bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytokine-regulated expression of survivinin myeloid leukemia
Authors: Carter Bing Z. , Milella Michele , Altieri Dario C. , Andreeff Michael 
Published: July 2002

AbstractSurvivin, a member of the inhibitors-of-apoptosis gene family, is expressed in a cell-cycle–dependent manner in all the most common cancers but not in normal differentiated adult tissues.Survivin expression and regulation were examined in acute myeloid leukemia (AML). Survivin was detected by Western blot analysis in all myeloid leukemia cell lines and in 16 of 18 primary AML samples tested. In contrast, normal CD34+ cells and normal peripheral blood mononuclear cells expressed no or very low levels of survivin. Cytokine stimulation increasedsurvivin expression in leukemic cell lines and in primary AML samples. In cultured primary samples, single-cytokine stimulation substantially increased survivin expression in comparison with control cells, and the combination of G-CSF, GM-CSF, and SCF increased survivin levels even further. Conversely, all-trans retinoic acid significantly decreased survivinprotein levels in HL-60, OCI-AML3, and NB-4 cells within 96 hours, parallel to the induction of myelomonocytic differentiation. Using selective pharmacologic inhibitors, the differential involvement of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol-3 kinase (PI3K) pathways were demonstrated in the regulation of survivin expression. The MEK inhibitor PD98059 down-regulated survivin expression in both resting and GM-CSF–stimulated OCI-AML3 cells, whereas the PI3K inhibitor LY294002 inhibited survivin expression only on GM-CSF stimulation. In conclusion, these results demonstrate thatsurvivin is highly expressed and cytokine-regulated in myeloid leukemias and suggest that hematopoietic cytokines exert their antiapoptotic and mitogenic effects, at least in part, by increasing survivin levels.
Immunodominant epitopes on glycoprotein IIb-IIIa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura
Authors: Kuwana Masataka , Kaburaki Junichi , Kitasato Hidero , Kato Miyako , Kawai Shinichi , Kawakami Yutaka , Ikeda Yasuo 
Published: July 2002

AbstractIt was recently reported that autoreactive CD4+ T cells to glycoprotein IIb-IIIa (GPIIb-IIIa) mediate antiplatelet autoantibody production in patients with immune thrombocytopenic purpura (ITP). To further examine the antigenic specificity of the GPIIb-IIIa–reactive T cells, 6 recombinant fragments encoding different portions of GPIIbα or GPIIIa were generated and tested for their ability to stimulate antigen-specific T-cell proliferation and anti–GPIIb-IIIa antibody production in vitro. T cells from the peripheral blood of 25 patients with ITP and 10 healthy donors proliferated in response to recombinant GPIIb-IIIa fragments in various combinations. The amino-terminal portions of both GPIIbα and GPIIIa (IIbα18-259 and IIIa22-262) were frequently recognized (60% and 64%, respectively) compared with other fragments (4%-28%) in patients with ITP, but this tendency was not detected in healthy donors. In subsequent analyses in patients with ITP, T-cell reactivities to IIbα18-259 and IIIa22-262 were consistently detected, whereas those to other fragments were sometimes lost. In vitro antigenic stimulation of peripheral blood mononuclear cells with IIbα18-259 or IIIa22-262 promoted the synthesis of anti–GPIIb-IIIa antibodies in patients with ITP, but not in healthy donors. Of 15 CD4+ T-cell lines specific for platelet-derived GPIIb-IIIa generated from 5 patients with ITP, 13 lines recognized IIbα18-259, IIIa22-262, or both. T-cell lines reactive to IIbα18-259 or IIIa22-262 promoted the production of anti–GPIIb-IIIa antibodies that were capable of binding to normal platelet surfaces. These results indicate that the immunodominant epitopes recognized by pathogenic CD4+ T cells in patients with ITP are located within the amino-terminal portions of both GPIIbα and GPIIIa.
p16

INK4a
andp15INK4b gene methylations in plasma cells from monoclonal gammopathy of undetermined significance
Authors: Guillerm Gaëlle , Gyan Emmanuel , Wolowiec Darius , Facon Thierry , Avet-Loiseau Hervé , Kuliczkowski Kazimierz , Bauters Francis , Fenaux Pierre , Quesnel Bruno 
Published: July 2002

Abstract
p15INK4b and p16INK4a proteins are cell cycle regulators involved in the inhibition of G1 phase progression. High frequency of methylation of both genes has been reported in multiple myeloma (MM), but it remains to be determined how and when these alterations contribute to tumorigenesis. Monoclonal gammopathy of undetermined significance (MGUS) represents an early disease stage in a fraction of MMs. Plasma cells from 33 patients with MGUS and 33 patients with MM were isolated and analyzed forp15INK4b and p16INK4amethylation by methylation-specific polymerase chain reaction. Selective methylation was found in 19% forp16INK4a, 36% forp15INK4b, and 6.5% for both genes in MGUS, and frequencies were similar in MM suggesting that methylation of these genes is an early event, not associated with transition from MGUS to MM. p15INK4b andp16INK4a gene methylation might contribute to immortalization of plasma cells rather than malignant transformation in the natural history of MM.
Thrombophilia in sickle cell disease: the red cell connection
Authors: Setty B. N. Yamaja , Rao A. Koneti , Stuart Marie J. 
Published: July 2002

Abstract
Complex pertubations of hemostasis occur in sickle cell disease (SCD). Although the procoagulant property of sickle erythrocytes in vitro is tied to exposure of phosphatidylserine (PS), no study has directly linked this PS positivity to in vivo thrombin generation. This study was designed to determine if thrombin generation in SCD correlates with erythrocyte PS, or whether platelets play a significant role. PS was quantified on erythrocytes and platelets from 40 patients with SCD (SS genotype = 25; SC genotype = 15) and 11 controls. Markers of thrombin generation (prothrombin fragment F1.2; thrombin-antithrombin or TAT complexes) and fibrin dissolution (D-dimer; plasmin-antiplasmin or PAP complexes) were also evaluated. Thrombin generation and activation of fibrinolysis occurred with elevations in F1.2, TAT, and D-dimer. Although numbers of both PS-positive erythrocytes and platelets were elevated, there was no correlation between PS-positive platelets and any hemostatic markers. In contrast, correlations were noted between PS-positive erythrocytes and F1.2 (P &lt; .0002), D-dimer (P &lt; .000002), and PAP (P &lt; .01). Correlations between F1.2 and D-dimer (P &lt; .0001) demonstrated that fibrinolysis was secondary to thrombin generation. In patients with the SC genotype, abnormalities in coagulation, although present, were of a lesser magnitude than in SS disease. This study suggests that the sickle erythrocyte is the cell responsible for the thrombophilic state in SCD because associations between erythrocyte PS and thrombin generation were observed. No such relationship with platelet PS was noted. The use of erythrocyte PS as a surrogate marker in trials testing new therapeutic modalities may provide insights into the vascular complications of SCD.
Localization of distal regulatory domains in the megakaryocyte-specific platelet basic protein/platelet factor 4 gene locus
Authors: Zhang Chunyan , Thornton Michael A. , Kowalska M. Anna , Sachis Bruce S. , Feldman Michael , Poncz Mortimer , McKenzie Steven E. , Reilly Michael P. 
Published: July 2002

AbstractThe genes for the related human (h) chemokines, PBP (platelet basic protein) and PF4 (platelet factor 4), are within 5.3 kilobases (kb) of each other and form a megakaryocyte-specific gene locus. The hypothesis was considered that the PBP and PF4 genes share a common distal regulatory region(s) that leads to their high-level megakaryocyte-specific expression in vivo. This study examined PBP and PF4 expression in transgenic mice using 4 distinct humanPBP/PF4 gene locus constructs. These studies showed that within the region studied there was sufficient information to regulate tissue-specific expression of both hPBP and hPF4. Indeed this region contained sufficient DNA information to lead to expression levels of PBP and PF4 comparable to the homologous mouse genes in a position-independent, copy number–dependent fashion. These studies also indicated that the DNA domains that led to this expression were distinct for the 2 genes; hPBP expression is regulated by a region that is 1.5 to 4.4 kb upstream of that gene. Expression of hPF4 is regulated by a region that is either intergenic between the 2 genes or immediately downstream of the hPF4 gene. Comparison of the available human and mouse sequences shows conserved flanking region domains containing potential megakaryocyte-related transcriptional factor DNA-binding sites. Further analysis of these regulatory regions may identify enhancer domains involved in megakaryopoiesis that may be useful in the selective expression of other genes in megakaryocytes and platelets as a strategy for regulating hemostasis, thrombosis, and inflammation.
Type I interferons in combination with bacterial stimuli induce apoptosis of monocyte-derived dendritic cells
Authors: Lehner Manfred , Felzmann Thomas , Clodi Katharina , Holter Wolfgang 
Published: July 2002

AbstractBoth type I interferons (IFNs) as well as lipopolysaccharide (LPS) individually compromise selected monocytic or dendritic cell (DC) functions. This study investigates the influence of these agents on the differentiation and the regulation of cell death of monocyte-derived DCs generated in the presence of granulocyte-macrophage colony-stimulating factor plus interleukin-4 (IL-4). It is reported that excessive apoptosis occurred rapidly in monocyte-derived DC cultures, if IFN-α or IFN-β was added in combination with LPS or lipoteichoic acid (LTA). The small fraction of cells surviving in such cultures displayed a mature DC phenotype with expression of CD83, CD80, and CD86. IL-10 was found in the supernatants of monocyte-derived DC cultures, if supplemented with LPS or IFN-α plus LPS but not in control cultures. When monocyte-derived DCs were generated in the presence of IFN-α without LPS, these cells displayed an immature DC phenotype with a reduction of cell recovery but no overt apoptosis. However, the addition of LPS, LTA, LPS plus IFN-γ, or tumor necrosis factor α (TNF-α) plus prostaglandin E2 to such cells again resulted in the rapid induction of apoptosis in the majority of cells, together with a reduced production of IL-12 p70 and TNF-α. Together, these data indicate an exquisite sensitivity of monocyte-derived DCs to activation-induced cell death if generated in the presence of IFN-α, indicating the existence of an important mechanism of immunosuppression caused by IFN-α–inducing agents, such as viral or bacterial stimuli.
Tumor necrosis factor (TNF)–mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells
Authors: Dybedal Ingunn , Bryder David , Fossum Anna , Rusten Leiv S. , Jacobsen Sten Eirik W. 
Published: July 2002

AbstractHematopoietic stem cell (HSC) fate decisions between self-renewal and commitment toward differentiation are tightly regulated in vivo. Recent developments in HSC culture and improvements of human HSC assays have facilitated studies of these processes in vitro. Through such studies stimulatory cytokines critically involved in HSC maintenance in vivo have been demonstrated to also promote HSC self-renewing divisions in vitro. Evidence for negative regulators of HSC self-renewal is, however, lacking. Tumor necrosis factor (TNF), if overexpressed, has been implicated to mediate bone marrow suppression. However, whether and how TNF might affect the function of HSC with a combined myeloid and lymphoid reconstitution potential has not been investigated. In the present studies in vitro conditions recently demonstrated to promote HSC self-renewing divisions in vitro were used to study the effect of TNF on human HSCs capable of reconstituting myelopoiesis and lymphopoiesis in nonobese diabetic–severe combined immunodeficient (NOD-SCID) mice. Although all cord blood and adult bone marrow CD34+CD38− cells were capable of undergoing cell divisions in the presence of TNF, cycling HSCs exposed to TNF in vitro and in vivo were severely compromised in their ability to reconstitute NOD-SCID mice and long-term cultures. The negative effect of TNF was not dependent on the Fas pathway, and a similar effect could be observed using a mutant TNF exclusively targeting the p55 TNF receptor. TNF did not appear to enhance apoptosis or affect cell-cycle distribution of cultured progenitors, but rather promoted myeloid differentiation. Thus, TNF might regulate HSC fate by promoting their differentiation rather than self-renewal.
Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients
Authors: Leporrier Michel , Chevret Sylvie , Cazin Bruno , Boudjerra Najda , Feugier Pierre , Desablens Bernard , Rapp Marie-José , Jaubert Jerome , Autrand Claudie , Divine Marine , Dreyfus Brigitte , Maloum Karim , Travade Philippe , Dighiero Guillaume , Binet Jacques-Louis , Chastang Claude 
Published: July 2002

Abstract
To comparatively assess first-line treatment with fludarabine and 2 anthracycline-containing regimens, namely CAP (cyclophosphamide, doxorubicin plus prednisone) and ChOP (cyclophosphamide, vincristine, prednisone plus doxorubicin), in advanced stages of chronic lymphocytic leukemia (CLL), previously untreated patients with stage B or C CLL were randomly allocated to receive 6 monthly courses of either ChOP, CAP, or fludarabine (FAMP), stratified based on the Binet stages. End points were overall survival, treatment response, and tolerance. From June 1, 1990 to April 15, 1998, 938 patients (651 stage B and 287 stage C) were randomized in 73 centers. Compared to ChOP and FAMP, CAP induced lower overall remission rates (58.2%; ChOP, 71.5%; FAMP; 71.1%; P &lt; .0001 for each), including lower clinical remission rates (CAP, 15.2%; ChOP, 29.6%; FAMP, 40.1%;P = .003). By contrast, median survival time did not differ significantly according to randomization (67, 70, and 69 months in the ChOP, CAP, and FAMP groups, respectively). Incidences of infections (&lt; 5%) and autoimmune hemolytic anemia (&lt; 2%) during the 6 courses were similar in the randomized groups, whereas fludarabine induced, compared to ChOP and CAP, more frequent protracted thrombocytopenia (P = .003) and less frequent nausea-vomiting (P = .003) and hair loss (P &lt; .0001). For patients with stage B and C CLL first-line fludarabine and ChOP regimens both provided similar overall survival and close response rates, and better results than CAP. However, there was an increase in clinical remission rate and a trend toward a better tolerance of fludarabine over ChOP that may influence the choice between these regimens as front-line treatments in patients with CLL.
Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy
Authors: Besson Caroline , Goubar Aicha , Gabarre Jean , Rozenbaum Willy , Pialoux Gilles , Châtelet François-Patrick , Katlama Christine , Charlotte Frédéric , Dupont Bertrand , Brousse Nicole , Huerre Michel , Mikol Jacqueline , Camparo Philippe , Mokhtari Karima , Tulliez Micheline , Salmon-Céron Dominique , Boué François , Costagliola Dominique , Raphaël Martine 
Published: July 2002

Abstract
HIV infection is associated with a high incidence of AIDS-related lymphomas (ARLs). Since the use of highly active antiretroviral therapy (HAART), the incidence of AIDS-defining illnesses has decreased, leading to a significant improvement in survival of HIV-infected patients. The consequences of HAART use on ARL are under debate. This study compared the incidence and the characteristics of ARL before and after the use of HAART in a large population of HIV-infected patients in the French Hospital Database on HIV (FHDH) and particularly in 3 centers including 145 patients with proven lymphoma. Within the FHDH, the incidence of systemic ARL has decreased between 1993-1994 and 1997-1998, from 86.0 per 10 000 to 42.9 per 10 000 person-years (P &lt; 10−30). The incidence of primary brain lymphoma has also fallen dramatically between the periods, from 27.8 per 10 000 to 9.7 per 10 000 person-years (P &lt; 10−11). The analysis of 145 cases of ARL in 3 hospitals showed that known HIV history was longer in the second period than in the first period among patients with systemic ARL (98 versus 75 months; P &lt; .01). Patients had a higher number of CD4 cells at diagnosis during the second period (191 versus 63/μL, P = 10−3). Survival of patients with systemic ARL also increased between the periods (from 6 to 20 months; P = .004). Therefore, the profile of ARL has changed since the era of HAART, with a lower incidence of systemic and brain ARL. The prognosis of systemic ARL has improved.
Real-time quantitation of minimal residual disease in inv(16)-positive acute myeloid leukemia may indicate risk for clinical relapse and may identify patients in a curable state
Authors: Buonamici Silvia , Ottaviani Emanuela , Testoni Nicoletta , Montefusco Vittorio , Visani Giuseppe , Bonifazi Francesca , Amabile Marilina , Terragna Carolina , Ruggeri Deborah , Piccaluga Pier Paolo , Isidori Alessandro , Malagola Michele , Baccarani Michele , Tura Sante , Martinelli Giovanni 
Published: July 2002

AbstractThe inv(16) cytogenetic subtype of acute myeloid leukemia (AML) has a relatively good prognosis. Many patients achieve complete remission (CR). The prognostic uncertainty of negative qualitative reverse transcription–polymerase chain reaction (RT-PCR) assays suggests the need to identify prognostically significant critical thresholds by real-time RT-PCR. A reliable and sensitive (10−5) real-time RT-PCR assay was set up for the evaluation of relevant CBFβ-MYH11/ABL transcript ratios and was applied to the 21 patients with inv(16) AML routinely referred for cytogenetic and molecular monitoring in Seràgnoli Institute (Bologna, Italy) since 1990. Among the 18 patients who underwent ablative chemotherapy, all achieved CR with a 3-year disease-free survival probability of 63% (95% CI, 40%-87%) and no recorded events after 26 months. Five patients had relapses; 2 died of disease and 3 entered second CR. Analysis of the 125 bone marrow (or peripheral blood) samples studied by real-time RT-PCR showed that transcript ratios of samples taken during CR at any time before a relapse were always greater than 0.12%, whereas those of samples taken during first or second CR from patients who did not subsequently have relapses were always less than 0.25%. This suggests that transcript ratios greater than 0.25% may correspond to high risk for relapse, whereas ratios below 0.12% might indicate the patient is in a curable state. If confirmed, such thresholds could open the way to a new phase in post-CR therapeutic decision making for patients with inv(16) AML.
Plasma levels of endothelial protein C receptor respond to anticoagulant treatment
Authors: Stearns-Kurosawa Deborah J. , Swindle Kandice , D'Angelo Armando , Della Valle Patrizia , Fattorini Annalisa , Caron Nathalie , Grimaux Marc , Woodhams Barry , Kurosawa Shinichiro 
Published: July 2002

AbstractThe endothelial protein C receptor (EPCR) facilitates protein C activation and plays a protective role in the response toEscherichia coli–mediated sepsis in primates. Previously, a soluble form of EPCR (sEPCR) in human plasma was characterized, and several studies indicated that generation of sEPCR is regulated by inflammatory mediators, including thrombin-mediated up-regulation of surface metalloproteolytic activity in vitro. This study addressed the question of whether plasma sEPCR levels reflect changes in thrombin generation in patients undergoing anticoagulant treatment. The sEPCR levels in patients treated with coumarin-type oral anticoagulants were significantly lower than those in healthy asymptomatic adult volunteers (105.3 ± 70.8 ng/mL [n = 55] versus 165.8 ± 115.8 ng/mL [n = 200]; P &lt; .0001). A similar decline in plasma sEPCR levels was found in patients treated with unfractionated heparin. In healthy volunteers, sEPCR levels declined to about 100 ng/mL within 3 days after initiation of an 8-day period of warfarin administration and increased within 2 days after its cessation. Plasma sEPCR levels returned to pretreatment values within 1 week, and the changes in plasma sEPCR levels mirrored changes in values for international normalized ratios. A similar decline in sEPCR levels with time was observed in 7 patients beginning treatment with warfarin for a thrombotic disorder. Prothrombin fragment 1 + 2 levels also decreased in volunteers and patients given warfarin. These results show that plasma sEPCR levels decline in response to treatment with anticoagulants whose mechanism of action is known to decrease in vivo thrombin production.
Cooperative binding of c-Myb and Pax-5 activates theRAG-2 promoter in immature B cells
Authors: Kishi Hiroyuki , Jin Zhe-Xiong , Wei Xing-Cheng , Nagata Takuya , Matsuda Tadashi , Saito Shigeru , Muraguchi Atsushi 
Published: July 2002

AbstractThe recombination activating gene-1 (RAG-1) andRAG-2 are expressed specifically in immature lymphoid cells undergoing the recombination of antigen receptor genes. The regulation of murine RAG-2 promoter was studied and it was revealed that the −41/−17 RAG-2 promoter region, which is conserved between humans and mice, was indispensable for theRAG-2 promoter activity in B-cell lines. The region contained 2 cis elements that bound c-Myb and Pax-5. Mutation in the c-Myb–binding site in the promoter reduced the promoter activity in B-cell lines. Cooperative activation of theRAG-2 promoter was seen by a combination of c-Myb and Pax-5 in a human embryonic kidney cell line (293T), via their synergistic DNA-binding. Deletion experiments showed that the C-terminus of c-Myb was responsible for their interaction. Furthermore, the dominant-negative c-Myb mutant suppressed the activation of theRAG-2 promoter in a pre–B-cell line as well as in 293T cells. These results suggest that cooperative binding of c-Myb and Pax-5 to the RAG-2 promoter is one of the mechanisms to direct the restricted expression of the RAG-2 in immature B cells.
Adenosine deaminase deficiency with mosaicism for a “second-site suppressor” of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy
Authors: Arredondo-Vega Francisco X. , Santisteban Ines , Richard Eva , Bali Pawan , Koleilat Majed , Loubser Michael , Al-Ghonaium Abdulaziz , Al-Helali Mariam , Hershfield Michael S. 
Published: July 2002

AbstractFour patients from 3 Saudi Arabian families had delayed onset of immune deficiency due to homozygosity for a novel intronic mutation, g.31701T&gt;A, in the last splice acceptor site of the adenosine deaminase (ADA) gene. Aberrant splicing mutated the last 4 ADA amino acids and added a 43-residue “tail” that rendered the protein unstable. Mutant complementary DNA (cDNA) expressed inEscherichia coli yielded 1% of the ADA activity obtained with wild-type cDNA. The oldest patient, 16 years old at diagnosis, had greater residual immune function and less elevated erythrocyte deoxyadenosine nucleotides than his 4-year-old affected sister. His T cells and Epstein-Barr virus (EBV) B cell line had 75% of normal ADA activity and ADA protein of normal size. DNA from these cells and his whole blood possessed 2 mutant ADA alleles. Both carried g.31701T&gt;A, but one had acquired a deletion of the 11 adjacent base pair, g.31702-12, which suppressed aberrant splicing and excised an unusual purine-rich tract from the wild-type intron 11/exon 12 junction. During ADA replacement therapy, ADA activity in T cells and abundance of the “second-site” revertant allele decreased markedly. This finding raises an important issue relevant to stem cell gene therapy.