bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of Smad5 gene leads to enhanced proliferation of high-proliferative potential precursors during embryonic hematopoiesis
Authors: Liu Bing , Sun Yanxun , Jiang Feizi , Zhang Shuangxi , Wu Ying , Lan Yu , Yang Xiao , Mao Ning 
Published: December 2002

AbstractSMAD proteins are downstream signal transducers of the transforming growth factor β (TGF-β) superfamily, which serve as pleiotropic regulators in embryonic and adult hematopoiesis. SMAD5, initially considered to mediate bone morphogenetic proteins (BMPs) signals, can also transduce the inhibitory signal of TGF-β1 on proliferation of hematopoietic progenitors derived from human bone marrow. To define its specific role in regulation of primitive multipotential progenitors during early embryonic hematopoiesis, we examined Smad5−/− yolk sacs at E9.0 to 9.5 and detected an elevated number of high-proliferative potential colony-forming cells (HPP-CFCs) with enhanced replating potential. To exclude the possible influence of microenvironmental deficit on embryonic hematopoiesis in vivo, we performed in vitro embryonic stem (ES) cell differentiation assay and investigated the HPP-CFCs in particular. Smad5−/− embryoid bodies (EBs) contained an elevated number of blast colony-forming cells (BL-CFCs), the in vitro equivalent of hemangioblast, in contrast to reduced proliferation of primitive erythroid precursors (Ery/Ps) within the mutant EBs. More importantly, profoundly increased frequency of HPP-CFCs, featured with a gene-dosage effect, was detected within day 6 Smad5−/−EBs compared with the wild type. In addition, Smad5−/−HPP-CFCs displayed enhanced self-renewal capacity and decreased sensitivity to TGF-β1 inhibition, suggesting a critical role of Smad5 in TGF-β1 regulation of embryonic HPP-CFCs. Consistently, reverse transcription-polymerase chain reaction analysis detected alterations of the transcription factors including GATA-2 and AML1 as well as cytokine receptors in Smad5−/− HPP-CFC colonies. Together, these data define an important function of SMAD5 in negative regulation of high-proliferative potential precursors during embryonic hematopoiesis.
Prospective testing for drug-dependent antibodies reduces the incidence of thrombocytopenia observed with the small molecule glycoprotein IIb/IIIa antagonist roxifiban: implications for the etiology of thrombocytopenia
Authors: Seiffert Dietmar , Stern Andrew M. , Ebling William , Rossi Richard J. , Barrett Yu Chen , Wynn Richard , Hollis Gregory F. , He Bokang , Kieras Cathy J. , Pedicord Donna L. , Cromley Debra A. , Hua Tsushung A. , Stein Robert B. , Daly Robert N. , Sferruzza Anthony , Pieniaszek Henry J. , Billheimer Jeffrey T. 
Published: December 2002

Abstract
Thrombocytopenia is a relatively common side effect observed during glycoprotein (GP) IIb/IIIa antagonist therapy. With the oral antagonist roxifiban, we observed thrombocytopenia, defined as 50% reduction of platelets over predose values or below 90 000/μL (9 × 1010/L), with a frequency of 2% (8 of 386). Thrombocytopenia occurred either early (days 2 to 4) or delayed (days 11 to 16). No additional cases were observed with up to 6 months of treatment. Retrospective analysis provided evidence for drug-dependent antibodies (DDABs) to GP IIb/IIIa in 5 of 6 subjects, suggestive of an immune etiology of thrombocytopenia. The hypothesis that excluding patients based on positive DDAB reaction would reduce the frequency of thrombocytopenia was tested. Patients were screened for DDABs during the study qualification period and, overall, 3.9% of the patients were excluded based on pre-existing DDAB concentrations above a statistically defined medical decision limit. An additional 2.6% were excluded based on therapy-related antibody production during the first 2 weeks. With antibody testing, 0.2% of patients (2 of 1044) developed immune-mediated thrombocytopenia. One case developed a rapidly increasing antibody concentration and presented with thrombocytopenia despite discontinuation of roxifiban therapy. The second case was related to a false-negative test result. The frequency of thrombocytopenia was statistically significantly reduced from 2% to 0.2% (P = .0007) comparing nonscreened and screened patients. Testing for DDABs can reduce the frequency of thrombocytopenia in patients treated with roxifiban and, by analogy, other GP IIb/IIIa antagonists. Thus, DDAB testing may be employed to increase the safety of GP IIb/IIIa antagonists.
Heterologous cells cooperate to augment stem cell migration, homing, and engraftment
Authors: Adams Gregor B. , Chabner Karissa T. , Foxall Russell B. , Weibrecht Kathryn W. , Rodrigues Neil P. , Dombkowski David , Fallon Robert , Poznansky Mark C. , Scadden David T. 
Published: December 2002

Abstract
T-lymphocyte depletion of bone marrow grafts compromises engraftment, suggesting a facilitating mechanism provided by the T cells that has been shown to associate with CD8+ but not CD4+ T cells. Explanations for this phenomenon have focused on immune targeting of residual host cells or cytokine production. We provide evidence for an alternative mechanism based on cooperative effects on cell motility. We observed that engraftment of CD34+ cells in a β2-microglobulin–deficient nonobese diabetic/severe combined immunodeficiency (β2m−/− NOD/SCID) mouse model paralleled clinical observations in humans, with an enhancing effect noted from the addition of CD8+ cells but not CD4+ cells. This correlated with CD8+ augmentation of CD34+cell homing to the bone marrow in vivo and CD8+cell–associated increases of CD34+ cell transmigration through a bone marrow endothelial cell line in vitro. The cooperative interaction was not sensitive to brefeldin A inhibition of protein secretion. However, cytochalasin D–induced inhibition of CD8+ cytoskeletal rearrangements abrogated CD34+ transendothelial migration and impaired CD34+ cell homing in vivo. CD8+ cells did not migrate in tandem with CD34+ cells or alter endothelial barrier integrity; rather, they affected phosphotyrosine-mediated signaling in CD34+ cells in response to the chemokine stromal derived factor-1α (SDF-1α). These data demonstrate cell-cell cooperativity between different cell types in mediating chemotactic events and provide one potential explanation for the clinically observed effect of CD8+ cells on bone marrow transplantation. This modification of cell migration by neighboring cells provides broad possibilities for combinatorial effects between cells of different types to influence cell localization.
Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial
Authors: Kern Wolfgang , Haferlach Torsten , Schoch Claudia , Löffler Helmut , Gassmann Winfried , Heinecke Achim , Sauerland Maria Christina , Berdel Wolfgang , Büchner Thomas , Hiddemann Wolfgang 
Published: December 2002

Abstract
Risk assessment in acute myeloid leukemia (AML) using pretreatment characteristics may be improved by incorporating parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age (median, 53 years) with de novo AML entered the trial and were evaluable. Treatment included TAD/HAM (thioguanine, cytosine arabinoside, and daunorubicin/high-dose cytosine arabinoside and mitoxantrone) double induction, TAD consolidation, and randomly either maintenance therapy or S-HAM consolidation. Cytogenetics were favorable, intermediate, unfavorable and not available in 10.0%, 48.3%, 13.1%, and 28.5%, respectively. Day 16 blasts ranged from 0% to 100% (median, 5%, mean ± SD, 18.6 ± 28.5%). Complete remission (CR) rate was 72.6%, 17.6% had persistent leukemia (PL), and 9.8% succumbed to hypoplastic death. Median overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were 18, 9, and 15 months with 28.4%, 21.6%, and 30.1% at 5 years, respectively. As a continuous variable, day 16 blasts were related to CR rate (P &lt; 0.0001), PL rate (P &lt; 0.0001), OS (P &lt; 0.0001), EFS (P &lt; 0.0001), and RFS (P = 0.0049). Multivariate analyses identified the following parameters to be associated with the respective end points. CR rate: day 16 blasts (P &lt; .0001), age (P = .0036), and LDH (P = .0072); OS: unfavorable cytogenetics (P &lt; .0001), day 16 blasts (P &lt; .0001), age (P &lt; .0001), and LDH (P = .0040); EFS: unfavorable cytogenetics (P &lt; .0001), LDH (P &lt; .0001), day 16 blasts (P &lt; .0001), and age (P = .0061); RFS: unfavorable cytogenetics (P &lt; .0001), LDH (P &lt; .0001), and day 16 blasts (P = .0359). The prognostic significance of day 16 blasts is independent of pretherapeutic parameters and predicts outcome even in patients achieving a CR.
An intrinsic thyrotropin-mediated pathway of TNF-α production by bone marrow cells
Authors: Wang Heuy-Ching , Dragoo Jolene , Zhou Qin , Klein John R. 
Published: December 2002

AbstractRecent studies have identified a role for thyroid-stimulating hormone (TSH; ie, thyrotropin) as an inductive signal for tumor necrosis factor-α (TNF-α) secretion by bone marrow (BM) cells, although the features of that activation pathway have not been defined. Using intracellular TSH staining and enzyme-linked immunoassay for detection of secreted TSH, we demonstrate that TSH synthesis in BM cells occurs within CD45+ (leukocyte common antigen) hematopoietic cells and that the majority of that activity resides in a component of CD11b+ BM cells that are not mature T cells, B cells, or Thy-1+ cells in the BM. Conversely, TSH-responsive BM cells defined by expression of TSH receptor (TSHR) using flow cytometry were selectively associated with a nonerythroid CD11b− lymphocyte precursor population. In vitro culture of magnetic-activated cell sorted CD11b− and CD11b+ cells with titrated amounts of purified TSH resulted in significantly higher levels of TNF-α secretion from CD11b− BM cells compared to non-TSH–treated cells, with no appreciable change in TNF-α production from CD11b+cells. These findings are the first to demonstrate TSH production by BM hematopoietic cells, and they demonstrate that TSH may be involved in the regulation of TNF-α by CD11b− BM cells. They also indicate that TSH-mediated regulation of TNF-α secretion within the BM most likely operates through an intrinsic network of TSH production and use between different types of BM cells, and they suggest that local TSH may be an important homeostatic regulator of hematopoiesis mediated by TNF-α.
Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses
Authors: Kantarjian Hagop M. , Cortes Jorge E. , O'Brien Susan , Giles Francis , Garcia-Manero Guillermo , Faderl Stefan , Thomas Deborah , Jeha Sima , Rios Mary Beth , Letvak Laurie , Bochinski Kathy , Arlinghaus Ralph , Talpaz Moshe 
Published: December 2002

Abstract
Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph &lt; 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P &lt; .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.
Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3)
Authors: Guasch Géraldine , Popovici Cornel , Mugneret Francine , Chaffanet Max , Pontarotti Pierre , Birnbaum Daniel , Pébusque Marie-Josèphe 
Published: December 2002

Abstract
FGFR1, a transmembrane receptor tyrosine kinase for fibroblast growth factors, is constitutively activated by chromosomal translocations in an atypical stem-cell myeloproliferative disorder. The FGFR1 tyrosine domain is fused to dimerization domains encoded by 4 alternative genes: FOP at 6q27, CEP110 at 9q33,FIM/ZNF198 at 13q12, and BCR at 22q11. In this study, we report the molecular cloning of the t(8;19)(p12;q13.3), the fifth translocation associated with this syndrome. Reverse transcriptase–polymerase chain reaction (RT-PCR) analysis and fluorescence in situ hybridization (FISH) demonstrated that the translocation resulted in a long terminal repeat of human endogenous retrovirus gene (HERV-K)/fibroblast growth factor receptor 1 (FGFR1) fusion transcript that incorporated 5′ sequences from HERV-K fused in frame to 3′ FGFR1 sequences encoding the kinase domain. RT-PCR detected only 1 of the 2 possible fusion transcripts,HERV-K/FGFR1.
LF 15-0195 immunosuppressive agent enhances activation-induced T-cell death by facilitating caspase-8 and caspase-10 activation at the DISC level
Authors: Ducoroy Patrick , Micheau Olivier , Perruche Sylvain , Dubrez-Daloz Laurence , de Fornel Daniel , Dutartre Patrick , Saas Philippe , Solary Eric 
Published: December 2002

AbstractThe deoxyspergualin derivative LF 15-0195 has demonstrated some efficacy in animal models of autoimmune and graft-versus-host diseases and is currently tested in clinics. The molecular mechanisms of LF 15-0195 immunosuppressive activity remained unknown. We show that exposure to LF 15-0195 sensitizes Jurkat T cells to apoptosis induced by an agonistic anti-CD95 antibody (CH11 clone) and by the cytokine TNF-related apoptosis-inducing ligand. LF 15-0195 does not demonstrate any significant effect on the postmitochondrial activation of caspases, nor does it modify overall expression of CD95, Fas-associated death domain, and procaspase-8. The compound facilitates the recruitment of these molecules to the death-inducing signaling complex (DISC) and enhances caspase-8 and -10 activation, thus increasing cytochrome c and direct IAP binding with low pI (DIABLO)/Smac mitochondrial release. LF 15-0195 also sensitizes Jurkat T cells to CD3-mediated apoptosis, an in vitro model for activation-induced T-cell death (AICD). LF 15-0195–mediated sensitization to AICD was further confirmed in human peripheral T cells exposed to anti-CD3 antibodies, then cultured in the presence of interleukin-2. In these cells, LF 15-0195 increased apoptosis triggered by either anti-CD95 antibodies or CD3 restimulation, whereas no effect was observed on “passive apoptosis.” Finally, in bone marrow recipient mice, LF 15-0195 enhanced allogeneic donor T-cell death, which required a functional CD95 pathway. These results suggest that LF 15-0195 sensitizes T cells to AICD by increasing caspase activation at the DISC level in response to CD95 engagement. This original mechanism, together with LF 15-0195 efficacy in various disease models, makes this compound a promising immunosuppressive drug.
Interferon-α, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia
Authors: Burchert Andreas , Wölfl Stefan , Schmidt Manuel , Brendel Cornelia , Denecke Barbara , Cai Dali , Odyvanova Larissa , Lahaye Tanja , Müller Martin C. , Berg Thomas , Gschaidmeier Harald , Wittig Burghardt , Hehlmann Rüdiger , Hochhaus Andreas , Neubauer Andreas 
Published: December 2002

AbstractChronic myeloid leukemia (CML) is a clonal disease of hematopoietic stem cells caused by a reciprocal translocation of the long arms of chromosomes 9 and 22. In human leukocyte antigen A*0201+ (HLA-A*0201+) individuals, response after interferon-α (IFN-α) was shown to be associated with the emergence of CML-specific cytotoxic T cells that recognize PR-1, a myeloblastin (MBN)–derived nonapeptide. In contrast, imatinib potently induces remissions from CML by specific inhibition of the ABL tyrosine kinase. Here, we explored molecular regulations associated with CML responses under different treatment forms using cDNA-array. Expression of MBN was found to be down-regulated in remission under imatinib therapy (0 of 7MBN+ patients). In contrast, MBNtranscription was readily detectable in the peripheral blood in 8 of 8 tested IFN-α patients in complete remission (P = .0002). IFN-α–dependent MBNtranscription was confirmed in vitro by stimulation of peripheral blood mononuclear cells (PBMCs) with IFN-α and by IFN-α–mediated activation of the MBN promoter in reporter gene assays. Finally, with the use of HLA-A*0201–restricted,MBN-specific tetrameric complexes, it was demonstrated that all of 4 IFN-α–treated patients (100%), but only 2 of 11 imatinib patients (19%), in complete hematological or cytogenetic remission developed MBN-specific cytotoxic T cells (P = .011). Together, the induction of MBNexpression by IFN-α, but not imatinib, may contribute to the specific ability of IFN-α to induce an MBN-specific T-cell response in CML patients. This also implies that the character of remissions achieved with either drug may not be equivalent and therefore a therapy modality combining IFN-α and imatinib may be most effective.
Differential chemokine expression profiles in human peripheral blood T lymphocytes: dependence on T-cell coreceptor and calcineurin signaling
Authors: Cristillo Anthony D. , Macri Mirtha J. , Bierer Barbara E. 
Published: December 2002

AbstractThe chemokine superfamily consists of small (8-10 kDa) molecules that function to attract, selectively, different subsets of leukocytes. Binding of chemokines to their appropriate G-protein–coupled receptors is necessary for primary immune responses and for homing of leukocytes to lymphoid tissues. Here, we have characterized the signaling pathways in primary T lymphocytes that regulate chemokine gene induction using an RNase protection assay. Dependence on stimulation through the coreceptor CD28 and sensitivity to the calcineurin inhibitors cyclosporine and tacrolimus were studied using purified human peripheral blood lymphocytes. Lymphotactin (Ltn), macrophage inflammatory protein (MIP)–1α, and MIP-1β were all rapidly induced and sensitive to cyclosporine treatment. At later time points, the expression of MIP-1α and MIP-1β, but not of Ltn, was restored despite the inhibition of calcineurin activity. By contrast, the induction of interleukin-8 was delayed and was found to be cyclosporine insensitive. Calcineurin activity of IP-10 mRNA induction was contingent on the specific T-cell stimulation conditions, suggesting that IP-10 expression is modulated by calcineurin-dependent and -independent signaling pathways. Differential chemokine expression profiles result from the engagement of T-cell coreceptors and the requirement for, and the dependence on, calcineurin phosphatase activity.
Signal transducer and activator of transcription 5a (STAT5a) is required for eosinophil differentiation of human cord blood–derived CD34+ cells
Authors: Buitenhuis Miranda , Baltus Belinda , Lammers Jan-Willem J. , Coffer Paul J. , Koenderman Leo 
Published: December 2002

AbstractSignal transducers and activators of transcription (STATs) have been reported to play a critical role in the differentiation of several myeloid cell lines, although the importance of STATs in the differentiation of primary human hematopoietic cells remains to be established. Terminal eosinophil differentiation is induced by interleukin-5 (IL-5), which has also been demonstrated to activate STAT5. We have investigated whether STAT5 plays a critical role during eosinophil differentiation using umbilical cord blood–derived CD34+ cells. In this ex vivo system, STAT5 expression and activation are high early during differentiation, and STAT5 protein expression is down-regulated during the final stages of eosinophil differentiation. Retroviral transductions were performed to ectopically express wild-type and dominant-negative STAT5a (STAT5aΔ750) in CD34+ cells. Transduction of cells with STAT5a resulted in enhanced proliferation compared with cells transduced with empty vector alone. Interestingly, ectopic expression of STAT5a also resulted in accelerated differentiation. In contrast, ectopic expression of STAT5aΔ750 resulted in a block in differentiation, whereas proliferation was also severely inhibited. Similar results were obtained with dominant-negative STAT5b. Forced expression of STAT5a enhanced expression of the STAT5 target genes Bcl-2 andp21WAF/Cip1, suggesting they may be important in STAT5a-mediated eosinophil differentiation. These results demonstrate that STAT5 plays a critical role in eosinophil differentiation of primary human hematopoietic cells.
VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells
Authors: Salven Petri , Mustjoki Satu , Alitalo Riitta , Alitalo Kari , Rafii Shahin 
Published: December 2002

Abstract
Human CD133 (AC133)+CD34+ stem and progenitor cells derived from fetal liver and from bone marrow and blood incorporate a functional population of circulating endothelial precursor cells. Vascular endothelial growth factor receptor 3 (VEGFR-3) regulates cardiovascular development and physiological and pathological lymphangiogenesis and angiogenesis. However, the origin of VEGFR-3+ endothelial cells (ECs) and the mechanisms by which these cells contribute to postnatal physiological processes are not known, and the possible existence of VEGFR-3+ lymphatic or vascular EC progenitors has not been studied. Using monoclonal antibodies to the extracellular domain of VEGFR-3, we show that 11% ± 1% of CD34+ cells isolated from human fetal liver, 1.9% ± 0.8% CD34+ cells from human cord blood, and 0.2% ± 0.1% of CD34+ cells from healthy adult blood donors are positive for VEGFR-3. CD34+VEGFR-3+ cells from fetal liver coexpress the stem/precursor cell marker CD133 (AC133). Because mature ECs do not express CD133, coexpression of VEGFR-3 and CD133 on CD34+cells identifies a unique population of stem and progenitor cells. Incubation of isolated CD34+VEGFR-3+ cells in EC growth medium resulted in a strong proliferation (40-fold in 2 weeks) of nonadherent VEGFR-3+ cells. Plating of these cells resulted in the formation of adherent VEGFR-3+Ac-LDL+ (Ac-LDL = acetylated low-density lipoprotein) EC monolayers expressing various vascular and lymphatic endothelial-specific surface markers, including CD34, VE-cadherin, CD51/61, CD105, LYVE-1, and podoplanin. These data demonstrate that human CD34+CD133+ cells expressing VEGFR-3 constitute a phenotypically and functionally distinct population of endothelial stem and precursor cells that may play a role in postnatal lymphangiogenesis and/or angiogenesis.