bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy
Authors: Pertusini Esther , Ratajczak Janina , Majka Marcin , Vaughn David , Ratajczak Mariusz Z. , Gewirtz Alan M. 
Published: July 2002

AbstractPaclitaxel and carboplatin chemotherapy is reported to be a platelet-sparing drug combination. This study investigated potential mechanisms for this observation by studying the effects of paclitaxel and carboplatin on (1) normal donor and chemotherapy patient-derived erythroid (burst-forming units-erythroid [BFU-E]), myeloid (colony-forming units-granulocyte/macrophage [CFU-GM]), and megakaryocyte (CFU-Meg) progenitor cell growth; (2) P-glycoprotein (P-gp) protein and glutathione S-transferase (GST) messenger RNA (mRNA) expression; (3) serum thrombopoietin (Tpo), stem cell factor (SCF), interleukin-6 (IL-6), IL-11, IL-1β, IL-8, and tumor necrosis factor-α levels in patients treated with paclitaxel and carboplatin; and (4) stromal cell production of Tpo and SCF after paclitaxel and carboplatin exposure. CFU-Meg were more resistant to paclitaxel alone, or in combination with carboplatin, than CFU-GM and BFU-E. Although all progenitors expressed P-gp protein and GST mRNA, verapamil treatment significantly, and selectively, increased the toxicity of paclitaxel and carboplatin to CFU-Meg, suggesting an important role for P-gp in megakaryocyte drug resistance. Compared to normal controls, serum Tpo levels in patients receiving paclitaxel and carboplatin were significantly elevated 5 hours after infusion and remained elevated at day 7 (287% ± 63% increase,P &lt; .001). Marrow stroma was shown to be the likely source of this Tpo. It is concluded here that P-gp–mediated efflux of paclitaxel, and perhaps GST-mediated detoxification of carboplatin, results in relative sparing of CFU-Meg, which may then respond to locally high levels of stromal cell–derived Tpo. The confluence of these events might lead to the platelet-sparing phenomenon observed in patients treated with paclitaxel and carboplatin chemotherapy.
Evidence that Hodgkin and Reed-Sternberg cells in Hodgkin disease do not represent cell fusions
Authors: Küppers Ralf , Bräuninger Andreas , Müschen Markus , Distler Verena , Hansmann Martin-Leo , Rajewsky Klaus 
Published: July 2002

Abstract
In most cases, Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin disease (HD) carry rearranged immunoglobulin (Ig) genes and thus derive from B cells. In rare cases, HRS cells originate from T cells. However, based on the unusual immunophenotype of HRS cells, often showing coexpression of markers typical for different hematopoetic lineages, and the regular detection of numerical chromosomal abnormalities, it has been speculated that HRS cells might represent cell fusions. Five cases of HD with 2 rearranged IgH alleles were analyzed for the presence of additional IgH alleles in germline configuration as a potential footprint of a cell fusion between a B and a non-B cell. Similarly, one case of T-cell–derived HD with biallelic T-cell receptor β (TCRβ) rearrangements was studied for the presence of unrearranged TCRβ alleles. In none of the 6 cases was evidence for additional IgH (or TCRβ) alleles obtained, strongly arguing against a role of cell fusion in HRS cell generation.
Postgrafting administration of granulocyte colony-stimulating factor impairs functional immune recovery in recipients of human leukocyte antigen haplotype–mismatched hematopoietic transplants
Authors: Volpi Isabella , Perruccio Katia , Tosti Antonella , Capanni Marusca , Ruggeri Loredana , Posati Sabrina , Aversa Franco , Tabilio Antonio , Romani Luigina , Martelli Massimo F. , Velardi Andrea 
Published: July 2002

AbstractIn human leukocyte antigen haplotype–mismatched transplantation, extensive T-cell depletion prevents graft-versus-host disease (GVHD) but delays immune recovery. Granulocyte colony-stimulating factor (G-CSF) is given to donors to mobilize stem cells and to recipients to ensure engraftment. Studies have shown that G-CSF promotes T-helper (Th)-2 immune deviation which, unlike Th1 responses, does not protect against intracellular pathogens and fungi. The effect of administration of G-CSF to recipients of mismatched hematopoietic transplants with respect to transplantation outcome and functional immune recovery was investigated. In 43 patients with acute leukemia who received G-CSF after transplantation, the engraftment rate was 95%. However, the patients had a long-lasting type 2 immune reactivity, ie, Th2-inducing dendritic cells not producing interleukin 12 (IL-12) and high frequencies of IL-4– and IL-10–producing CD4+ cells not expressing the IL-12 receptor β2 chain. Similar immune reactivity patterns were observed on exposure of donor cells to G-CSF. Elimination of postgrafting administration of G-CSF in a subsequent series of 36 patients with acute leukemia, while not adversely affecting engraftment rate (93%), resulted in the anticipated appearance of IL-12–producing dendritic cells (1-3 months after transplantation versus &gt; 12 months in transplant recipients given G-CSF), of CD4+ cells of a mixed Th0/Th1 phenotype, and of antifungal T-cell reactivity in vitro. Moreover, CD4+ cell counts increased in significantly less time. Finally, elimination of G-CSF–mediated immune suppression did not significantly increase the incidence of GVHD (&lt; 15%). Thus, this study found that administration of G-CSF to recipients of T-cell–depleted hematopoietic transplants was associated with abnormal antigen-presenting cell functions and T-cell reactivity. Elimination of postgrafting administration of G-CSF prevented immune dysregulation and accelerated functional immune recovery.
A novel myeloid-restricted zebrafish CCAAT/enhancer-binding protein with a potent transcriptional activation domain
Authors: Lyons Susan E. , Shue Bixiong C. , Oates Andrew C. , Zon Leonard I. , Liu P. Paul 
Published: July 2002

AbstractThe CCAAT/enhancer-binding protein (C/EBP) family consists of transcription factors essential for hematopoiesis. The defining feature of the C/EBPs is a highly conserved carboxy-terminal bZIP domain that is necessary and sufficient for dimerization and DNA binding, whereas their amino-terminal domains are unique. This study reports a novelc/ebp gene (c/ebp1) from zebrafish that encodes a protein homologous to mammalian C/EBPs within the bZIP domain, but with an amino terminus lacking homology to any C/EBP or to any known sequence. In zebrafish embryos, c/ebp1 expression was initially observed in cells within the yolk sac circulation valley at approximately the 16-to 18-somite stage, and at 24 hours postfertilization (hpf), also in circulating cells. Mostc/ebp1+cells also expressed a known early macrophage marker, leukocyte-specific plastin (l-plastin). Expression of both markers was lost in cloche, a mutant affecting hematopoiesis at the level of the hemangioblast. Expression of both markers was retained in m683 andspadetail, mutants affecting erythropoiesis, but not myelopoiesis. Further, c/ebp1 expression was lost in a mutant with defective myelopoiesis, but intact erythropoiesis. These data suggest that c/ebp1 is expressed exclusively in myeloid cells. In electrophoretic mobility shift assays, c/ebp1 was able to bind a C/EBP consensus DNA site. Further, a chimeric protein containing the amino-terminal domain of c/ebp1 fused to the DNA-binding domain of GAL4 induced a GAL4 reporter 4000-fold in NIH3T3 cells. These results suggest that c/ebp1 is a novel member of the C/EBP family that may function as a potent transcriptional activator in myeloid cells.
Phagocytic dendritic cells from myelomas activate tumor-specific T cells at a single cell level
Authors: Dembic Zlatko , Røttingen John-Arne , Dellacasagrande Jérôme , Schenck Karl , Bogen Bjarne 
Published: July 2002

AbstractAntigen-presenting cells (APCs) from subcutaneous mouse MOPC315 plasmacytoma phagocytosed immunoglobulin G–coated magnetic beads, enabling efficient isolation within 2 hours by magnetic separation (APC-MB). Cell morphology was heterogeneous, with some of the cells having dendrites. The surface phenotype of purified tumor APCs-MB was CD11b+, CD11c+, CD40+, CD80+, CD86+, and MHC class II+. Tumor APCs-MB expressed messenger RNA for fractalkine and ABCD-1 chemokines, and for CC-type chemokine receptors CCR5 and CCR7, indicating the presence of mature dendritic cells (DCs). Visualized at a single cell level within 4 hours after disruption of the tumor, APCs-MB induced rapid Ca++ mobilization in MHC class II–restricted tumor idiotype (Id)–specific cloned CD4+ T cells. In long-term assays, tumor APCs-MB induced proliferation of naive T cells from Id-specific T-cell receptor transgenic mice. The results suggest that tumor APCs-MB represent a heterogeneous cell population that includes myeloid-derived DCs of various stages of maturation. A considerable fraction (≥ 15%) of DCs is spontaneously primed with tumor-specific antigen.
Role of p21Cip1/Waf1 in cell-cycle exit of endomitotic megakaryocytes
Authors: Baccini Véronique , Roy Lydia , Vitrat Natacha , Chagraoui Hédia , Sabri Siham , Couedic Jean-Pierre Le , Debili Najet , Wendling Françoise , Vainchenker William 
Published: July 2002

Abstract
The cyclin-dependent kinase inhibitor p21Waf-1/Cip-1 is expressed at high level during megakaryocyte differentiation, but its precise function remains unknown. In this study, it is confirmed that p21 was expressed at a high level in hypoploid (2N and 4N) and polyploid (at least 8N) human megakaryocytes derived from CD34+ cells. A high expression of p27Kip1, p16, cyclin E, and cyclin D3 was also found in both populations associated with a hypophosphorylated form of retinoblastoma protein, suggesting that the majority of hypoploid and polyploid megakaryocytes are G1-arrested cells. As human megakaryocytes grown in vitro present a defect in their polyploidization, the study switched to the murine model. The modal ploidy of megakaryocytes derived from lineage-negative cells was 32N, and an elevated expression of p21 was found in high-ploidy megakaryocytes. In addition, p21 and p27 were coexpressed in the majority of mature polyploid megakaryocytes. The p21 was detected by immunofluorescence in megakaryocytes derived from p53−/− mice, demonstrating a p53-independent regulation during megakaryocyte differentiation. Megakaryocytopoiesis of p21−/− mice was subsequently studied. No marked abnormality in the ploidy of primary or cultured megakaryocytes was detected. Overexpression of p21 in p21−/− or normal murine megakaryocytes and in human megakaryocytes showed in all these cases a marked inhibition in megakaryocyte polyploidization. In conclusion, while a reciprocal relation is observed between p21 levels in megakaryocytes and the cycling state of the cells, p21 is not essential for the determination of the ploidy profile in normal megakaryocytes in vivo. However, high levels of its expression in cultured megakaryocytes arrest the endomitotic cell cycle.
Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease
Authors: Liu Jinli , Anderson Britt E. , Robert Marie E. , McNiff Jennifer M. , Emerson Stephen G. , Shlomchik Warren D. , Shlomchik Mark J. 
Published: July 2002

AbstractGraft-versus-host disease (GVHD) is a major cause of morbidity and mortality of allogeneic stem cell transplantation. Strategies to control GVHD while maintaining graft versus leukemia (GVL) include herpes simplex virus thymidine kinase (HSV-tk) gene transduction of donor T cells followed by treatment with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by distinct processes. In this regard, whether cytokine polarization occurs and to what degrees various subsets of cytokine-producing T cells mediate GVHD or GVL has been an active area of research using cytokine or cytokine antibody infusion or genetically deficient mice. This study takes a different approach that allows simultaneous investigation into both the mechanisms underlying GVHD reactions and the efficacy of HSV-tk suicide gene-based T-cell deletion. A source of donor T cells, splenocytes from mice transgenic for HSV-tk controlled by elements of either the interleukin-2 (IL-2) or IL-4 promoters (IL-2-tk and IL-4-tk, respectively) was used, thus allowing investigation into the roles of T1 and T2 cells in ongoing GVHD reactions. To assess treatment rather than prevention of GVHD, GCV was started at peak disease. Remarkably, treatment at this late time point rescued mice from the clinical effects of GVHD caused by T cells expressing either transgene. Thus, both T1 and T2 cells play an important role in clinical GVHD in a minor histocompatibility antigen-mismatched setting. In addition, because clinical disease was reversible even at its maximum, these observations provide controlled evidence that this strategy of treating ongoing GVHD could be effective clinically.
Partial amino acid sequence of purified von Willebrand factor–cleaving protease
Authors: Gerritsen Helena E. , Robles Rodolfo , Lämmle Bernhard , Furlan Miha 
Published: July 2002

Abstract
von Willebrand factor–cleaving protease (vWF-cp) is responsible for the continuous degradation of plasma vWF multimers released from endothelial cells. It is deficient in patients with thrombotic thrombocytopenic purpura, who show unusually large vWF multimers in plasma. Purified vWF-cp may be useful for replacement in these patients, who are now treated by plasma therapy. In this study, vWF-cp was purified from normal human plasma by affinity chromatography on the IgG fraction from a patient with autoantibodies to vWF-cp and by a series of further chromatographic procedures, including affinity chromatography on Protein G, Ig-TheraSorb, lentil lectin, and heparin. Four single-chain protein bands, separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under nonreducing conditions, showed Mr of 150, 140, 130, and 110 kd and were found to share the same N-terminal amino acid sequence, suggesting that they were derived from the same polypeptide chain that had been partially degraded at the carboxy-terminal end. A hydrophobic sequence (Ala-Ala-Gly-Gly-Ile-Leu-His-Leu-Glu-Leu-Leu-Val-Ala-Val-Gly) of the first 15 residues was established. The protease migrates in gel filtration as a high-molecular-weight complex with clusterin, a 70-kd protein with chaperonelike activity. vWF-cp bound to clusterin is dissociated by the use of concentrated chaotropic salts. vWF-cp in normal human plasma or serum is not associated with clusterin, suggesting that the observed complex is due to vWF-cp denaturation during the purification procedure. Activity of vWF-cp is unusually stable during incubation at 37°C; its in vitro half-life in citrated human plasma, heparin plasma, or serum is longer than 1 week. There was even a temporary increase in protease activity during the first 3 days of incubation.
The dynamics of hepatitis C virus binding to platelets and 2 mononuclear cell lines
Authors: Hamaia Samir , Li Chengyao , Allain Jean-Pierre 
Published: July 2002

AbstractHepatitis C virus (HCV) binds to platelets in chronically infected patients where free HCV constitutes only about 5% of total circulating virus. Free HCV preferentially binds to human mononuclear cell lines but free and complexed virus binds equally to platelets. The extent of free HCV binding to human Molt-4 T cells (which express CD81) and to human promonocytic U937 cells or to platelets (which do not express CD81) was similar. The binding of free HCV to the cell lines was saturated at a virus dose of 1 IU HCV RNA per cell but binding to platelets was not saturable. Human anti-HCV IgG, but not anti-CD81, markedly inhibited HCV binding to target cells in a dose-dependent manner. Human antibodies to HCV hypervariable region 1 of E2 glycoprotein partially inhibited viral binding to target cells. Recombinant E2 also inhibited viral binding to target cells in a dose-dependent manner, with the efficacy of this decreasing in the rank order of Molt-4 cells more than U937 cells more than platelets. In contrast to HCV, recombinant E2 bound to Molt-4 cells to an extent markedly greater than that apparent with U937 cells or platelets. These results suggest that the binding of HCV to blood cells is mediated by multiple cell surface receptors and that recombinant E2 binding may not be representative of the interaction of the intact virus with target cells.
General T-cell receptor antagonists to immunomodulate HLA-A2–restricted minor histocompatibility antigen HA-1–specific T-cell responses
Authors: den Haan Joke M. M. , Mutis Tuna , Blokland Els , IJzerman Ad P. , Goulmy Els 
Published: July 2002

AbstractT-cell receptors (TCRs) of a series of minor histocompatibility antigen (mHag) HA-1–specific cytotoxic T-cell (CTL) clones isolated from 3 unrelated patients have been shown to use the same BV6S4A2 segment with conserved amino acids in the CDR3Vβ region. This suggests that different HA-1–specific TCRs interact similarly to the HA-1 antigen presented by the HLA-A2 molecule. The mHag HA-1 forms an immunogenic complex with HLA-A2 and induces strong alloimmune responses after stem cell transplantation (SCT). It was questioned, therefore, whether clonal and polyclonal HA-1–specific CTL responses can be antagonized by a single TCR antagonistic peptide. Functional analysis and molecular modeling of single and double amino acid substitutions of TCR contact residues, adjacent residues, and HLA-A2 binding residues resulted in 4 peptides with high affinity for HLA-A2 and with the capacity to inhibit the lysis of endogenously HA-1–expressing EBV-BLCL by 3 different HA-1–specific CTL clones. These peptides also efficiently antagonized HA-1–specific polyclonal CTL lines derived from 3 patients and significantly reduced the number of interferon-γ–producing HA-1–specific CTL of a patient with graft-versus-host disease after HA-1–mismatched SCT. These data show that general TCR antagonists can be developed that inhibit HLA-A2–restricted HA-1–specific CTL responses on the clonal and the polyclonal level and that TCR antagonists may modulate the immunodominant mHag HA-1 responses.
CD8α+ dendritic cells originate from the CD8α− dendritic cell subset by a maturation process involving CD8α, DEC-205, and CD24 up-regulation
Authors: del Hoyo Gloria Martı́nez , Martı́n Pilar , Arias Cristina Fernández , Marı́n Alvaro Rodrı́guez , Ardavı́n Carlos 
Published: July 2002

AbstractCD8α+ and CD8α− dendritic cells (DCs) have been considered as independent DC subpopulations both ontogenetically and functionally during recent years. However, it has been demonstrated that both DC subsets can be generated from a single precursor population, supporting the concept that they do not represent separate DC lineages. By using highly purified splenic CD8α− DCs, which were injected intravenously and traced by means of an Ly5.1/Ly5.2 transfer system, this study shows that CD8α− DCs acquired the phenotypic characteristics of CD8α+ DCs, by a differentiation process involving CD8α, DEC-205, and CD24 up-regulation, paralleled by the down-regulation of CD11b, F4/80, and CD4. These data demonstrate that CD8α+DCs derive from CD8α− DCs, and strongly support that CD8α− and CD8α+ DCs represent different maturation or differentiation stages of the same DC population. Therefore, CD8α+ DCs would represent the last stage of DC differentiation, playing an essential role in the induction of T-cell responses, due to their antigen-presenting potential, cross-priming ability, and capacity to secrete large amounts of key cytokines such as interferon γ and interleukin-12.
Impact of Referral Patterns on the Use of Chemotherapy for Lung Cancer
Authors: Earle Craig C. , Neumann Peter J. , Gelber Richard D. , Weinstein Milton C. , Weeks Jane C. 
Published: July 2002

PURPOSE: To determine the extent to which unexplained variation in the use of chemotherapy for advanced lung cancer is due to access to oncologists’ services as opposed to treatment decisions made after seeing an oncologist. METHODS: We performed a retrospective cohort study of 12,015 patients over age 65 diagnosed with metastatic lung cancer between 1991 and 1996 while living in one of 11 regions monitored by a Survival, Epidemiology, and End Results (SEER) tumor registry. Assessment by an oncologist and subsequent treatment with chemotherapy were determined by examining linked Medicare claims. RESULTS: Of patients who did not receive chemotherapy, 36% were never assessed by a physician who provides chemotherapy. Patients living in certain areas, those diagnosed in more recent years, and those who received care in a teaching hospital were all more likely to see a cancer specialist. These factors were unrelated to subsequent treatment decisions, however. Conversely, age and comorbidity did not have a significant effect on whether a patient was seen by an oncologist, but they were associated with the likelihood of subsequently receiving chemotherapy. Black race, probably acting as a proxy for lower socioeconomic status, was associated with both a diminished likelihood of seeing a cancer specialist and subsequently receiving chemotherapy. CONCLUSION: Nonmedical factors are important determinants of whether a lung cancer patient is seen by a physician who provides chemotherapy. After seeing such a physician, treatment decisions seem to be mostly explained by appropriate medical factors. Racial and socioeconomic disparities still exist at both steps, however. As therapeutic options expand, referring physicians must ensure that biases and barriers to care do not deprive patients of the opportunity to consider all of their treatment options.