bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic and prognostic value of bone marrow angiogenesis and megakaryocyte c-Mpl expression in essential thrombocythemia
Authors: Mesa Ruben A. , Hanson Curtis A. , Li Chin-Yang , Yoon Soo-Young , Rajkumar S. Vincent , Schroeder Georgene , Tefferi Ayalew
Published: October 2002

The lack of diagnostic certainty in some patients makes it difficult to distinguish between primary and secondary forms of thrombocytosis. To augment current diagnostic studies for thrombocytosis, we retrospectively evaluated clinical records and bone marrow trephine specimens of 183 patients with thrombocytosis—164 with essential thrombocythemia (ET), 19 with reactive thrombocytosis (RT)—for bone marrow angiogenesis, bone marrow megakaryocyte c-Mpl staining, and morphologic evidence of megakaryocyte proliferation. Angiogenesis was increased in patients with ET compared with healthy controls (P < .0001) and patients with RT (P = .006). In addition, an increase in angiogenesis was associated with certain disease features such as splenomegaly (P = .004) and reticulin fibrosis (P = .005). Decreased megakaryocyte c-Mpl staining was observed in a heterogeneous pattern in ET compared with healthy controls (P < .0001) and RT (P < .0001). Histologic stratifying criteria incorporating increased angiogenesis, decreased megakaryocyte c-Mpl expression, and marked megakaryocyte proliferation in the bone marrow was highly sensitive (97%) and specific (95%) for distinguishing ET from RT (P < .0001). However, with the current duration of follow-up available on the patients, none of the histologic features evaluated have yet demonstrated prognostic value for subsequent clinical course, vascular events, or survival.
Total body irradiation causes profound changes in endothelial traffic molecules for hematopoietic progenitor cell recruitment to bone marrow
Authors: Mazo Irina B. , Quackenbush Elizabeth J. , Lowe John B. , von Andrian Ulrich H.
Published: October 2002

Nonirradiated bone marrow (BM) venules and sinusoids in murine skull support hematopoietic progenitor cell (HPC) rolling through constitutively expressed endothelial (P- and E-) selectins and VCAM-1. Using intravital microscopy, we tested whether host conditioning with total body irradiation (TBI) changes the molecular mechanisms by which murine HPCs from fetal livers (FL) interact with BM endothelial cells. Although a high dose of TBI did not affect the overall frequency of HPC rolling in BM microvessels, the underlying molecular mechanisms differed from those in nonirradiated BM. TBI induced VCAM-1 up-regulation in BM microvessels, whereas P-selectin expression was reduced and the low baseline level of E-selectin remained unchanged. Only the administration of anti–VCAM-1, but not anti–P- or –E-selectin monoclonal antibodies, decreased FL HPC rolling. Rolling was frequently followed by firm arrest (sticking), even in nonirradiated BM microvessels in which sticking was entirely pertussis toxin–insensitive—that is, Gαi-coupled signaling events (eg, through chemokines) were apparently not required. TBI increased the frequency of sticking FL HPC. This irradiation-induced additional sticking was reversed when FL HPCs were pretreated with pertussis toxin, suggesting that TBI induced elevated expression of a Gαi-protein–coupled chemotactic signal in the BM. This chemoattractant was probably distinct from SDF-1α because, unlike adult HPCs, FL HPCs (day 11 of gestation) responded poorly to SDF-1α in vitro. These results demonstrate that TBI induces profound changes in the expression of endothelial traffic molecules in the BM, and they indicate that FL HPCs can home to the BM in the absence of SDF-1α and other Gαi-protein–coupled signals.
Donor-derived interferon γ separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells
Authors: Yang Yong-Guang , Qi Jin , Wang Min-Guang , Sykes Megan
Published: October 2002

The graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD)–inducing activity of CD8 T cells was compared in murine recipients of wild-type (WT) or interferon γ (IFN-γ)–deficient (GKO) allogeneic donor cells. CD8 T cells (or CD4-depleted splenocytes) from GKO donor mice induced more severe GVHD in lethally irradiated allogeneic recipients compared to the same cell populations from WT donors. Consistent with GVHD severity, donor CD8 T-cell expansion in allogeneic recipients was augmented in the absence of IFN-γ. These results demonstrate that IFN-γ does not stimulate but instead down-modulates GVHD induced by donor CD8 T cells. Remarkably, antihost lymphohematopoietic reactions, including GVL effects against host leukemia/lymphoma cells, of CD8 T cells correlated inversely with their GVHD-inducing activity, and those of GKO donors were markedly weaker than those mediated by WT donor CD8 T cells. These data show for the first time that GVHD-inducing activity and GVL effects of allogeneic CD8 T cells can be separated by a single cytokine, IFN-γ.
Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia
Authors: Yuille Martin , Condie Alison , Hudson Chantelle , Kote-Jarai Zsofia , Stone Elaine , Eeles Rosalind , Matutes Estella , Catovsky Daniel , Houlston Richard
Published: October 2002

Interindividual differences in susceptibility to hematologic malignancies may be mediated in part through polymorphic variability in the bioactivation and detoxification of carcinogens. The glutathione S–transferases (GSTs) have been implicated as susceptibility genes in this context for a number of cancers. The aim of this study was to examine whether polymorphic variation in GSTs confers susceptibility to chronic lymphocytic leukemia (CLL). GSTM1, GSTT1, andGSTP1 genotypes were determined in 138 patients and 280 healthy individuals. The frequency of both GSTM1 andGSTT1 null genotypes and the GSTP1-Ile allele was higher in cases than in controls. There was evidence of a trend in increasing risk with the number of putative “high-risk” alleles of the GST family carried (P = .04). The risk of CLL associated with possession of all 3 “high-risk” genotypes was increased 2.8-fold (OR = 2.8, 95% confidence interval: 1.1-6.9). Our findings suggest that heritable GST status may influence the risk of developing CLL.
Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer
Authors: Bregni Marco , Dodero Anna , Peccatori Jacopo , Pescarollo Alessandra , Bernardi Massimo , Sassi Isabella , Voena Claudia , Zaniboni Alberto , Bordignon Claudio , Corradini Paolo
Published: October 2002

The feasibility and toxicity of allogeneic stem cell transplantation after nonmyeloablative conditioning including thiotepa, fludarabine, and cyclophosphamide have been investigated in 6 patients with breast cancer and 7 patients with renal cell cancer. The program included the use of escalating doses of donor lymphocyte infusions (DLI) and/or interferon alpha (IFNα) for patients showing no tumor response and no graft-versus-host disease (GVHD). Patients were at high risk of transplant-related mortality (TRM) because of age, advanced stage, and previous treatments. We observed a partial remission in 4 renal cancer and in 2 breast cancer patients (one at the molecular level in the bone marrow), occurring after cyclosporine withdrawal or after DLI and/or IFNα. All the responses were accompanied by the occurrence of acute GVHD. We conclude that reduced-intensity allogeneic stem cell transplantation is a feasible procedure in renal and breast cancer, and that the exploitation of graft-versus-tumor effect after DLI is a promising finding.
Autologous stem cell transplantation for primary systemic amyloidosis
Authors: Comenzo Raymond L. , Gertz Morie A.
Published: October 2002

High-dose melphalan with autologous blood stem cell transplantation (SCT) can reverse the disease process in selected patients with primary systemic amyloidosis (AL); however, SCT for AL remains controversial because of the treatment-related mortality in patients with cardiac and multisystem organ involvement. In this review, we briefly discuss recent advances in AL, such as the free light-chain assay and the role of immunoglobulin light-chain variable region germline genes in the disease, and then we discuss the current status of SCT for AL with emphases on patient selection, approaches to stem cell mobilization, and peri-SCT management. It is clear that patients with AL who have advanced amyloid cardiomyopathy or more than 2 major viscera involved with disease are poor candidates for SCT. Therefore, the importance of patient selection cannot be overemphasized, and patients with 1 or 2 involved organs or with early cardiac involvement are usually appropriate candidates for SCT. Because the toxicity of melphalan is dose-related and survival with AL may be age-related, patient age and the extent of organ involvement can provide a basis for patient stratification. We discuss such a risk-adapted approach to melphalan dosing in detail and conclude with a brief overview of current research using SCT to treat patients with AL.
Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes
Authors: La Nasa Giorgio , Giardini Claudio , Argiolu Francesca , Locatelli Franco , Arras Marcella , De Stefano Piero , Ledda Antonio , Pizzati Antonella , Sanna Maria A. , Vacca Adriana , Lucarelli Guido , Contu Licinio
Published: October 2002

Allogeneic bone marrow transplantation (BMT) from a genotypically identical family donor is an accepted therapeutic option for homozygous beta-thalassemia. However, only a minority of patients have access to this curative procedure. The aim of this study is to explore the feasibility of matched unrelated transplants in thalassemia and the possibility of reducing the risk of immunologic complications through careful selection of donor/recipient pairs. Since November 1992, 32 patients (age range, 2-28 years) have been enrolled. There were 4 patients assigned to risk-class I, 11 to risk-class II, and 17 to risk-class III of the Pesaro classification. Extended haplotype analysis and family segregation studies were employed for identification of suitable donors. Of the 32 donor/recipient pairs, 24 were identical for HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 loci; 7 pairs were identical for 2 extended haplotypes, and 15 pairs shared one extended haplotype. Grade II-IV acute graft-versus-host disease (GVHD) developed in 11 cases (41%) and chronic GVHD in 6 (25%) out of 24 patients at risk. There are 22 patients (69%) who are alive and transfusion-independent after a median follow-up of 30 months (range, 7-109 months). There were 6 patients (19%) who engrafted and subsequently died from transplant-related complications. In 4 cases (12.5%) graft rejection was observed within 30 days and it was followed by autologous reconstitution. Out of 22 patients with a donor identical for at least one extended haplotype, there are 19 who survived, 17 of them being transfusion-independent. Among the 10 recipients who did not share any extended haplotype with the donor, only 5 are alive without thalassemia and 3 patients died. Of the 6 patients who died, 5 belonged to risk-class III and only 1 to risk-class II. BMT from well-selected unrelated donors may offer results comparable to those obtained in transplantations using HLA-identical family donors, especially for patients with lesser iron overload.
High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution
Authors: Chakrabarti Suparno , Mackinnon Stephen , Chopra Raj , Kottaridis Panagiotis D. , Peggs Karl , O'Gorman Peter , Chakraverty Ronjon , Marshall Timothy , Osman Husam , Mahendra Premini , Craddock Charles , Waldmann Herman , Hale Geoff , Fegan Christopher D. , Yong Kwee , Goldstone Anthony H. , Linch David C. , Milligan Donald W.
Published: October 2002

Nonmyeloablative conditioning is increasingly used for transplantation in a wide range of diseases, but little is known about its impact on the incidence of infections and immune reconstitution. We examined the pattern and outcome of cytomegalovirus (CMV) infections monitored by polymerase chain reaction–based assays and treated preemptively in 101 patients following nonmyeloablative conditioning containing in vivo Campath-1H. Fifty-one patients (50%) had a CMV infection at a median of 27 days after transplantation with a probability of 84.8% in patients at risk of CMV infection. The probability of recurrence of CMV infection before and after 100 days was 53.6% and 46.6%, respectively, and was more common in unrelated donor transplant recipients. All 3 patients who developed CMV disease died of this complication. The 2 patients with late CMV disease had grade III to IV graft-versus-host-disease (GVHD), which occurred de novo in only 4% of patients and in another 10% following donor lymphocyte infusions. The median time to CD4+ T-cell count more than 200/μL was 9 months in the 48 patients studied. The probabilities of overall survival and nonrelapse mortality at 18 months were 65% and 27.8%, respectively, with no significant difference in survival between CMV-infected and -uninfected patients. The use of Campath-1H appeared to be associated with a low incidence of GVHD but a high incidence of CMV infections and prolonged immune paresis.
Adenovirus encoding vascular endothelial growth factor–D induces tissue-specific vascular patterns in vivo
Authors: Byzova Tatiana V. , Goldman Corey K. , Jankau Jurek , Chen Juhua , Cabrera Gustavo , Achen Marc G. , Stacker Steven A. , Carnevale Kevin A. , Siemionow Maria , Deitcher Steven R. , DiCorleto Paul E.
Published: October 2002

The capacity of an adenovirus encoding the mature form of vascular endothelial growth factor (VEGF)–D, VEGF-DΔNΔC, to induce angiogenesis, lymphangiogenesis, or both was analyzed in 2 distinct in vivo models. We first demonstrated in vitro that VEGF-DΔNΔC encoded by the adenovirus (Ad-VEGF-DΔNΔC) is capable of inducing endothelial cell proliferation and migration and that the latter response is primarily mediated by VEGF receptor-2 (VEGFR-2). Second, we characterized a new in vivo model for assessing experimental angiogenesis, the rat cremaster muscle, which permits live videomicroscopy and quantitation of functional blood vessels. In this model, a proangiogenic effect of Ad-VEGF-DΔNΔC was evident as early as 5 days after injection. Immunohistochemical analysis of the cremaster muscle demonstrated that neovascularization induced by Ad-VEGF-DΔNΔC and by Ad-VEGF-A165 (an adenovirus encoding the 165 isoform of VEGF-A) was composed primarily of laminin and VEGFR-2–positive vessels containing red blood cells, thus indicating a predominantly angiogenic response. In a skin model, Ad-VEGF-DΔNΔC induced angiogenesis and lymphangiogenesis, as indicated by staining with laminin, VEGFR-2, and VEGFR-3, whereas Ad-VEGF-A165 stimulated the selective growth of blood vessels. These data suggest that the biologic effects of VEGF-D are tissue-specific and dependent on the abundance of blood vessels and lymphatics expressing the receptors for VEGF-D in a given tissue. The capacity of Ad-VEGF-DΔNΔC to induce endothelial cell proliferation, angiogenesis, and lymphangiogenesis demonstrates that its potential usefulness for the treatment of coronary artery disease, cerebral ischemia, peripheral vascular disease, restenosis, and tissue edema should be tested in preclinical models.
Heme oxygenase-1–derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth
Authors: Peyton Kelly J. , Reyna Sylvia V. , Chapman Gary B. , Ensenat Diana , Liu Xiao-ming , Wang Hong , Schafer Andrew I. , Durante William
Published: October 2002

Vascular smooth muscle cells (SMCs) generate carbon monoxide (CO) via the catabolism of heme by the enzyme heme oxygenase (HO). In the present study, we found that serum stimulated a time- and concentration-dependent increase in the levels of HO-1 messenger RNA (mRNA) and protein in vascular SMCs. The induction of HO-1 expression by serum was inhibited by actinomycin D or cycloheximide. In addition, serum stimulated HO activity, as reflected by an increase in the concentration of bilirubin in the culture media. Treatment of vascular SMCs with serum stimulated DNA synthesis and this was potentiated by the HO inhibitors, zinc and tin protoporphyrin-IX as well as by the CO scavenger, hemoglobin. The iron chelator desferrioxamine had no effect on DNA synthesis. However, exposure of vascular SMCs to exogenous CO inhibited serum-stimulated SMC proliferation and the phosphorylation of retinoblastoma protein. In addition, CO arrested SMCs at the G1/S transition phase of the cell cycle and selectively blocked the serum-stimulated expression of cyclin A mRNA and protein without affecting the expression of cyclin D1 and E. CO also inhibited the serum-stimulated activation of cyclin A–associated kinase activity and cyclin-dependent kinase 2 activity. These results demonstrate that serum stimulates HO-1 gene expression and CO synthesis. Furthermore, they show that CO acts in a negative feedback fashion to inhibit vascular SMC growth by regulating specific components of the cell cycle machinery. The capacity of vascular mitogens to induce CO synthesis may provide a novel mechanism by which these agents modulate cell growth.
Attachment of the PSGL-1 cytoplasmic domain to the actin cytoskeleton is essential for leukocyte rolling on P-selectin
Authors: Snapp Karen R. , Heitzig Christine E. , Kansas Geoffrey S.
Published: October 2002

P-selectin glycoprotein ligand–1 (PSGL-1) serves as the leukocyte ligand for P-selectin, and many of the structural features of its ectodomain required for interactions with P-selectin have been uncovered. In contrast, the function of the highly conserved PSGL-1 cytoplasmic domain has not been explored. Stable transfectants expressing similar levels of either wild-type PSGL-1 or truncated PSGL-1 in which only 4 cytoplasmic residues were retained (designated PSGL-1Δcyto), were analyzed. Transfectants expressing full-length PSGL-1 rolled well on P-selectin. In contrast, rolling was almost completely absent in cells transfected with PSGL-1Δcyto, even at low shear. Importantly, cells expressing truncated PSGL-1 were able to bind soluble P-selectin and to bind COS cells overexpressing P-selectin, demonstrating that the P-selectin binding site on the PSGL-1Δcyto transfectants was intact and was capable of recognizing P-selectin. Impaired rolling by PSGL-1Δcyto transfectants was not due to alterations in subcellular localization because both wild-type and truncated PSGL-1 had similar surface distributions on K562 transfectants. Treatment of cells expressing native PSGL-1 with actin cytoskeletal toxins inhibited adhesion in a dose-dependent way. PSGL-1 was associated with the actin cytoskeleton, and this interaction was greatly impaired in PSGL-1Δcyto– expressing cells. The PSGL-1 cytoplasmic domain interacted selectively with the ezrin/radixin/moesin (ERM) protein moesin, but not with other ERM proteins or several other cytoskeletal linker proteins. Pharmacologic disruption of interactions between moesin and F-actin in cells expressing PSGL-1 resulted in a dose-dependent inhibition of rolling on P-selectin. Thus, attachment of PSGL-1 to the leukocyte cortical cytoskeleton is essential for leukocyte rolling on P-selectin.
Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis
Authors: Nieborowska-Skorska Malgorzata , Hoser Grazyna , Kossev Plamen , Wasik Mariusz A. , Skorski Tomasz
Published: October 2002

BCR/ABL oncogenic tyrosine kinase activates STAT5, which plays an important role in leukemogenesis. The downstream effectors of the BCR/ABL→STAT5 pathway remain poorly defined. We show here that expression of the antiapoptotic protein A1, a member of the Bcl-2 family, and the serine/threonine kinase pim-1 are enhanced by BCR/ABL. This up-regulation requires activation of STAT5 by the signaling from SH3+SH2 domains of BCR/ABL. Enhanced expression of A1 and pim-1 played a key role in the BCR/ABL-mediated cell protection from apoptosis. In addition, pim-1 promoted proliferation of the BCR/ABL-transformed cells. Both A1 and pim-1 were required to induce interleukin 3–independent cell growth, inhibit activation of caspase 3, and stimulate cell cycle progression. Moreover, simultaneous up-regulation of both A1 and pim-1 was essential for in vitro transformation and in vivo leukemogenesis mediated by BCR/ABL. These data indicate that induction of A1 and pim-1 expression may play a critical role in the BCR/ABL-dependent transformation.
Multiple PU.1 sites cooperate in the regulation ofp40phox transcription during granulocytic differentiation of myeloid cells
Authors: Li Sen-Lin , Valente Anthony J. , Qiang Mei , Schlegel Werner , Gamez Maria , Clark Robert A.
Published: October 2002

The p40phox protein, a regulatory component of the phagocyte NADPH oxidase, is preferentially expressed in cells of myeloid lineage. We investigated transcriptional regulation of thep40phox gene in HL-60 myeloid cells. Deletion analysis of approximately 6 kb of the 5′-flanking sequence of the gene demonstrated that the proximal 106 base pair of the promoter exhibited maximum reporter activity. This region contains 3 potential binding sites for PU.1, a myeloid-restricted member of theets family of transcription factors. Mutation or deletion of each PU.1 site decreased promoter activity, and the level of activity mediated by each site correlated with its binding avidity for PU.1, as determined by gel shift competition assays. Mutation of all 3 sites abolished promoter activity in myeloid cells. PU.1-dependent expression was also observed in the Raji B-cell line, whereas the moderate level of promoter reporter activity in the nonmyeloid HeLa cell line was independent of PU.1. Chromatin immunoprecipitation assay demonstrated occupation of the PU.1 sites by PU.1 in vivo in HL-60 cells. Cotransfection of the pGL3-p40-106 reporter construct with a dominant-negative PU.1 mutant dramatically reduced promoter activity, whereas the overexpression of PU.1 increased promoter activity. Promoter activity and transcript levels ofp40phox increased in HL-60 cells during dimethyl sulfoxide–induced differentiation toward the granulocyte phenotype, and this was associated with increased cellular levels of PU.1 protein. Our findings demonstrate that PU.1 binding at multiple sites is required for p40phox gene transcription in myeloid cells and that granulocytic differentiation is associated with the coordinated up-regulation of PU.1 andp40phox expression.
Deletion analysis of p16INKa and p15INKb in relapsed childhood acute lymphoblastic leukemia
Authors: Graf Einsiedel Hagen , Taube Tillmann , Hartmann Reinhard , Wellmann Sven , Seifert Georg , Henze Günter , Seeger Karl
Published: October 2002

This study aimed at determining the prevalence of INK4deletions and their impact on outcome in 125 children with acute lymphoblastic leukemia (ALL) at first relapse using real-time quantitative polymerase chain reaction. Patients were enrolled into relapse trials ALL-REZ BFM (ALL-Relapse Berlin–Frankfurt–Münster) 90 and 96. The prevalence of p16INK4a and p15INK4bhomozygous deletions was 35% (44 of 125) and 30% (38 of 125), respectively. A highly significant association of both gene deletions was found with the 2 major adverse prognostic factors known for relapsed childhood ALL: T-cell immunophenotype and first remission duration. There was no correlation between INK4 deletions and probability of event-free survival. These findings argue against an independent prognostic role of INK4 deletions in relapsed childhood ALL.
Narrowing and genomic annotation of the commonly deleted region of the 5q− syndrome
Authors: Boultwood Jacqueline , Fidler Carrie , Strickson Amanda J. , Watkins Fiona , Gama Susana , Kearney Lyndal , Tosi Sabrina , Kasprzyk Arek , Cheng Jan-Fang , Jaju Rina J. , Wainscoat James S.
Published: October 2002

The 5q− syndrome is the most distinct of the myelodysplastic syndromes, and the molecular basis for this disorder remains unknown. We describe the narrowing of the common deleted region (CDR) of the 5q− syndrome to the approximately 1.5-megabases interval at 5q32 flanked by D5S413 and theGLRA1 gene. The Ensembl gene prediction program has been used for the complete genomic annotation of the CDR. The CDR is gene rich and contains 24 known genes and 16 novel (predicted) genes. Of 40 genes in the CDR, 33 are expressed in CD34+ cells and, therefore, represent candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment. A number of the genes assigned to the CDR represent good candidates for the 5q− syndrome, including MEGF1, G3BP, and several of the novel gene predictions. These data now afford a comprehensive mutational/expression analysis of all candidate genes assigned to the CDR.
Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia
Authors: Pedersen-Bjergaard Jens , Andersen Mette K. , Christiansen Debes H. , Nerlov Claus
Published: October 2002

Therapy-related acute myeloid leukemia (t-AML) in most cases develops after chemotherapy of other malignancies and shows characteristic chromosome aberrations. Two general types of t-AML have previously been identified. One type is observed after therapy with alkylating agents and characteristically presents as therapy-related myelodysplasia with deletions or loss of the long arms of chromosomes 5 and 7 or loss of the whole chromosomes. The other type is observed after therapy with topoisomerase II inhibitors and characteristically presents as overt t-AML with recurrent balanced chromosome aberrations. Recent research suggests that these 2 general types of t-AML can now be subdivided into at least 8 genetic pathways with a different etiology and different biologic characteristics.
BCR ligation reprograms B cells for migration to the T zone and B-cell follicle sequentially
Authors: Casamayor-Pallejà Montserrat , Mondière Paul , Verschelde Claire , Bella Chantal , Defrance Thierry
Published: October 2002

We have studied the impact of B-cell receptor (BCR) or CD40 ligation on the in vitro chemotactic response of tonsillar B cells to 4 chemokines: stromal cell–derived factor (SDF)–1α, macrophage inflammatory protein (MIP)–3α, MIP-3β, and B-cell–attracting chemokine (BCA)–1. In the tonsil, SDF-1 and MIP-3α are both expressed in the crypt epithelium, while MIP-3β is found in the T zone and BCA-1 in the follicles. Resting virgin and memory B cells display a similar chemotaxis pattern, and they both have the potential to migrate in vitro to all 4 chemokines studied. This pattern of responsiveness is strongly modified by a surrogate antigen (Ag) but is not altered by CD40 ligand. We report here that surrogate Ag induces a profound and sustained suppression of the response to the crypt chemokines SDF-1α and MIP-3α, while it exacerbates the migratory response to MIP-3β. The effect of surrogate Ag on the response to BCA-1 is biphasic: After an initial phase of suppression, chemotaxis toward BCA-1 is strongly up-regulated. Our results suggest that Ag is primarily responsible for reprogramming the B-cell chemotaxis responsiveness during the humoral response. We propose that it initiates an ordered change of the chemotaxis machinery allowing Ag-activated B cells to relocate in the T zone and B-cell follicles sequentially.
Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation
Authors: Weisdorf Daniel J. , Anasetti Claudio , Antin Joseph H. , Kernan Nancy A. , Kollman Craig , Snyder David , Petersdorf Effie , Nelson Gene , McGlave Philip
Published: October 2002

Allogeneic bone marrow transplantation (BMT) offers the only curative therapy for chronic myelogenous leukemia. We compared prospectively collected results of 2464 unrelated donor (URD) transplantations with 450 HLA-identical, matched sibling donor (MSD) transplantations performed at collaborating National Marrow Donor Program institutions. A total of 63% of URDs were matched at HLA-A, -B, and at -DRB1 alleles; all MSDs were genotypically identical at major histocompatibility loci. URD recipients were younger (median 36 vs 39, P = .001) than MSDs and underwent BMT later after diagnosis (median 17 [0-325 months] vs 7 [1-118 months],P = .001) and less often in chronic phase (CP) (67% vs 82%, P = .001). Multivariate analysis demonstrated a significantly increased risk of graft failure and acute graft versus host disease after URD BMT. The risk of hematologic relapse was low after either matched URD or MSD transplantations. We observed significantly though modestly poorer survival and disease-free survival (DFS) after URD transplantations. However, for those undergoing transplantation during CP within 1 year from diagnosis, 5-year DFS was similar or only slightly inferior after matched URD versus MSD transplantation (age < 30: URD 61% ± 8% vs MSD 68% ± 15%,P = .18; 30-40: URD 57% ± 9% vs MSD 67% ± 10%,P = .05; > 40: URD 46% ± 9% vs MSD 57% ± 9%,P = .02). Delay from diagnosis to BMT in CP patients led to substantially poorer 5-year DFS after matched URD than MSD BMT (CP 1-2 years: URD 39% ± 6% vs MSD 63% ± 12%; beyond 2 years: URD 33% ± 7% vs MSD 50% ± 20%). Outcome of matched URD BMT for early CP chronic myelogenous leukemia yields survival and DFS approaching that of MSD transplantation. However, delay may compromise URD outcomes to a greater extent. Improvements in URD and MSD transplantation are still needed, and results of newer, nontransplantation therapies should be evaluated against the established curative potential of URD and MSD marrow transplantation.
Platelet-derived growth factor inhibits basic fibroblast growth factor angiogenic properties in vitro and in vivo through its α receptor
Authors: De Marchis Francesco , Ribatti Domenico , Giampietri Claudia , Lentini Alessandro , Faraone Debora , Scoccianti Marco , Capogrossi Maurizio C. , Facchiano Antonio
Published: October 2002

Basic fibroblast growth factor (bFGF) and platelet-derived growth factor-BB (PDGF-BB) modulate vascular wall cell function in vitro and angiogenesis in vivo. The aim of the current study was to determine how bovine aorta endothelial cells (BAECs) respond to the simultaneous exposure to PDGF-BB and bFGF. It was found that bFGF-dependent BAEC migration, proliferation, and differentiation into tubelike structures on reconstituted extracellular matrix (Matrigel) were inhibited by PDGF-BB. The role played by PDGF receptor α (PDGF-Rα) was investigated by selective stimulation with PDGF-AA, by blocking PDGF-BB-binding to PDGF-Rα with neomycin, or by transfecting cells with dominant-negative forms of the receptors to selectively impair either PDGF-Rα or PDGF-Rβ function. In all cases, PDGF-Rα impairment abolished the inhibitory effect of PDGF-BB on bFGF-directed BAEC migration. In addition, PDGF-Rα phosphorylation was increased in the presence of bFGF and PDGF, as compared to PDGF alone, whereas mitogen-activated protein kinase phosphorylation was decreased in the presence of PDGF-BB and bFGF compared with bFGF alone. In vivo experiments showed that PDGF-BB and PDGF-AA inhibited bFGF-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane assay and that PDGF-BB inhibited bFGF-induced angiogenesis in Matrigel plugs injected subcutaneously in CD1 mice. Taken together these results show that PDGF inhibits the angiogenic properties of bFGF in vitro and in vivo, likely through PDGF-Rα stimulation.
Anatomic location and T-cell stimulatory functions of mouse dendritic cell subsets defined by CD4 and CD8 expression
Authors: McLellan Alexander D. , Kapp Michaela , Eggert Andreas , Linden Christian , Bommhardt Ursula , Bröcker Eva-B. , Kämmerer Ulrike , Kämpgen Eckhart
Published: October 2002

Mouse spleen contains CD4+, CD8α+, and CD4−/CD8α− dendritic cells (DCs) in a 2:1:1 ratio. An analysis of 70 surface and cytoplasmic antigens revealed several differences in antigen expression between the 3 subsets. Notably, the Birbeck granule–associated Langerin antigen, as well as CD103 (the mouse homologue of the rat DC marker OX62), were specifically expressed by the CD8α+ DC subset. All DC types were apparent in the T-cell areas as well as in the splenic marginal zones and showed similar migratory capacity in collagen lattices. The 3 DC subtypes stimulated allogeneic CD4+ T cells comparably. However, CD8α+ DCs were very weak stimulators of resting or activated allogeneic CD8+ T cells, even at high stimulator-to-responder ratios, although this defect could be overcome under optimal DC/T cell ratios and peptide concentrations using CD8+ F5 T-cell receptor (TCR)–transgenic T cells. CD8α− or CD8α+DCs presented alloantigens with the same efficiency for lysis by cytotoxic T lymphocytes (CTLs), and their turnover rate of class I–peptide complexes was similar, thus neither an inability to present, nor rapid loss of antigenic complexes from CD8α DCs was responsible for the low allostimulatory capacity of CD8α+ DCs in vitro. Surprisingly, both CD8α+ DCs and CD4−/CD8− DCs efficiently primed minor histocompatibility (H-Y male antigen) cytotoxicity following intravenous injection, whereas CD4+ DCs were weak inducers of CTLs. Thus, the inability of CD8α+ DCs to stimulate CD8+ T cells is limited to certain in vitro assays that must lack certain enhancing signals present during in vivo interaction between CD8α+ DCs and CD8+ T cells.
Interleukin-17 inhibits tumor cell growth by means of a T-cell–dependent mechanism
Authors: Benchetrit Fabrice , Ciree Arnaud , Vives Virginie , Warnier Guy , Gey Alain , Sautès-Fridman Catherine , Fossiez François , Haicheur Nacilla , Fridman Wolf H. , Tartour Eric
Published: October 2002

Interleukin 17 (IL-17) is a proinflammatory cytokine produced by activated CD4+ memory T cells. We previously showed that IL-17 increased the growth rate of human cervical tumors transplanted into athymic nude mice. To address the possible role of T cells in the biologic activity of IL-17 for tumor control, we grafted 2 murine hematopoietic immunogenic tumors (P815 and J558L) transfected with a complementary DNA encoding murine IL-17 into syngeneic immunocompetent mice. We found that growth of the 2 IL-17–producing tumors was significantly inhibited compared with that of mock-transfected tumors. In contrast to the antitumor activity of IL-17 observed in immunocompetent mice, we observed no difference in the in vivo growth of IL-17–transfected or mock-transfected P815 cells (P815–IL-17 and P815-Neo, respectively) transplanted into nude mice. We then showed that IL-17 increased generation of specific cytolytic T lymphocytes (CTLs) directed against the immunodominant antigens from P815 called A, B, C, D, and E, since all mice injected with P815–IL-17 developed a P815-specific CTL response, whereas only 6 of 16 mice immunized with P815-Neo had a specific CTL response against the antigens. The induction of CTLs was associated with establishment of a tumor-protective immunity. These experiments suggest that T lymphocytes are involved in the antitumor activity of IL-17. Therefore, IL-17, like other cytokines, appears to be a pleiotropic cytokine with possible protumor or antitumor effects on tumor development, which often depends on the immunogenicity of tumor models.
The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression
Authors: Medina Francisco , Segundo Carmen , Campos-Caro Antonio , González-Garcı́a Inés , Brieva José A.
Published: October 2002

Plasma cells (PCs) are the final B-cell differentiation stage. Recent evidence reveals relevant functional differences within the PC compartment. In rodents, early PCs formed in secondary lymphoid tissues show enhanced apoptosis and short life span, whereas PCs present in a final destination organ, such as the bone marrow (BM), have reached a stable prolonged survival state. BM PCs arrive at this organ as a circulating precursor whose cellular nature remains uncertain. An initial aim of this study was to characterize this circulating cell. We hypothesized that antibody-secreting cells detectable in the human blood after immunization might be a candidate precursor. These cells were obtained from the blood of volunteers immunized 6 days earlier with tetanus toxoid (tet), and they were unambiguously identified as PCs, as demonstrated by their expression of the CD38h phenotype, by morphology, by immunoglobulin (Ig) intracytoplasmic staining, and by IgG-tet–secreting capacity in vitro. In addition, by using the common CD38h feature, human PCs from tonsil (as a possible source of early PCs), from blood from tet-immunized donors (as the putative precursors of BM PCs), and from BM (as a deposit organ) have been purified and their phenotypes compared. The results show that a variety of differentiation molecules, proteins involved in the control of apoptosis, the B-cell transcription factors, positive regulatory domain I-binding factor 1/B lymphocyte-induced maturation protein 1 and B cell–specific activating protein and, at least partially, the chemokine receptor CXCR4 were expressed by human PCs following a gradient of increasing maturity in the direction: tonsil→blood→BM. However, PCs from these different organs showed a local pattern of adhesion molecule expression. These observations are discussed in light of the complex physiology of the human PC compartment.
Comparison of anti-inflammatory and clinical effects of beclomethasone dipropionate and salmeterol in moderate asthma
Authors: Bacci E. , Di Franco A. , Bartoli M.L. , Carnevali S. , Cianchetti S. , Dente F.L. , Giannini D. , Vagaggini B. , Ruocco L. , Paggiaro P.L.
Published: October 2002

Inhaled corticosteroids and long-acting β2‐agonists effectively control asthma symptoms and improve airway function. The effects of beclomethasone were compared with those of salmeterol on markers of eosinophilic inflammation in induced sputum in steroid-naïve asthmatic subjects with moderate asthma.

Fifteen moderate asthmatics were treated with either beclomethasone dipropionate (500 µgb.i.d) or salmeterol (50 µgb.i.d) for 4 weeks, according to a randomised, double-blind, parallel-group study design. All patients underwent spirometry, methacholine test, sputum induction, and blood sampling before and after 2 and 4 weeks of treatment. They also recorded daily symptoms and peak expiratory flow (PEF).

Sputum eosinophils, eosinophil cationic protein (ECP) and eosinophil protein X (EPX), and blood eosinophils, as well as the forced expiratory volume in one second (FEV1) and morning PEF, significantly improved after beclomethasone but not after salmeterol. PEF variability, the symptom score and rescue β2‐agonist use significantly improved after both treatments, although the improvement in the symptom score tended to be greater after beclomethasone. After 2 and 4 weeks of beclomethasone treatment, both serum ECP and EPX decreased. With salmeterol, only serum EPX decreased, after 4 weeks. Bronchial hyperresponsiveness to methacholine did not change after either treatment.

The authors conclude that beclomethasone, but not salmeterol, substantially improves airway inflammation in asthma. Beclomethasone also had an overall greater clinical effect, although the improvement in symptoms and peak expiratory flow variability was similar after both treatments.
Quality of life in patients with chronic alveolar hypoventilation
Authors: Dellborg C. , Olofson J. , Midgren B. , Caro O. , Skoogh B-E. , Sullivan M.
Published: October 2002

Measurements of health-related quality of life (HRQL) have not been reported in patients with chronic alveolar hypoventilation (CAH) before starting home mechanical ventilation. The purpose of this study was to investigate quality of life in a population of such patients.

Forty-four consecutive patients with CAH due to previous polio, scoliosis, healed pulmonary tuberculosis or neuromuscular disease answered a battery of condition specific and generic (Sickness Impact Profile, Hospital Anxiety and Depression scale, Mood Adjective Check List) self-report questionnaires. Spirometry, arterial blood gases and overnight oxygen saturation were measured.

Patients with untreated CAH had significantly impaired HRQL compared to historical data from a healthy reference population. Sleep-related problems were frequent. Age, underlying disease, and standard bicarbonate correlated significantly with HRQL measures, albeit with modest levels of explained variance (8–37%).

Patients with chronic alveolar hypoventilation due to neuromuscular or restrictive chest wall disorders had severely impaired health-related quality of life. Age, the underlying disease and severity of hypoventilation are each related to the health-related quality of life decrements. Health-related quality of life measurements add important information to traditional clinical observations.
Longitudinal analyses of chest radiographs from the European Carbon Black Respiratory Morbidity Study
Authors: van Tongeren M.J.A. , Gardiner K. , Rossiter C.E. , Beach J. , Harber P. , Harrington M.J.
Published: October 2002

High levels of exposure to carbon black have been linked with an increased prevalence of chest radiograph abnormalities. However, it is unclear to what extent current levels of exposure in the carbon black manufacturing industry are associated with new cases of and progression in small opacities.

Longitudinal analyses were carried out on data from workers in the European carbon black manufacturing industry who provided three full-size chest radiographs sequentially between 1987–1995. All chest radiographs were independently read by three experienced readers according to the International Labour Organisation (ILO) classification.

After exclusion of participants with previous lung diseases or injuries, females, unreadable chest radiographs and from factories with a low participation rate, data from 675 workers were available for the longitudinal analyses. An association was observed between cumulative carbon black exposure and new cases of chest radiograph abnormalities (ILO category ≥1/0) and progression in small opacities. These associations were mainly related to changes in chest radiographs from workers at one factory. A large percentage of workers with chest radiograph abnormalities reversed to normal chest films; however, after adjusting for other factors, this was not associated with levels of exposure to carbon black dust.

In conclusion, the results show that exposure to carbon black is associated with increased risk of chest radiographic abnormalities, which may be reversible after reduction or cessation of exposure.
Adverse pulmonary vascular effects of high dose tricyclic antidepressants: acute and chronic animal studies
Authors: Liu X. , Emery C.J. , Laude E. , Herget J. , Gill G. , Cope G. , Barer G.R.
Published: October 2002

Overdose of tricyclic antidepressants, which inhibit cellular serotonin (5-HT) uptake, sometimes causes acute respiratory syndrome-like symptoms. Their acute and chronic cardiopulmonary actions, which might be implicated, utilising bothin vivoandex vivoanimal studies, were investigated in this study.

Acute amitriptyline (AMI), iprindole and imipramine caused dose-dependent prolonged rises in pulmonary artery pressure and oedema in anaesthetised catsin vivo. Acute AMI, in isolatedex vivoblood-perfused rat lungs, also caused dose-dependent sustained vasoconstriction, which could be attenuated with either calcium channel inhibition or a nitric oxide donor. It was demonstrated that the pressor effects of AMI were not due to release of histamine, serotonin, noradrenaline, or the activities of cycloxygenase or lipoxygenase. After AMI, hypoxic pulmonary vasoconstriction and the pressor actions of 5‐HT and noradrenaline were diminished, possibly due to uptake inhibition. Activities of the endothelial-based enzymes, nitric oxide synthase and endothelin-converting enzyme, were undiminished. Large acute doses of AMI caused oedema with rupture of capillaries and alveolar epithelium.

Chronic iprindole raised pulmonary artery pressure and right ventricle (RV)/left ventricle (LV) + septal (S) weight. Chronic AMI led to attenuation of the pressor action of 5‐HT, especially when associated with chronic hypoxic-induced pulmonary hypertension. RV/LV+S weight increased, attributable to LV decline.

The acute and chronic effects observed might have relevance to clinical overdose, while the attenuation of acute effects offers possible therapeutic options.
Allergy and immunity to fungal infections and colonization
Authors: Crameri R. , Blaser K.
Published: October 2002

Innate and cell-mediated immunity are considered as the principal defence lines against fungal infections in humans. Most opportunistic mycoses occur in individuals with defective innate and/or adaptive cellular immunity. The morbidity and mortality rates associated with infections caused by fungal pathogens are high, and prevention, diagnosis and treatment of these infections remain quite difficult.

A variety of pathological conditions, including impaired immune function, are believed to cause host susceptibility to fungal infections as well as to determine the severity and characteristics of the associated pathology. Nonspecific cellular immunity, mediated by macrophages, neutrophils and natural killer cells, provides efficient protection against fungal infections in healthy individuals. A major reason for the increase in systemic mycoses is undoubtedly related to an increased number of patients with congenital or acquired immunodeficiencies.

However, there is increasing clinical and experimental evidence indicating that antigen-specific cellular immunity may also play a critical role in host protection against fungi. A better understanding of reciprocal regulation between innate, humoral and adaptive immune responses in the development of an optimal antifungal immunity and, in particular, the improved definition of fungal antigens, may lead to a clarification of the mechanisms involved in host immunity to fungal infections.

Molecular cloning and characterization of fungal antigens reveals the involvement of related cross-reactive molecular structures produced by different fungi as pathological molecules involved in development of allergic reactions.
Relationship between exhaled air temperature and exhaled nitric oxide in childhood asthma
Authors: Piacentini G.L. , Bodini A. , Zerman L. , Costella S. , Zanolla L. , Peroni D.G. , Boner A.L.
Published: October 2002

Airway inflammation is a characteristic of asthma. Exhaled nitric oxide (eNO) has been demonstrated to be related to actual levels of airway inflammation in asthmatic patients. The purpose of this study was to investigate whether the temperature of exhaled air is related to eNO levels.

Temperature of exhaled air and eNO were measured in 52 asthmatic children with a cross-sectional design.

A significant relationship was demonstrated between eNO and temperature of peak and plateau exhaled air temperature. The relationship between both the peak and the plateau values and eNO was more evident when it was corrected for environmental temperature.

These results suggest a relationship between exhaled nitric oxide and the temperature of exhaled air in asthmatic patients not treated with systemic steroids.