged (n = 7). HuCD40LT also induced expression of CD80/B7-1, CD86/B7-2, and CD95/Fas and up-regulated the expression of HLA-DR (n = 6). With the use of bromodeoxyuridine incorporation in triple-color flow cytometric analysis, it was found that huCD40LT induced cell-cycle progression in light chain–restricted cells only, of which a median of 14% (range, 0.5% to 29%; n = 4) returned to G0/1 phase DNA content after bromodeoxyuridine incorporation, demonstrating completion of at least one cell cycle in the presence of huCD40LT. Thus, primary clonal MCL cells are activated and can proliferate in the presence of huCD40LT as a single agent.
Synergism of multiple adhesion molecules in mediating cytoadherence of Plasmodium falciparum–infected erythrocytes to microvascular endothelial cells under flow
Authors: Yipp Bryan G. , Anand Samantha , Schollaardt Tineke , Patel Kamala D. , Looareesuwan Sornchai , Ho May 
Published: October 2019

AbstractPlasmodium falciparum–infected erythrocytes (IRBCs) have been shown to interact with a number of endothelial adhesion molecules expressed on transfectants, on cell lines, and as immobilized purified receptor proteins under flow conditions. However, the experiments were designed in such a way that maximal numbers of adhesion molecules were provided as substratum. Whether the interactive events actually occur on microvascular endothelium, where the distribution and expression of adhesion molecules may be less, remains undetermined. In this study, the cytoadherance of IRBCs on human dermal microvascular endothelial cells (HDMECs) as a model of human microvasculature was examined. IRBCs were observed to tether, roll, and adhere on resting HDMECs, which constitutively expressed CD36 and intercellular adhesion molecule-1 (ICAM-1) at an optimal shear stress of 1 dyne/cm2. Stimulation of HDMECs with tumor necrosis factor–α for 5 and 24 hours, which resulted in up-regulation of ICAM-1 and induction of vascular cell adhesion molecule-1 expression, significantly increased the percentage of rolling cells that adhered without affecting the rolling flux. In contrast, P-selectin expression on HDMECs induced by oncostatin M led to an increase in both rolling flux and adhesion. Inhibition studies with receptor-specific monoclonal antibodies revealed that adhesion of IRBCs on HDMECs was largely CD36 dependent, whereas rolling could be mediated by any of the adhesion molecules studied. Collectively, these findings indicate that IRBCs interact synergistically with multiple adhesion molecules on vascular endothelium. The rolling of IRBCs may be the rate-limiting step in cytoadherance, since it can be modulated by cytokines to enhance CD36-mediated IRBC adhesion.
Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: evidence for selectin-dependent and independent mechanisms
Authors: Frenette Paul S. , Weiss Linnea 
Published: October 2019

AbstractThe adhesive mechanisms leading to the mobilization of hematopoietic progenitor cells (HPCs) from the bone marrow into the blood are poorly understood. We report on a role for selectins and fucoidan in progenitor mobilization. Baseline levels of circulating HPCs are increased in endothelial selectin-deficient (P/E−/−) mice. Similar levels are observed when E-selectin null (E−/−) mice are treated with anti-P-selectin antibody or with fucoidan (which inhibits P- and L-selectin function). In particular, administration of 2 doses of fucoidan (25 mg/kg) over 6 hours produces profound mobilization of progenitors in wild-type mice and the response is greatly enhanced in E−/− and P/E−/− mice. Competitive reconstitution experiments reveal that fucoidan also elicits long-term (more than 6 months) repopulating stem cells. Mobilization assays using chimeric mice harboring L-selectin–deficient progenitors and wild-type progenitors expressing the green fluorescence protein suggest that L-selectin expression is not required but confers an advantage for fucoidan-induced mobilization. Sulfation is critical as desulfated fucoidan is ineffective. In addition, sulphogalactosylceramide (sulfatide) but not heparin can induce HPC mobilization. Our results indicate that administration of sulfated glycans, especially with concurrent inhibition of E-selectin function, represents a powerful novel method for rapid mobilization of long-term–repopulating stem cells. These findings may help elucidate the mechanisms of HPC trafficking during development and adult life.
Maturation of dendritic cells leads to up-regulation of cellular FLICE-inhibitory protein and concomitant down-regulation of death ligand–mediated apoptosis
Authors: Leverkus Martin , Walczak Henning , McLellan Alex , Fries Hans-Werner , Terbeck Gabi , Bröcker Eva-B. , Kämpgen Eckhart 
Published: October 2019

AbstractDendritic cells (DCs) disappear from lymph nodes 1 to 2 days after antigen presentation, presumably by apoptosis. To evaluate the role of death ligands in elimination of DCs, we analyzed the sensitivity of human DCs to CD95 ligand (CD95L) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found mature DCs to be resistant to killing via CD95L or TRAIL, whereas only immature DCs were partially sensitive. However, all DC populations expressed CD95, TRAIL-R2, and TRAIL-R3 at comparable levels, suggesting that sensitivity to death ligand-induced DC apoptosis is not regulated at the receptor level. Interestingly, mature DCs highly expressed the caspase 8 inhibitory protein cFLIP, whereas only low levels were detected in immature DCs. Thus, death ligand sensitivity proved to be dependent on DC maturation and inversely correlated with expression levels of cFLIP. Induction of apoptosis by TRAIL or CD95L does not seem to play a role in the elimination of mature DCs, but instead might serve to regulate immature DC populations.
Cell cycle exit during terminal erythroid differentiation is associated with accumulation of p27Kip1 and inactivation of cdk2 kinase
Authors: Hsieh Fen F. , Barnett Lou Ann , Green Wayne F. , Freedman Karen , Matushansky Igor , Skoultchi Arthur I. , Kelley Linda L. 
Published: October 2019

Abstract
Progression through the mammalian cell cycle is regulated by cyclins, cyclin- dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs). The function of these proteins in the irreversible growth arrest associated with terminally differentiated cells is largely unknown. The function of Cip/Kip proteins p21Cip1and p27Kip1 during erythropoietin-induced terminal differentiation of primary erythroblasts isolated from the spleens of mice infected with the anemia-inducing strain of Friend virus was investigated. Both p21Cip1 and p27Kip1 proteins were induced during erythroid differentiation, but only p27Kip1 associated with the principal G1CDKs—cdk4, cdk6, and cdk2. The kinetics of binding of p27Kip1 to CDK complexes was distinct in that p27Kip1 associated primarily with cdk4 (and, to a lesser extent, cdk6) early in differentiation, followed by subsequent association with cdk2. Binding of p27Kip1 to cdk4 had no apparent inhibitory effect on cdk4 kinase activity, whereas inhibition of cdk2 kinase activity was associated with p27Kip1binding, accumulation of hypo-phosphorylated retinoblastoma protein, and G1 growth arrest. Inhibition of cdk4 kinase activity late in differentiation resulted from events other than p27Kip1 binding or loss of cyclin D from the complex. The data demonstrate that p27Kip1 differentially regulates the activity of cdk4 and cdk2 during terminal erythroid differentiation and suggests a switching mechanism whereby cdk4 functions to sequester p27Kip1 until a specified time in differentiation when cdk2 kinase activity is targeted by p27Kip1 to elicit G1 growth arrest. Further, the data imply that p21Cip1 may have a function independent of growth arrest during erythroid differentiation.
Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: implications for capillary-like tube formation in a fibrin matrix
Authors: Kroon Marielle E. , Koolwijk Pieter , van der Vecht Bea , van Hinsbergh Victor W. M. 
Published: October 2019

AbstractHypoxia stimulates angiogenesis, the formation of new blood vessels. This study evaluates the direct effect of hypoxia (1% oxygen) on the angiogenic response of human microvascular endothelial cells (hMVECs) seeded on top of a 3-dimensional fibrin matrix. hMVECs stimulated with fibroblast growth factor–2 (FGF-2) or vascular endothelial growth factor (VEGF) together with tumor necrosis factor–α (TNF-α) formed 2- to 3-fold more tubular structures under hypoxic conditions than in normoxic (20% oxygen) conditions. In both conditions the in-growth of capillary-like tubular structures into fibrin required cell-bound urokinase-type plasminogen activator (uPA) and plasmin activities. The hypoxia-induced increase in tube formation was accompanied by a decrease in uPA accumulation in the conditioned medium. This decrease in uPA level was completely abolished by uPA receptor-blocking antibodies. During hypoxic culturing uPA receptor activity and messenger RNA (mRNA) were indeed increased. This increase and, as a consequence, an increase in plasmin formation contribute to the hypoxia-induced stimulation of tube formation. A possible contribution of VEGF-A to the increased formation under hypoxic conditions is unlikely because there was no increased VEGF-A expression detected under hypoxic conditions, and the hypoxia-induced tube formation by FGF-2 and TNF-α was not inhibited by soluble VEGFR-1 (sVEGFR-1), or by antibodies blocking VEGFR-2. Furthermore, although the αv-integrin subunit was enhanced by hypoxia, blocking antibodies against αvβ3- and αvβ5-integrins had no effect on hypoxia-induced tube formation. Hypoxia increases uPA association and the angiogenic response of human endothelial cells in a fibrin matrix; the increase in the uPA receptor is an important determinant in this process.