bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasminogen supports tumor growth through a fibrinogen-dependent mechanism linked to vascular patency
Authors: Palumbo Joseph S. , Talmage Kathryn E. , Liu Hong , La Jeunesse Christine M. , Witte David P. , Degen Jay L. 
Published: July 2003

AbstractThe growth of Lewis lung carcinoma (LLC) was sustained in plasminogen-deficient mice when transplanted into the dorsal skin but was dramatically suppressed in another anatomic location, the footpad. This unanticipated negative effect of plasminogen deficiency on footpad tumor growth was entirely relieved by superimposing a deficit in fibrinogen. This finding was not simply an unusual feature of LLC tumors—T241 fibrosarcoma growth in the footpad was also restricted by plasminogen deficiency in a fibrinogen-dependent manner. The probable mechanistic basis for suppression of tumor growth was revealed through transmission electron microscopy studies of tumor tissues. Occlusive microvascular thrombi were commonplace within footpad tumors from plasminogen-deficient mice, whereas no such lesions were observed within either dorsal skin tumors from plasminogen-deficient mice or footpad tumors from mice that also lacked fibrinogen. The data infer that tumor growth in the footpad of plasminogen-deficient mice is compromised as a function of the formation and persistence of vaso-occlusive thrombi that limit tumor blood supply. These studies indicate that plasminogen and fibrinogen can serve as critical determinants of tumor growth, but their relative importance is dependent on the tumor microenvironment. Furthermore, these studies suggest that one target of plasmin(ogen) relevant to tumor progression in vivo is intravascular fibrin.
Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease
Authors: Kralovics Robert , Stockton David W. , Prchal Josef T. 
Published: July 2003

AbstractFamilial clustering of malignancies provides a unique opportunity to identify molecular causes of cancer. Polycythemia vera (PV) is a myeloproliferative disorder due to an unknown somatic stem cell defect that leads to clonal myeloid hyperproliferation. We studied 6 families with PV. The familial predisposition to PV appears to follow an autosomal dominant inheritance pattern with incomplete penetrance. All examined females informative for a transcriptional clonality assay had clonal hematopoiesis. We excluded linkage between PV and a number of previously proposed candidate disease loci (c-mpl, EPOR, 20q, 13q, 5q, 9p). Therefore, mutations at these loci are unlikely primary causes of familial PV. The finding of erythropoietin-independent erythroid progenitors in healthy family members indicated the presence of the PV stem cell clone in their hematopoiesis. This finding, together with clonal hematopoiesis in the affected individuals, supports the hypothesis of multiple genetic defects involved in the early pathogenesis of PV. (Blood. 2003;102:3793-3796)
The nature of diversity and diversification at the ABO locus
Authors: Seltsam Axel , Hallensleben Michael , Kollmann Anke , Blasczyk Rainer 
Published: July 2003

AbstractIn this study we analyzed the complete genomic sequences, except intron 1, and 2 regulatory regions of 6 common (ABO*A101, ABO*A201, ABO*B101, ABO*O01, ABO*O02, and ABO*O03) and 18 rare ABO alleles, 3 of which were new. This was done by phylogenetic analysis and correlating sequence data with the ABO phenotypes. The study revealed multiple polymorphisms in noncoding regions. The intron-based phylogenetic analysis revealed 5 main lineages: ABO*A, ABO*B, ABO*O01, ABO*O02, and ABO*O03. The genomic sequences of most rare ABO alleles differed slightly from those of the common alleles. Singular mutations or hybrid alleles were most common, but a few exhibited mosaic sequence pattern containing multiple exon and/or intron motifs from other ABO lineages. Thus, both an accumulation of mutations as well as an assortment of the mutations by recombination seems to be responsible for the ABO gene diversity. The prevalence of replacement mutations indicates positive selection for allelic diversity. Phenotype-genotype correlation showed that sequence variations within the complete coding sequence can affect A- and B-antigen expression. All variant ABO*A/B alleles and one new ABO*O03-like allele were associated with weak ABO phenotypes. These findings are suggestive of the requirement of a comprehensive coding sequence database for sequence-based phenotype prediction.
A caspaselike activity is triggered by LPS and is required for survival of human dendritic cells
Authors: Franchi Luigi , Condò Ivano , Tomassini Barbara , Nicolò Chiara , Testi Roberto 
Published: July 2003

Abstract
Bacterial endotoxin (lipopolysaccharide [LPS]) is a potent inducer of human dendritic cell (DC) maturation and survival. Here we show that immature DCs exposed to LPS trigger an early and sustained caspaselike activity, which can be blocked by zVAD (z-Val-Ala-Asp), in the absence of detectable caspase 8 and caspase 10 activation, or poly(ADP-ribose) polymerase (PARP)–cleaving activity. Preventing LPS-induced caspaselike activation in DC results in massive cell death. Importantly, triggering of the caspaselike activity is required for LPS-induced activation of extracellular signal-regulated kinases (ERKs) and for LPS-induced up-regulation of cFLIP (Fas-associating protein with death domain–like interleukin-1β–converting enzyme [FLICE]–like inhibitory protein). Therefore, a caspase-dependent pathway initiated by LPS controls survival of human DCs.
Anti-D initially stimulates an Fc-dependent leukocyte oxidative burst and subsequently suppresses erythrophagocytosis via interleukin-1 receptor antagonist
Authors: Coopamah Malini D. , Freedman John , Semple John W. 
Published: July 2003

AbstractPrevious results have demonstrated that anti-D therapy in children with chronic auto-immune thrombocytopenic purpura (AITP) induced a significant increase in several pro- and anti-inflammatory plasma cytokines within 2 hours of administration. To investigate the biologic basis of these early in vivo responses, we developed a flow cytometric assay to measure Fc-dependent responses of human peripheral leukocytes with fluorescently labeled and anti-D–opsonized red blood cells (RBCs). When anti-D–opsonized RBCs were incubated with peripheral blood leukocytes, the earliest detectible event observed was a significant oxidative burst in both monocytes (P &lt; .05) and granulocytes (P &lt; .0001), characterized by the production of hydrogen peroxide (H2O2), peroxynitrite (ONOO–), superoxide (O –2), and hydroxyl (OH) by 10 minutes which declined by 1 hour. By 2 hours, the opsonized RBCs were phagocytosed, particularly by granulocytes (P &lt; .001), but the phagocytosis subsequently declined by 6 hours of incubation. The decline in phagocytosis was correlated with a significant production of interleukin-1 receptor antagonist (IL1ra) by both monocytes (P = .036) and granulocytes (P = .0002) within 4 hours. None of these events occurred if the RBCs were coated with anti-D F(ab)′2 fragments. When recombinant IL1ra was titrated into the assay, phagocytosis of the opsonized RBCs was significantly inhibited (P = .002). Taken together, these results suggest that at least one mechanism of action of anti-D is via the production of the anti-inflammatory cytokine IL1ra which can negatively regulate the ability of leukocytes to phagocytose opsonized cells.
Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma
Authors: Yawalkar Nikhil , Ferenczi Katalin , Jones David A. , Yamanaka Keiichi , Suh Ki-Young , Sadat Sarah , Kupper Thomas S. 
Published: July 2003

AbstractCutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T cells. A major feature of CTCL is profound immunosuppression, such that patients with advanced mycosis fungoides or Sézary syndrome have been compared with patients with advanced HIV disease and are susceptible to opportunistic infection. The etiology of this immunosuppression is unclear. We analyzed peripheral blood T cells of patients with CTCL with stage I to IV disease, using a sensitive beta-variable complementarity-determining region 3 spectratyping approach. Our data revealed a profound disruption of the complexity of the T-cell repertoire, which was universally observed in patients with advanced disease (stages III and IV), and present in up to 50% of patients with early-stage disease (stages I and II). In most patients, multiple monoclonal and oligoclonal complementarity-determining region 3 (CDR3) spectratype patterns in many different beta-variable families were seen. Equally striking was a reduction of normal T cells (as judged by absolute CD4 counts) across multiple beta-variable families. In general, CTCL spectratypes were reminiscent of advanced HIV spectratypes published elsewhere. Taken together, these data are most consistent with a global assault on the T-cell repertoire in patients with CTCL, a process that can be observed even in early-stage disease. (Blood. 2003;102:4059-4066)
Toll-like receptors stimulate human neutrophil function
Authors: Hayashi Fumitaka , Means Terry K. , Luster Andrew D. 
Published: July 2003

AbstractThe first immune cell to arrive at the site of infection is the neutrophil. Upon arrival, neutrophils quickly initiate microbicidal functions, including the production of antimicrobial products and proinflammatory cytokines that serve to contain infection. This allows the acquired immune system enough time to generate sterilizing immunity and memory. Neutrophils detect the presence of a pathogen through germ line-encoded receptors that recognize microbe-associated molecular patterns. In vertebrates, the best characterized of these receptors are Toll-like receptors (TLRs). We have determined the expression and function of TLRs in freshly isolated human neutrophils. Neutrophils expressed TLR1, 2, 4, 5, 6, 7, 8, 9, and 10—all the TLRs except TLR3. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment increased TLR2 and TLR9 expression levels. The agonists of all TLRs expressed in neutrophils triggered or primed cytokine release, superoxide generation, and L-selectin shedding, while inhibiting chemotaxis to interleukin-8 (IL-8) and increasing phagocytosis of opsonized latex beads. The response to the TLR9 agonist nonmethylated CpG-motif-containing DNA (CpG DNA) required GM-CSF pretreatment, which also enhanced the response to the other TLR agonists. Finally, using quantitative polymerase chain reaction (QPCR), we demonstrate a chemokine expression profile that suggests that TLR-stimulated neutrophils recruit innate, but not acquired, immune cells to sites of infection. (Blood. 2003;102:2660-2669)
Formation of trisomies and their parental origin in hyperdiploid childhood acute lymphoblastic leukemia
Authors: Paulsson Kajsa , Panagopoulos Ioannis , Knuutila Sakari , Jee Kowan Ja , Garwicz Stanislaw , Fioretos Thoas , Mitelman Felix , Johansson Bertil 
Published: July 2003

Abstract
High hyperdiploidy, common in childhood acute lymphoblastic leukemia (ALL) with a favorable prognosis, is characterized by specific trisomies. Virtually nothing is known about its formation or pathogenetic impact. We evaluated 10 patients with ALL using 38 microsatellite markers mapped to 18 of the 24 human chromosomes to investigate the mechanisms underlying hyperdiploidy and to ascertain the parental origin of the trisomies. Based on the results, doubling of a near-haploid clone and polyploidization with subsequent losses of chromosomes could be excluded. The finding of equal allele dosage for tetrasomy 21 suggests that hyperdiploidy originates in a single aberrant mitosis, though a sequential gain of chromosomes other than 21 in consecutive cell divisions remains a possibility. Our study, the first to address experimentally the parental origin of trisomies in ALL, revealed no preferential duplication of maternally or paternally inherited copies of X, 4, 6, 9, 10, 17, 18, and 21. Trisomy 8 was of paternal origin in 4 of 4 patients (P = .125), and +14 was of maternal origin in 7 of 8 patients (P = .0703). Thus, the present results indicate that imprinting is not pathogenetically important in hyperdiploid childhood ALL, with the possible exception of the observed parental skewness of +8 and +14.
Evidence for a positive role of SHIP in the BCR-ABL–mediated transformation of primitive murine hematopoietic cells and in human chronic myeloid leukemia
Authors: Jiang Xiaoyan , Stuible Matthew , Chalandon Yves , Li Andra , Chan Wing Yiu , Eisterer Wolfgang , Krystal Gerald , Eaves Allen , Eaves Connie 
Published: July 2003

AbstractPrevious studies suggested that the SH2-containing inositol-5-phosphatase (SHIP) may play a tumor suppressor-like function in BCR-ABL–mediated leukemogenesis. To investigate this possibility, we first developed a new assay for quantitating transplantable multilineage leukemia-initiating cells (L-ICs) in hematopoietic stem cell (HSC)–enriched mouse bone marrow (BM) cells transduced with a BCR-ABL–GFP (green fluorescent protein) retrovirus. The frequency of L-ICs (1 of 430 Sca-1+lin– cells) was 7-fold lower than the frequency of HSCs in the Sca-1+lin– subset transduced with a control virus (1 of 65 cells). Forced BCRABL expression was also accompanied by a loss of regular HSC activity consistent with the acquisition of an increased probability of differentiation. Interestingly, the frequency and in vivo behavior of wild-type (+/+) and SHIP–/– L-ICs were indistinguishable, and in vitro, Sca-1+lin– BCR-ABL–transduced SHIP–/– cells showed a modestly reduced factor independence. Comparison of different populations of cells from patients with chronic myeloid leukemia (CML) in chronic phase and normal human BM showed that the reduced expression of full-length SHIP proteins seen in the more mature (CD34–lin+) leukemic cells is not mirrored in the more primitive (CD34+lin–) leukemic cells. Thus, SHIP expression appears to be differently altered in the early and late stages of differentiation of BCR-ABL–transformed cells, underscoring the importance of the cellular context in which its mechanistic effects are analyzed.
Dexamethasone accelerates catabolism of leukotriene C4in bronchial epithelial cells
Authors: Zaitsu M. , Hamasaki Y. , Tsuji K. , Matsuo M. , Fujita I. , Aoki Y. , Ishii E. , Kohashi O. 
Published: June 2003

Leukotriene (LT)C4, a potent chemical mediator in bronchial asthma, is metabolised to the less active LTE4viaLTD4in two consecutive reactions catalysed by enzymes of the glutamyl transpeptidase and dipeptidase families. The activities of these catabolic enzymes may be influenced by glucocorticosteroids. This study was conducted to examine whether this inactivation of LTC4is affected by dexamethasone (DEX) in transformed human bronchial epithelial cells and normal human bronchial epithelial cells.After incubation with DEX for 0–5 days, cells were resuspended in the presence of exogenous LTC4, and conversion of LTC4to LTE4was measured using high-performance liquid chromatography. γ‐Glutamyl transpeptidase (GGT) and GGT-related enzyme (GGTRE) messenger ribonucleic acid (mRNA) expression were examined using reverse transcriptase-polymerase chain reaction analysis, and GGT activity by enzyme assay.Conversion to LTE4was accelerated by DEX pretreatment. GGTRE but not GGT mRNA expression was enhanced after incubation with DEX.The results indicate that dexamethasone transcriptionally upregulates the activity of γ‐glutamyl transpeptidase-related enzyme in human bronchial epithelial cells, which accelerates inactivation of leukotriene C4viaconversion to leukotriene E4. This is a novel mechanism of glucocorticosteroids in human bronchial epithelial cells.
The role of genetic factors in occupational asthma: Table 1
Authors: Mapp C.E. 
Published: June 2003

This article explores the influence of genetic factors on the development of sensitisation and occupational asthma (OA).First, several types of studies aimed at examining the role of genes, as well as the role of gene-environment interactions in asthma, including the available data for OA specifically, were reviewed. Genetic approaches include linkage and allele-sharing analysis and segregation analysis. Secondly, deoxyribonucleic acid banking for epidemiological studies was focused upon, highlighting the factors to be considered in choosing the appropriate specimens for genotyping.OA, like asthma, is a multifactorial condition and, to date, no ideal genetic study has been described to examine complex gene-environment interactions. Most studies in OA have examined human leukocyte antigen-associated polymorphisms with some nonreproducible results.The search for genes in occupational asthma is still in progress, and much of the information obtained has been based on small sample sizes, using different strategies for the recruitment of subjects. The best methodological approach still needs to be determined and the results of genetic identification need to be confirmed in different samples.
Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF‐β and IL-10
Authors: Bergeron A. , Soler P. , Kambouchner M. , Loiseau P. , Milleron B. , Valeyre D. , Hance A.J. , Tazi A. 
Published: June 2003

Modulation of cytokine expression represents a potentially useful approach for the treatment of idiopathic pulmonary fibrosis (IPF).To identify potential targets for such intervention, semi-quantitative reverse transcriptase-polymerase chain reaction was used to compare the expression of messenger ribonucleic acids (mRNAs) coding for 17 cytokines in lung tissue obtained from patients with IPF at the time of diagnosis and control subjects. Some cytokines were also studied at the protein level by immunohistochemical techniques.mRNAs coding for all of the cytokines evaluated were detected in both control and fibrotic lung samples. Only transforming growth factor (TGF)‐β and interleukin (IL)-10 mRNAs were quantitatively increased in lung biopsies from patients with IPF compared with those of controls, results confirmed at the protein level by immunohistochemistry. Although mRNAs for platelet-derived growth factor (PDGF)-BB and keratinocyte growth factor (KGF) were expressed in similar amounts in lungs from patients with IPF and controls, localised accumulation of both factors was also observed in IPF. Hyperplastic alveolar epithelial cells were a prominent source of cytokines, where IL-10, PDGF-BB and KGF were present in increased amounts, although increased accumulation in fibroblasts, smooth-muscle cells and matrix components was also observed (PDGF-BB, TGF‐β).These results offer new insights into the cytokines produced in the lung in idiopathic pulmonary fibrosis and suggest that modulation of the production of transforming growth factor‐β and interleukin-10 may represent a potentially useful therapeutic strategy for this disabling disease.
Patient mortality of active pulmonary tuberculosis requiring mechanical ventilation
Authors: Lee P.L. , Jerng J.S. , Chang Y.L. , Chen C.F. , Hsueh P.R. , Yu C.J. , Yang P.C. , Luh K.T. 
Published: June 2003

Mortality remains high among patients with pulmonary tuberculosis requiring mechanical ventilation (TBMV). This study was carried out to establish the mortality rates of TBMV and to identify factors that contribute to in-hospital mortality.From January 1996–April 2001, there were 825 patients with active pulmonary tuberculosis at the National Taiwan University Hospital, Taipei, Taiwan. Of these, 41 suffered acute respiratory failure and required mechanical ventilation in the intensive care unit (ICU). Of these 41 patients, 38 were followed up for 180 days. In-hospital deaths were documented in the medical records and all possible parameters contributing to mortality were collected.Of the 41 patients, 27 died in the hospital and 14 were discharged alive (in-hospital mortality rate 65.9%), with (mean±sd) 40.7±35.4 admission days before death. Of the 27 that died, 25 died during ICU admission and two died after being transferred to the ward. The mortality rate for the 180-day monitoring period was 79%. Factors contributing to in-hospital mortality included consolidations on chest radiographs and multiple organ failure.The mortality rate in the patients with pulmonary tuberculosis requiring mechanical ventilation is very high, with two factors affecting in-hospital mortality. These factors were multiple organ failure and consolidation on chest radiographs.
Sleep-disordered breathing and hormones
Authors: Saaresranta T. , Polo O. 
Published: June 2003

Sleep-disordered breathing (SDB) is not only a problem of the upper airway but is a systemic condition with endocrine and metabolic interactions. The accumulating body of evidence shows that SDB induces changes in the serum levels or secretory patterns of several hormones. Conversely, various endocrine disorders and hormone therapies may induce, exacerbate or alleviate SDB.Much of the understanding of the interactions between hormones and sleep-disordered breathing derive from intervention studies with nasal continuous positive airway pressure therapy. Better understanding of hormones and breathing may open new perspectives in developing strategies to prevent, alleviate or cure sleep-disordered breathing and its systemic consequences.
Glutamate-cysteine ligase modulatory subunit in BAL alveolar macrophages of healthy smokers
Authors: Neurohr C. , Lenz A-G. , Ding I. , Leuchte H. , Kolbe T. , Behr J. 
Published: June 2003

The antioxidant glutathione (GSH) is increased in the epithelial lining fluid (ELF) of chronic smokers. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), also known as γ‐glutamylcysteine synthetase, consisting of a heavy, catalytic (GCLC) and a light, modulatory (GCLM) subunit.To determine the contribution of bronchoalveolar lavage (BAL) cells to GSH levels in ELF, BAL was performed in eight smokers and eight never-smokers. Intra- and extracellular total glutathione (GSHt) levels and GCL subunit expression were assessed.GSHtwas increased in ELF from smokers (1,090.1±163.0 µMversus559.2±48.2 µM). GSHtcontent of BAL cells (nmol·mg protein−1) was decreased in smokers without differences reaching statistical significance (8.0±1.4versus12.4±2.6). GCLM expression was also reduced in smokers (0.6±0.1versus2.8±0.4) and correlated with intracellular GSHtcontent. There was no significant difference in GCLC expression and in differential cell counts in BAL fluid.The authors conclude that smoking does increase glutathione levels in the epithelial lining fluid but not intracellular levels in bronchoalveolar lavage cells. The data suggest that the intracellular glutathione concentration of bronchoalveolar lavage cells (predominately alveolar macrophages) is regulated by the modulatory glutamate-cysteine ligase subunit rather than the catalytic subunit.