bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transgenic expression of CD40 ligand produces an in vivo antitumor immune response against both CD40+ and CD40− plasmacytoma cells
Authors: Dotti Gianpietro , Savoldo Barbara , Yotnda Patricia , Rill Donna , Brenner Malcolm K. 
Published: October 2002

AbstractBecause tumor-specific antigens have been identified in multiple myeloma (MM), immunotherapy might provide an additional treatment modality for the disease. Expression of CD40 ligand (CD40L) proximate to the MM cells might serve this purpose, either by increasing their capacity to present self-antigens by activation through their CD40 receptor or by the recruitment of professional antigen-presenting cells (APCs) able to take up and present tumor-associated antigens. To distinguish between these possibilities and predict whether human CD40− myeloma might respond to this approach, we examined 3 murine plasmacytoma cell lines, 2 (MPC-11 and S107) expressing the CD40 molecule and 1 (X-24) lacking such expression. Syngeneic BALB/CBYJ mice were inoculated subcutaneously with tumor cells mixed with CL7.1 fibroblasts, retrovirally transduced to express either the mCD40L or the neo gene. For all 3 plasmacytoma cell lines, coinjection with CL7.1/mCD40L significantly reduced local tumor growth compared with controls. This effect was mediated by a systemic antitumor immune response, since mice immunized with tumor and CL7.1/mCD40L were resistant to subsequent challenge with tumor, and tumor growth inhibition was abolished when CD8+or CD4+ lymphocytes were depleted. Because expression of CD40L gave equivalent protection from CD40+ and CD40− tumors and transgenic-CD40L failed to up-regulate costimulatory molecules in either tumor, the protective effects of CD40L probably resulted from recruitment/activation of professional APCs rather than from CD40 activation of plasmacytoma cells. As further support of this concept, we found that mice were also well protected if CL7.1 and CD40L were injected together with apoptotic plasmacytoma cells from these tumors. Hence, transgenic CD40L expression may produce an antimyeloma immune response against either CD40+ or CD40− tumors and may be of therapeutic value for both types of myeloma in humans.
Impact of trisomy 8 (+8) on clinical presentation, treatment response, and survival in acute myeloid leukemia: a Southwest Oncology Group study
Authors: Wolman Sandra R. , Gundacker Holly , Appelbaum Frederick R. , Slovak Marilyn L. 
Published: October 2002

AbstractThe prognostic impact of trisomy 8, alone or with other clonal aberrations, was evaluated in 849 patients with previously untreated acute myeloid leukemia (AML) who were registered to 5 Southwest Oncology Group trials. At presentation, 108 (12.7%) patients had +8 in their karyotypes, including 43 (5.1%) patients with +8 as the sole aberration; 307 (36.2%) were normal, and 434 (51.1%) had other cytogenetic abnormalities. Patients with +8 were slightly older (P = .033), had lower WBC (P = .011), and had lower percentages of peripheral blasts (P = .0004) than the patients without +8. Median survival time for all patients with +8 was 9.9 months (95% CI, 6.5-12.5), similar to that of “unfavorable” cytogenetics risk groups (8.3 months; 95% CI, 6.8-9.5.) Patients with +8 had significantly lower peripheral blasts (P = .0002), WBC (P &lt; .0001) counts, and decreased overall survival (OS) than patients with normal cytogenetics (9.9 months vs 15.4 months; P = .006). However, survival of patients with +8 as the sole aberration did not differ significantly from those with normal cytogenetics (P = .36). Thus, the trisomy 8 group as a whole had poor survival, which was largely attributable to worsened outcomes among patients whose trisomy 8 was associated with other unfavorable cytogenetic abnormalities.
Activated platelets of patients with paroxysmal nocturnal hemoglobinuria express cellular prion protein
Authors: Holada Karel , Simak Jan , Risitano Antonio M. , Maciejewski Jaroslaw , Young Neal S. , Vostal Jaroslav G. 
Published: October 2002

Abstract
Cellular prion protein (PrPc) is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein that contains a putative membrane-spanning section. Patients with paroxysmal nocturnal hemoglobinuria (PNH) lack GPI proteins on the surface of somatically mutated hematopoietic stem cell and its progeny. Platelet expression of PrPc was studied in 8 PNH patients. Resting PNH (CD55−) platelets were devoid of surface PrPc, but activation of platelets resulted in the surface expression of PrPc. Expressed PrPc was detected by 2 monoclonal antibodies (mAbs) against the N-terminal part of the molecule but not by mAb 6H4, which binds at the C-terminus beyond the membrane-spanning section. However, 6H4 detected PrPc on Western blots of PNH platelets, demonstrating that the lack of 6H4 binding was not caused by PrPc truncation. Our results indicate that in the absence of GPI anchor, PrPc can be expressed intracellularly and up-regulated on the platelet membrane, likely in a transmembrane form with the C-terminal part of the molecule inserted into the cytoplasm.
Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers
Authors: Shibolet Oren , Ilan Yaron , Gillis Shmuel , Hubert Ayala , Shouval Daniel , Safadi Rifaat 
Published: October 2002

Abstract
Viral reactivation in hepatitis B surface antigen (HBsAg) carriers undergoing immunosuppressive therapy is well documented. To evaluate the role of lamivudine prophylaxis in Hepatitis B virus (HBV) carriers treated with immunosuppression for nonhepatic disorders, we reviewed our experience between 1997 and 2000 at Hadassah University Hospital (Jerusalem, Israel). Controls were patients who were HBV carriers and who, between 1990 and 1995, were treated for hematological malignancies but were not treated with lamivudine. Eighteen HBsAg-positive patients were treated with immunosuppression. Fourteen were males, with a mean age of 48 years. Eleven patients had lymphoma; 2 had colonic adenocarcinoma; and 5 had cryoglobulinemia, enophthalmitis, vasculitis, malignant histocytosis, or ulcerative colitis. Fourteen patients were treated with chemotherapy, and 4 with prolonged high-dose corticosteroids. All patients were HBsAg-positive; 4 had hepatitis B e antigen, and 10 had HBV DNA by polymerase chain reaction. Lamivudine was administered to 13 patients in the treatment group 1 to 60 days (mean, 15 days) before immunosuppressive treatment and continued 0.5 to 24 months (mean, 7 months) following initiation of immunosuppression. Mean follow-up after lamivudine administration was 21 months. Three patients died of lymphoma complications and 10 (77%) survived. None of the patients had clinical or serological evidence of HBV reactivation during or after lamivudine prophylaxis. Of 6 patients who presented with liver function test disturbances, 5 improved during combined lamivudine and immunosuppression treatment. At the end of follow-up, HBV DNA became undetectable in 2 of 10 patients. In 2 patients, seroconversion from HBsAg to anti-HBs was observed. In contrast, 2 of 5 control patients had HBV reactivation. Lamivudine prophylaxis in HBsAg carriers receiving immunosuppressive therapy may prevent HBV reactivation and hepatic failure.
Hematopathologic and cytogenetic findings in imatinib mesylate–treated chronic myelogenous leukemia patients: 14 months' experience
Authors: Braziel Rita M. , Launder Teresa M. , Druker Brian J. , Olson Susan B. , Magenis R. Ellen , Mauro Michael J. , Sawyers Charles L. , Paquette Ronald L. , O'Dwyer Michael E. 
Published: October 2002

Abstract
Imatinib mesylate, an Abl kinase inhibitor, produces sustained complete hematologic responses (CHRs) in chronic myelogenous leukemia (CML) patients, but the sequence and timing of morphologic and cytogenetic changes in CML patients during prolonged imatinib mesylate treatment has not been described. In this report, we document sequential hematologic and bone marrow findings in 19 interferon-refractory/interferon-intolerant chronic phase CML patients on imatinib mesylate for at least 14 months. Patients treated at an effective oral dose (300 to 600 mg per day) were followed with peripheral blood (PB) counts, marrow examination, and cytogenetic studies at 0, 2, 5, 8, 11, and 14 months. By 2 months, 17 of 19 patients achieved CHR; 1 reached CHR by 5 months, and 1 at 11 months. Five of 19 patients developed cytopenias requiring treatment interruption and/or dose reduction, but all were able to continue in CHR on study. In contrast to interferon-alfa treatment, imatinib mesylate–treated CML patients achieved not only CHR but complete morphologic marrow response. Normalization of marrow lagged behind PB response; however, by 8 months, all marrows showed normal or reduced cellularity without morphologic evidence of CML. Eighteen of 19 patients continued in CHR and morphologic marrow remission at 14 months; 1 patient relapsed with chronic phase CML. Although hematologic and marrow responses were uniform, cytogenetic responses were variable. Complete cytogenetic responses occurred in 6 patients, with 4 also in remission by fluorescent in situ hybridization and/or reverse-transcription–polymerase chain reaction. Six of 19 had partial and 7 of 19 no cytogenetic response. Several patients acquired additional clonal cytogenetic abnormalities during therapy, a finding with significant implications for prognosis and laboratory monitoring in imatinib mesylate–treated CML patients.
Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy
Authors: Ballen Karen K. , Becker Pamela S. , Emmons Robert V. B. , Fitzgerald Thomas J. , Hsieh Chung C. , Liu Qin , Heyes Christine , Clark Yeteive , Levy William , Lambert Jean Francois , Chiafari Frank , Szymanski Irma , Rososhansky Sarah , Popovsky Mark A. , Stewart F. Marc , Quesenberry Peter J. 
Published: October 2002

AbstractAllogeneic stem cell transplantation is curative for certain cancers, but the high doses of chemotherapy/radiotherapy lead to toxicity. Here, we treat patients with refractory cancer with 100 cGy total body irradiation (TBI) followed by infusion of nonmobilized pheresed allogeneic peripheral blood cells. Twenty-five patients, with a median age of 47 years, with refractory cancers were enrolled. Eighteen patients received sibling and 7 received unrelated cord blood cells. Donor chimerism was assessed at weeks 1, 2, 3, 4, and 8 after transplantation. Seven patients with solid tumors received a sibling transplant and 6 received a cord blood transplant; none achieved donor chimerism, but 1 treated at the higher dose level of 1 × 108 CD3+ cells/kg had a transient nodal response. Twelve patients with hematologic malignancies were treated; 1 received a cord blood transplant and 11 received sibling donor cells. Nine of these 11 patients achieved donor chimerism, ranging from 5% to 100%. Four patients had sustained complete remission of their cancers, including one patient with transient 5% donor chimerism. The development of chimerism correlated with hematologic malignancy (P &lt; .001), total previous myelotoxic chemotherapy (P &lt; .001), T-cell dose (P = .03), and graft-versus-host disease (P = .01). Tumor response correlated with donor chimerism (P = .01). Engraftment was achieved in patients with hematologic malignancies who had been heavily pretreated, suggesting the degree of immunosuppression may be a determinant of engraftment. Low-dose TBI and allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy.
Prostaglandin-E2 enhances EPO-mediated STAT5 transcriptional activity by serine phosphorylation of CREB
Authors: Boer Arjen-Kars , Drayer A. Lyndsay , Rui Hallgeir , Vellenga Edo 
Published: October 2002

AbstractErythroid colony formation in response to erythropoietin (EPO) stimulation is enhanced by costimulating the cells with prostaglandin-E2 (PGE2). The present study further analyzed the underlying mechanisms and demonstrated that EPO-mediated STAT5 transactivation in the erythroid AS-E2 cell line was enhanced 6-fold by PGE2 (10 μM), without affecting the STAT5 tyrosine phosphorylation or STAT5-DNA binding. Moreover, the PGE2-enhancing effect was independent of STAT5 serine phosphorylation. In AS-E2 cells STAT5 is constitutively phosphorylated on Ser780 (STAT5A) and EPO-dependently phosphorylated on Ser726/731 (STAT5A/STAT5B), but overexpression of STAT5 serine mutants did not affect STAT5 transactivation. In addition, PGE2 did not affect STAT5 serine phosphorylation. Instead, the stimulatory effect of PGE2 on STAT5 signaling could be mimicked by dibutyryl-cyclic adenosine monophosphate (cAMP) and the phosphodiesterase inhibitor IBMX, suggesting that the effect was mediated by cAMP. Activation of the cAMP pathway resulted in cAMP-response element binding protein (CREB) phosphorylation, which was sustained in the presence of EPO plus PGE2 and transient on EPO stimulation alone. The costimulatory effect of PGE2 on EPO-mediated STAT5 transactivation was inhibited by overexpression of serine-dead CREB or protein kinase A (PKA) inhibitor (PKI), in contrast to EPO-mediated transactivation, which was PKA independent. Furthermore, CREB-binding protein (CBP)/p300 was shown to be involved in EPO-mediated STAT5 transactivation, and a CBP mutant with increased affinity for CREB resulted in an additional enhancement of the PGE2 effect. Finally, we demonstrated that the STAT5 target genes Bcl-X, SOCS2, andSOCS3 were up-regulated by costimulation with PGE2. In summary, these studies demonstrate that PGE2 enhancement of EPO-induced STAT5 transactivation is mediated by the cAMP/PKA/CREB pathway.
A role for glycoprotein Ib in Streptococcus sanguis–induced platelet aggregation
Authors: Kerrigan Steven W. , Douglas Ian , Wray Ann , Heath Jason , Byrne Michael F. , Fitzgerald Desmond , Cox Dermot 
Published: October 2002

AbstractNumerous studies have implicated bacteria in cardiovascular disease, but there is a paucity of information on the mechanism involved. In this study we show how the common oral bacteriumStreptococcus sanguis can directly interact with platelets, resulting in activation and aggregate formation. Platelet aggregation was dependent on glycoprotein IIb/IIIa (GPIIb/IIIa) and thromboxane. Platelets could also directly bind to S sanguis, but this interaction was not inhibited by GPIIb/IIIa antagonists. Antibodies to GPIb could inhibit both platelet aggregation and platelet adhesion to bacteria. This suggested a direct interaction between GPIb and S sanguis; however, this interaction did not require von Willebrand factor, the normal ligand for GPIb. By use of a range of monoclonal antibodies to GPIb and the enzyme mocharagin, which cleaves GPIb at amino acid 282, the interaction was localized to a region within the N-terminal 1-225 portion of GPIbα. Furthermore S sanguisfailed to induce aggregation of platelets from a patient with Bernard-Soulier disease, the organism bound to Chinese hamster ovary cells transfected with the GPIbα gene but did not bind to mock-transfected cells and biotin-labeled S sanguis cells bound to purified GPIb in ligand blots. It is suggested that the interaction between S sanguis and GPIb is important in the pathogenesis of infective endocarditis and may also play a contributory role in some cases of myocardial infarction.
C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils
Authors: Wojta Johann , Kaun Christoph , Zorn Gerlinde , Ghannadan Minoo , Hauswirth Alexander W. , Sperr Wolfgang R. , Fritsch Gerhard , Printz Dieter , Binder Bernd R. , Schatzl Georg , Zwirner Joerg , Maurer Gerald , Huber Kurt , Valent Peter 
Published: October 2002

AbstractWe have recently shown that resting human mast cells (MCs) produce tissue-type plasminogen activator (t-PA) without simultaneously expressing plasminogen activator inhibitor 1 (PAI-1). In the present study we have identified the anaphylatoxin rhC5a as a potent inducer of PAI-1 expression in human MCs and basophils. In primary human skin MCs and primary blood basophils, exposure to rhC5a was followed by an increase from undetectable to significant levels of PAI-1. In addition, rhC5a induced a concentration- and time-dependent increase in PAI-1 antigen in the MC line HMC-1 and the basophil cell line KU-812 and increased the expression of PAI-1 mRNA in HMC-1. In conditioned media of HMC-1 treated with rhC5a, active PAI-1 could be detected. A simultaneous loss of t-PA activity in conditioned media from the same cells indicated that rhC5a-induced PAI-1 was capable of inhibiting the enzymatic activity of coproduced t-PA. Correspondingly, the levels of t-PA–PAI-1 complexes increased in rhC5a-treated cells. When HMC-1 cells were incubated with pertussis toxin or anti-C5a receptor antibodies, the effect of rhC5a on PAI-1 production was completely abolished. Treatment of C5a with plasmin resulted in loss of its ability to induce PAI-1 production in MCs. Considering the suggested role for MCs and components of the complement system in the development of cardiovascular diseases, we hypothesize that MCs, by producing t-PA in a resting state and by expressing PAI-1 when activated by C5a, might participate in the modulation of the balance between proteases and protease inhibitors regulating tissue injury and repair in such disease processes.
Soluble syndecan-1 promotes growth of myeloma tumors in vivo
Authors: Yang Yang , Yaccoby Shmuel , Liu Wei , Langford J. Kevin , Pumphrey Carla Y. , Theus Allison , Epstein Joshua , Sanderson Ralph D. 
Published: October 2002

AbstractSyndecan-1 (CD138) is a transmembrane heparan sulfate–bearing proteoglycan expressed by most myeloma plasma cells that regulates adhesion, migration, and growth factor activity. In patients with myeloma, shed syndecan-1 accumulates in the bone marrow, and high levels of syndecan-1 in the serum are an indicator of poor prognosis. To test the effect of soluble syndecan-1 on tumor cell growth and dissemination, ARH-77 B-lymphoid cells were engineered to produce a soluble form of syndecan-1. Controls included vector only (neo)–transfected cells and cells transfected with full-length syndecan-1 complementary DNA that codes for the cell surface form of syndecan-1. Assays reveal that all 3 transfectants have similar growth rates in vitro, but cells expressing soluble syndecan-1 are hyperinvasive in collagen gels relative to controls. When injected into the marrow of human bones that were implanted in severe combined immunodeficient mice, tumors formed by cells expressing soluble syndecan-1 grow faster than tumors formed by neo-transfected cells or by cells expressing cell surface syndecan-1. In addition, cells bearing cell surface syndecan-1 exhibit a diminished capacity to establish tumors within the mice as compared with both neo- and soluble syndecan-1–transfected cells. Tumor cell dissemination to a contralateral human bone is detected significantly more often in the tumors producing soluble syndecan-1 than in controls. Thus, high levels of soluble syndecan-1 present in patients with myeloma may contribute directly to the growth and dissemination of the malignant cells and thus to poor prognosis.
Randomized trial of different regimens of heparins and in vivo thrombin generation in acute deep vein thrombosis
Authors: Kakkar Vijay V. , Hoppenstead Debra A. , Fareed Jawed , Kadziola Zbigniew , Scully Mike , Nakov Roumen , Breddin Hans K. 
Published: October 2002

AbstractLow-molecular-weight and unfractionated heparins are frequently used to treat venous thromboembolism, but it is not known whether they are equally effective in inhibiting in vivo generation of thrombin. In this multicenter trial, 1048 patients were randomized to intravenous unfractionated heparin (group A), twice daily low-molecular-weight heparin (reviparin) for 1 week (group B), or once daily reviparin for 4 weeks (group C). All patients received vitamin K antagonists. Blood samples withdrawn at the baseline and at weeks 1 and 3 were analyzed using markers of in vivo thrombin generation and other coagulation parameters. During the first 3 weeks symptomatic recurrent deep vein thrombosis–pulmonary embolism (DVT/PE) occurred in 17 (4.5%) of 375 patients in group A compared with 4 (1.0%) of 388 patients in group B, and 9 (2.4%) of 374 patients in group C. Forty percent of patients in group A, 53.4% in group B, and 53.5% in group C showed 30% or greater reduction in thrombus size assessed by venography. Patients in group B had significantly greater reduction in D-dimer, prothrombin fragments 1 and 2 (F1 + 2), endogenous thrombin potential (ETP), and thrombin-antithrombin (TAT) complexes compared to groups A and C. Greater release of tissue factor pathway inhibitor (TFPI) and reduction in levels of thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen were significantly more pronounced in group C patients. Reviparin administered twice daily plus vitamin K antagonist is more effective in inhibiting in vivo thrombin generation compared to intravenous unfractionated heparin plus vitamin K antagonist, and reviparin once daily produced significantly higher TFPI release and greater reduction in TAFI and fibrinogen levels.
A randomized comparison of nativeEscherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study
Authors: Avramis Vassilios I. , Sencer Susan , Periclou Antonia P. , Sather Harland , Bostrom Bruce C. , Cohen Lewis J. , Ettinger Alice G. , Ettinger Lawrence J. , Franklin Janet , Gaynon Paul S. , Hilden Joanne M. , Lange Beverly , Majlessipour Fataneh , Mathew Pracad , Needle Michael , Neglia Joseph , Reaman Gregory , Holcenberg John S. 
Published: October 2002

Abstract
For this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases. Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase. In the first delayed intensification phase, 26% of native asparaginase patients had high-titer antibodies, whereas 2% of pegaspargase patients had those levels. High-titer antibodies were associated with low asparaginase activity in the native arm, but not in the pegaspargase arm. Adverse events, infections, and hospitalization were similar between arms. Event-free survival at 3 years was 82%. A population pharmacodynamic model using the nonlinear mixed effects model (NONMEM) program was developed that closely fit the measured enzyme activity and asparagine concentrations. Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase, respectively. There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum. In cerebrospinal fluid asparagine, depletion was similar with both enzyme preparations. Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population.