bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response at Three Months Is a Good Predictive Factor for Newly Diagnosed Chronic Myeloid Leukemia Patients Treated by Recombinant Interferon-
Authors: Mahon F.X. , Fabères C. , Pueyo S. , Cony-Makhoul P. , Salmi R. , Boiron J.M. , Marit G. , Bilhou-Nabera C. , Carrère A. , Montastruc M. , Pigneux A. , Bernard Ph. , Reiffers J. 
Published: October 2019

Abstract
In a single institution, we have used recombinant interferon- (IFN-) to treat 116 newly diagnosed Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients and analyzed the predictive factors for response and survival. The patients whose median age was 50.3 years (range, 9 to 70) were administered IFN- (5 million units/m2/d) subcutaneously. The IFN- dose was subsequently adjusted to maintain the white blood cell and platelet counts between 1.5 and 5 × 109/L, 50 and 100 × 109/L, respectively. At diagnosis, the Sokal score was used to classify the patients into three groups: low (n = 57), intermediate (n = 42), and high risk (n = 16). A complete hematological response (CHR) was achieved in 93 cases (80.2%). Of the 116 patients, 113 were available for cytogenetic evaluation. Fifty patients (43%) achieved a major cytogenetic response (MCR) (=65% marrow Ph− cells), 37 of them having a complete cytogenetic response (CCR). The estimated 5-year survival of the 116 patients was 68% ± 11% (95% confidence interval [CI]) with a median follow-up of 42 months (range, 3 to 114) and 85% ± 11% (95% CI) with a median follow-up of 30.9 (range, 3 to 111) when patients were censored at the time of transplantation. Event-free survival at 5 years (adding death and transplant as event) was 46% ± 11% (95% CI). Using proportional hazards regression to study time-dependent variables, we confirmed that the most significant factor associated with survival was the cytogenetic response (MCR or CCR) (P &lt; .0001). This factor was independent compared with the Sokal score and baseline variables used to calculate the Sokal score. Moreover, using either univariate or multivariate analysis, the achievement of CHR within 3 months was strongly correlated with MCR (P &lt; .0001). Minimum cytogenetic response (mCR, ie, at least 5% of Ph− metaphases) at 3 months was also a significant predictive factor for MCR (P &lt; .0001). These results show that IFN- can induce a high rate of hematological and cytogenetic response when administered in doses leading to myelosuppression. Factors such as the achievement of CHR and mCR within 3 months could be useful to identify early those patients who will not respond to IFN- and who need alternative treatments such as stem cell transplantation.
Influence of Cytokines on the Growth Kinetics and Immunophenotype of Daughter Cells Resulting From the First Division of Single CD34+Thy-1+lin− Cells
Authors: Goff Julie P. , Shields Donna S. , Greenberger Joel S. 
Published: October 2019

AbstractThere is a need to determine whether culture conditions may exist for ex vivo expansion of hematopoeitic stem cells (HSC), which favor solely proliferative self-renewal of HSC as opposed to proliferation with differentiation. Using single cells, we studied the effects of individual and combinations of cytokines in serum-free medium on the kinetics of the first cell doubling and the resulting phenotype of each of individual daughter cell. CD34+Thy-1+lin−cells were plated 1 cell per well in Terasaki plates in serum-free medium containing cytokines. Each well containing a single cell was monitored daily over 7 days for maintenance, division, or death. When division occurred in an individual well, the phenotype of the daughter cells was determined by staining with anti-CD34 fluorescein isothiocyanate (FITC)- and phycoerythrin (PE)-conjugated lineage specific antibodies. The cumulative percent of wells with an undivided single cell, wells in which the cell had divided, and wells in which the cell had died were scored. The number of doublets with conserved phenotype (CD34+lin−) was compared to those wells with one or more differentiated daughter cells (CD34+lin+). Over 7 days, cells cultured in single factors showed that between 13% (interleukin-6 [IL-6]) and 29% (thrombopoietin [TPO]) of the cells were undivided, between 13% (IL-1) and 35% (TPO) of the cells doubled, and between 35% (TPO) and greater than 60% (IL-11, IL-1, or hepatocyte growth factor [HGF]) died. When combinations of cytokines were used over 7 days, between 5% (FLT-3 ligand [FLT-3L], stem cell factor [SCF], IL-3, IL-6, granulocyte colony-stimulating factor [G-CSF], β nerve growth factor [βNGF]) and 22% (FLT-3L + HGF) of the cells remained undivided, between 15% (HGF, IL-1, IL-11, G-CSF) and 68% (SCF + TPO) of the cells had doubled and between 27% (FLT-3L + TPO) and 70% (HGF, IL-1, IL-11, G-CSF) died. The combination of FLT-3L + TPO induced the highest total percent (64.6%) of cells with conserved phenotype (percent conserved doublets + percent with 1 cell conserved), followed by SCF + TPO, (50%) and the combination of FLT-3L, SCF, IL-3, IL-6, G-CSF, βNGF (53%). These combinations also produced the highest yield of cells with conserved phenotype after one division (FLT-3L + TPO − 81 cells/100 initial cells, SCF + TPO − 68 cells/100 initial cells) (P = .01). Observation of the time of the initial cell division and phenotype of the daughter cells allowed us to identify candidate combinations of cytokines that promote maintenance of lin− cells (TPO), or recruit the primitive cells to divide and undergo phenotypic self-renewal (FLT-3L + TPO, SCF + TPO).
Interleukin-6 (IL-6) Prevents Activation-Induced Cell Death: IL-2–Independent Inhibition of Fas/fasL Expression and Cell Death
Authors: Ayroldi Emira , Zollo Ornella , Cannarile Lorenza , D’ Adamio Francesca , Grohmann Ursula , Delfino Domenico V. , Riccardi Carlo 
Published: October 2019

AbstractTriggering of the TCR/CD3 complex with specific antigen or anti-CD3 monoclonal antibody initiates activation-induced cell death (AICD) in mature T cells, an effect also mediated by the Fas/FasL system. We have previously shown that CD2 stimulation rescues T cells from TCR/CD3-induced apoptosis by decreasing the expression of Fas and FasL. In the present study, we examined whether the endogenous production of IL-2 plays a role in the effects mediated by CD2 triggering. The results indicated that transcription of Fas/FasL is controlled by interleukin-2 (IL-2) production and that CD2 triggering rescues a T-cell hybridoma from AICD via decreased production of IL-2. To ascertain whether modulation of IL-2 may be a general mechanism of AICD control, we examined other stimuli, capable of modulating the expression of the Fas/FasL system and the ensuing AICD, for ability to affect production of IL-2. We found that IL-6 reduced the level of TCR/CD3-induced apoptosis and the expression of Fas/FasL, yet failed to inhibit IL-2 production. Because IL-2 is involved in both apoptosis and activation events, these results indicate that, in contrast to CD2, which inhibits apoptosis and T cell activation, IL-6 inhibits apoptosis but not IL-2–induced activation. These observations may provide the basis for differential control of T-cell activation and apoptosis.
Generation of Cells With Hodgkin’s and Reed-Sternberg Phenotype Through Downregulation of CD99 (Mic2)
Authors: Kim Soon Ha , Choi Eun Young , Shin Young Kee , Kim Tae Jin , Chung Doo Hyun , Chang Sung Ik , Kim Noe Kyeong , Park Seong Hoe 
Published: October 2019

AbstractDespite the fact that Hodgkin’s and Reed-Sternberg (H-RS) cells are morphological hallmarks of Hodgkin’s disease (HD), the nature of H-RS cells still remains to be resolved. Here we report that downregulation of CD99 (Mic2) leads to the generation of cells with an H-RS phenotype. IM9 and BJAB B-cell lines that were transfected with an antisense CD99 expression construct showed the morphological and immunological characteristics of H-RS cells such as multinuclearity, expression of CD15, decreased expression of major histocompatibility complex (MHC) class I and CD45RB, and deregulated secretion of cytokines. The reduced expression of CD99 was also confirmed in H-RS cells of patient’s lymph nodes and three HD-derived cell lines, L428, KM-H2, and HDLM-2. Moreover, features characteristic of H-RS cells were completely abolished by forced expression of CD99 and by a constitutively active form of Rac, which functions downstream of CD99. We suggest that CD99 molecules play a crucial role in regulating functions and morphology of cells through a Rac-Rho signaling pathway and that the loss of CD99 expression is a significant molecular event to generate H-RS cells.
Coinduction of Embryonic and Adult-Type Globin mRNAs by Sodium Butyrate and Trichostatin A in Two Murine Interleukin-3–Dependent Bone Marrow–Derived Cell Lines
Authors: Ishiguro Kimiko , Sartorelli Alan C. 
Published: October 2019

AbstractUsing an RNase protection assay, globin mRNA species expressed in clones derived from Ba/F3 and B6SUtA cells transfected with the erythropoietin receptor (EpoR) and selected with erythropoietin (Epo) were compared with globin mRNA species induced in corresponding parental cells by sodium butyrate (SB) and trichostatin A (TSA). βMajor/βminor- and -1/-2–globin mRNAs were the major species, with trace amounts of ɛ-globin mRNA, formed in Epo-stimulated EpoR+ Ba/F3 clones, whereas SB and TSA allowed expression of all species of globin mRNAs, ie, ɛ, βh1, βmajor/βminor, ζ, and -1/-2, in parental Ba/F3 cells. In contrast, ɛ- and -1/-2–globin mRNAs were the major species present in Epo-stimulated EpoR+ B6SUtA clones, whereas SB and TSA activated ɛ-, βh1-, βS/βT-, and -1/-2–globin genes in parental B6SUtA cells; ζ-globin mRNA was not detected in SB- and TSA-treated B6SUtA cells. Because TSA is a specific inhibitor of histone deacetylase, the mimicry of action exhibited by SB and TSA suggests that the effects of SB are mediated through its ability to inhibit histone deacetylase and that histone deacetylase is an integral part of the repression of globin genes in these interleukin-3–dependent cells. Efficient coinduction of embryonic and adult types of globin mRNA in bone marrow cell lines derived from adult mice indicates that adult hematopoietic precursors possess an embryonic nature. These cell lines are useful models to study the mechanism(s) of developmental globin gene switching.
Functional Cell Surface Expression of Band 3, the Human Red Blood Cell Anion Exchange Protein (AE1), in K562 Erythroleukemia Cells: Band 3 Enhances the Cell Surface Reactivity of Rh Antigens
Authors: Beckmann Roland , Smythe Jonathan S. , Anstee David J. , Tanner Michael J.A. 
Published: October 2019

AbstractHuman K562 erythroleukemia cells were transfected with human band 3 (anion exchanger 1 [AE1]) cDNA, using the pBabe retroviral vector. Stable K562 clones expressing band 3 were isolated by flow cytometry, and surface expression was quantified by immunoblotting. The function of band 3 expressed at the cell surface was demonstrated in chloride transport assays. K562 cells expressing band 3 also displayed high levels of the Wrb blood group antigen, confirming the role of band 3 in Wrb expression, and an increase in the low levels of endogenous Rh antigen activity. We also performed coexpression experiments with K562 clones that had previously been transduced with cDNAs encoding RhD or RhcE polypeptides. The transfection and expression of band 3 in these clones substantially increased the levels of RhD and cE antigen activity expressed on the cells and also increased the reactivity of the cells with antibody to the endogenous Rh glycoprotein (RhGP, Rh50). The increased reactivity of Rh antigens may result from cell surface or intracellular interactions of band 3 with the protein complex which contains the Rh polypeptides and RhGP, or from indirect effects of band 3 on the membrane environment. This work establishes a system for cell surface expression of band 3 in a mammalian cell line, which will enable further studies of the protein and its interactions with other membrane components.
Reconstitution of the T-Cell Compartment After Bone Marrow Transplantation: Restoration of the Repertoire by Thymic Emigrants
Authors: Dumont-Girard Florence , Roux Etienne , van Lier René A. , Hale Geoff , Helg Claudine , Chapuis Bernard , Starobinski Michel , Roosnek Eddy 
Published: October 2019

AbstractWe have studied the reconstitution of the T-cell compartment after bone marrow transplantation (BMT) in five patients who received a graft-versus-host disease (GVHD) prophylaxis consisting of methotrexate, cyclosporin, and 10 daily injections (day −4 to day +5) of Campath-1G. This treatment eliminated virtually all T cells (7 ± 8 T cells/μL at day 14) which facilitated the analysis of the thymus-dependent and independent pathways of T-cell regeneration. During the first 6 months, the peripheral T-cell pool was repopulated exclusively through expansion of residual T cells with all CD4+ T cells expressing the CD45RO-memory marker. In two patients, the expansion was extensive and within 2 months, the total number of T cells (CD8&gt;&gt;CD4) exceeded 1,000/μL. In the other three patients, T cells remained low (87 ± 64 T cells/μL at 6 months) and remained below normal values during the 2 years of the study. In all patients, the first CD4+CD45RA+RO− T cells appeared after 6 months and accumulated thereafter. In the youngest patient (age 13), the increase was relatively fast and naive CD4+ T cells reached normal levels (600 T cells/μL) 1 year later. In the four adult patients (age 25 ± 5), the levels reached at that time-point were significantly lower (71 ± 50 T cells/μL). In all patients, the T-cell repertoire that had been very limited, diversified with the advent of the CD4+CD45RA+RO− T cells. Cell sorting experiments showed that this could be attributed to the complexity of the T-cell repertoire of the CD4+CD45RA+RO− T cells that was comparable to that of a normal individual and that, therefore, it is likely that these cells are thymic emigrants. We conclude that after BMT, the thymus is essential for the restoration of the T-cell repertoire. Because the thymic activity is restored with a lag time of approximately 6 months, this might explain why, in particular in recipients of a T-cell–depleted graft, immune recovery is delayed.
The Human Poliovirus Receptor Related 2 Protein Is a New Hematopoietic/Endothelial Homophilic Adhesion Molecule
Authors: Lopez Marc , Aoubala Mustapha , Jordier François , Isnardon Daniel , Gomez Sophie , Dubreuil Patrice 
Published: October 2019

AbstractWe have recently described Poliovirus Receptor Related 2 (PRR2), a new cell surface molecule homologous to the poliovirus receptor (PVR/CD155). Both molecules are transmembrane glycoproteins belonging to the Ig superfamily (IgSF). They contain 3 Ig domains of V, C2, and C2 types in their extracellular regions that share 51% aa identity. The PRR2 gene encodes two mRNA isoforms of 3.0 kb (hPRR2 [short form]) and 4.4 kb (hPRR2δ [long form]), both widely expressed in human tissues, including hematopoietic cells. To further characterize PRR2 expression during hematopoiesis and to analyze its function, we have developed a monoclonal antibody (MoAb) directed against its extracellular region (R2.477). PRR2 was expressed in 96% of the CD34+, 88% of the CD33+, and 95% of the CD14+ hematopoietic lineages and faintly in the CD41 compartment. Ectopic expression of both PRR2 cDNAs induced marked cell aggregation. A soluble chimeric receptor construct with the Fc fragment of human IgG1 (PRR2-Fc) as well as a fab fragment of the anti-PRR2 MoAb (R2.477) inhibit aggregation. PRR2-Fc binds specifically to PRR2-expressing cells. These results suggest that PRR2 is a homophilic adhesion receptor. PRR2 was also expressed at the surface of endothelial cells at the intercellular junctions of adjacent cells but not at the free cellular edges. Homophilic interactions are associated with dimerization of isoforms of PRR2 and lead to the tyrosine phosphorylation of PRR2δ. Altogether, these results suggest that homophilic properties of PRR2 could participate to the regulation of hematopoietic/endothelial cell functions.
A Novel Mutation in the D3 Domain of von Willebrand Factor Markedly Decreases Its Ability to Bind Factor VIII and Affects Its Multimerization
Authors: Jorieux S. , Gaucher C. , Goudemand J. , Mazurier C. 
Published: October 2019

AbstractIn type 2N von Willebrand disease (vWD), von Willebrand factor (vWF) is characterized by normal multimeric pattern, normal platelet-dependent function, but a markedly decreased affinity for factor VIII (FVIII). In this report, we describe the case of a vWD patient who has an abnormal vWF multimers distribution associated with a markedly decreased vWF ability to bind FVIII. Sequencing analysis of patient’s vWF gene showed, at heterozygous state, a G→A transition resulting in the substitution of Asn for Asp at position 116 of the mature vWF subunit and a C→T transition, changing the codon for Arg 896 into a stop codon. His sister who has a subnormal vWF level, but a normal FVIII/vWF interaction, was found to be heterozygous for the Arg896ter mutation only. Recombinant vWF (rvWF) containing the candidate (Asn116) missense mutation was expressed in COS-7 cells. The expression level of Asn116rvWF was significantly decreased compared with wild-type rvWF. The multimeric pattern of Asn116rvWF was greatly impaired as shown by the decrease in high molecular weight forms. The FVIII binding ability of Asn116rvWF was dramatically decreased. These data show that the Asp116Asn substitution is the cause of both the defective FVIII/vWF interaction and the impaired multimeric pattern observed in the patient’s vWF. The monoclonal antibody 31H3 against D’ domain of vWF (epitope aa 66-76) that partially inhibits the FVIII binding and recognizes only nonreduced vWF, showed a decreased ability to bind Asn116rvWF when used as capture-antibody in enzyme-linked immunosorbent assay (ELISA). This result suggests that a potential conformation change in the D’ domain is induced by the Asp116Asn substitution, which is localized in the D3 domain.
Interleukin-10 Suppresses IP-10 Gene Transcription by Inhibiting the Production of Class I Interferon
Authors: Tebo Julie M. , Kim Hee Sun , Gao Jing , Armstrong David A. , Hamilton Thomas A. 
Published: October 2019

AbstractInterleukin-10 (IL-10) selectively inhibited lipopolysaccharide (LPS)-induced chemoattractant cytokine gene expression: levels of IP-10 mRNA were markedly suppressed in IL-10–treated mouse peritoneal macrophages, whereas the expression of the RANTES mRNA was only modestly reduced. IL-10 inhibited IP-10 mRNA accumulation by reducing IP-10 gene transcription as demonstrated by nuclear run-on analysis. Interestingly, the ability of IL-10 to inhibit expression of IP-10 was dependent on the inducing stimulus; IL-10 did not suppress interferon γ (IFNγ)- or IFNβ-stimulated IP-10 transcription or mRNA accumulation. These results suggested that IL-10 might act indirectly to suppress IP-10 expression by inhibiting LPS-induced class I IFN production. This hypothesis was supported by the following observations. First, LPS-induced IP-10 mRNA expression was blocked in cells cotreated with cycloheximide. Second, IL-10 inhibited the production of IFN/β-mediated antiviral activity. Finally, the IL-10–mediated suppression of LPS-stimulated IP-10 production could be rescued by cotreatment with IFNβ.
Association Between Pretransplant Interferon-α and Outcome After Unrelated Donor Marrow Transplantation for Chronic Myelogenous Leukemia in Chronic Phase
Authors: Morton A. James , Gooley Ted , Hansen John A. , Appelbaum Frederick R. , Bruemmer Barbara , Bjerke Jean W. , Clift Reg , Martin Paul J. , Petersdorf Effie W. , Sanders Jean E. , Storb Rainer , Sullivan Keith M. , Woolfrey Ann , Anasetti Claudio 
Published: October 2019

Abstract
Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-α (IFN-α), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-α results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-α on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-α therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-α, whereas 22, 23, and 25 patients received IFN-α for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-α therapy administered for ≥6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2.1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-α therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight ≥110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-α for less than 6 months before transplant, who were ≤50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% ± 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-α when the patient is ≤50 years of age and has an HLA-compatible unrelated volunteer donor.
Blood Dendritic Cells From Myeloma Patients Are Not Infected With Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8)
Authors: Yi Qing , Ekman Marianne , Anton Doina , Bergenbrant Susanne , Österborg Anders , Georgii-Hemming Patrik , Holm Göran , Nilsson Kenneth , Biberfeld Peter 
Published: October 2019

Abstract
In recent studies, the sequence of Kaposi's sarcoma-associated herpes virus (KSHV) or human herpes virus-8 (HHV-8) was detected in dendritic cells (DC) of patients with multiple myeloma (MM). A concern was raised whether there is an causal association between the viral infection and development of these tumors. In the present study, we have examined DC generated from blood adherent cells from 8 Swedish MM patients at different clinical stages and 2 patients with monoclonal gammopathy of undetermined significance. In addition, 6 myeloma cell lines and bone marrow cells from 2 MM patients were also studied. By polymerase chain reaction (PCR), including nested PCR, no virus DNA was demonstrable in the patients' DC or in myeloma cell lines or fresh bone marrow cells. Moreover, no antibody against KSHV was found in the serum of these 10 patients. Thus, our results indicate that blood-derived DC of MM patients in Sweden usually are not infected with KSHV/HHV-8. This study also suggests that KSHV/HHV-8 is not regularly associated with MM and consequently does not play a primary role in the pathogenesis of these tumors.