bluuebunny/crossref_metadata_2025_split huggingface dataset:
CC chemokine ligand 20 partially controls adhesion of naive B cells to activated endothelial cells under shear stress
Authors: Meissner Anja , Zilles Olaf , Varona Rosa , Jozefowski Katrin , Ritter Uwe , Marquez Gabriel , Hallmann Rupert , Körner Heinrich 
Published: June 2003

AbstractChemokines are thought to control lymphocyte recruitment to the inflamed endothelium. To dissect chemokine-mediated adhesion, binding of ex vivo isolated splenocytes to tumor necrosis factor (TNF)–activated endothelial cells was analyzed under shear stress. We observed specific adhesion of naive follicular B cells, which could be blocked by pertussis toxin. This indicated a G protein–mediated binding and pointed at a contribution of chemokine receptors to B-cell adhesion. Analysis of chemokines expressed by TNF-activated endothelial cells showed that CC chemokine ligand 2 (CCL2), CCL17, and CCL20 were up-regulated. Only on follicular B cells was the cognate receptor for CCL20, CC chemokine receptor 6 (CCR6), expressed strongly, and a functional transmigration assay with CCR6-negative B cells demonstrated conclusively the sole signaling of CCL20 through CCR6. Desensitization of CCR6 on naive B cells with CCL20 resulted in receptor down-regulation and reduced B-cell adhesion. We conclude that CCL20 plays a vital role in B-cell adhesion to the inflamed endothelium.
Molecular characterization of the recurrent unbalanced translocation der(1;7)(q10;p10)
Authors: Wang Lili , Ogawa Seishi , Hangaishi Akira , Qiao Ying , Hosoya Noriko , Nanya Yasuhito , Ohyashiki Kazuma , Mizoguchi Hideaki , Hirai Hisamaru 
Published: June 2003

Abstract
An unbalanced translocation der(1;7)(q10; p10) is a nonrandom chromosomal aberration commonly observed in myelodysplastic syndrome and acute myeloid leukemia. We molecularly analyzed the breakpoints of der(1;7)(q10;p10) by quantitative fluorescent in situ hybridization (FISH) analyses using centromeric satellite DNAs mapped to chromosomes 1 and 7 as probes. We found that the signal intensities of 2 centromere alphoid probes, D1Z7 on chromosome 1 and D7Z1 on chromosome 7, were almost invariably reduced on the derivative chromosome compared with those on their normal counterparts. These results suggest that this translocation results from the recombination between the 2 alphoids, which was further confirmed by fiber FISH experiments. Because the relative reduction in the intensities of D1Z7 and D7Z1 signals on the derivative chromosomes was highly variable among patients, it was estimated that the breakpoints in these patients were randomly distributed over several megabase pairs within each alphoid cluster except for its extreme end to the short arm. Our results provide a novel insight into the structural basis for generation of this translocation as well as its leukemogenic roles. (Blood. 2003;102:2597-2604)
Distinct hematopoietic stem/progenitor cell populations are responsible for repopulating NOD/SCID mice compared with nonhuman primates
Authors: Horn Peter A. , Thomasson Bobbie M. , Wood Brent L. , Andrews Robert G. , Morris Julia C. , Kiem Hans-Peter 
Published: June 2003

AbstractThe nonobese diabetic/severe combined immune-deficient (NOD/SCID) mouse xenotransplantation assay is the most commonly used surrogate assay for the study of human candidate stem cells. In contrast to large animal and human studies, however, it is limited by the short life span of the recipients, the limited proliferative demand placed on the transplanted cells, and the inability to support differentiation into all hematopoietic lineages. In the present study, we directly compared hematopoietic repopulation in NOD/SCID mice with autologous reconstitution in the baboon, a well-established preclinical large animal model for stem cell transplantation. Baboon CD34-enriched marrow cells were retrovirally marked and infused into the irradiated baboon and the NOD/SCID mice. Although the percentage of gene-marked cells was high and remained stable in NOD/SCID mice up to 12 weeks and in those that underwent secondary transplantation, we observed a considerable decline and overall a significantly (10-fold) lower percentage of gene-marked cells in the baboons. In addition, clonal integration site analysis revealed common proviral vector integrants in NOD/SCID repopulating cells and in the baboon at 6 weeks but not at 6 months after transplantation. These results suggest that distinct hematopoietic stem/progenitor cells are responsible for hematopoietic reconstitution in NOD/SCID mice compared with nonhuman primates. (Blood. 2003;102:4329-4335)
NF-κB activation in premalignant mouse tal-1/scl thymocytes and tumors
Authors: O'Neil Jennifer , Ventura Juan-Jose , Cusson Nicole , Kelliher Michelle 
Published: June 2003

Abstract
TAL-1/SCL activation is a common genetic event in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Expression of tal-1/scl or a DNA binding mutant of tal-1/scl induces arrest of thymocyte development, resulting in decreases in double-positive and single-positive CD4 thymocytes. Moreover, nuclear p65/p50 heterodimers are detected in premalignant tal-1/scl and mut tal-1/scl thymocytes, suggesting that E2A depletion may induce developmental arrest and stimulate NF-κB activation. Increased NF-κB activity is also observed in tal-1/scl tumors and bcl-2 is overexpressed. To examine the contribution of NF-κB to tal-1/scl tumor growth in vivo, we expressed a mutant form of IκBα in tal-1/scl tumor cells. Although expression of mutant IκBα inhibited the tumor necrosis factor alpha (TNF-α)-induced NF-κB response, it had no effect on tumor growth in mice. These data suggest that NF-κB activation is an early event in tal-1/scl-induced leukemogenesis, associated with arrest of thymocyte development, and does not appear to contribute to tal-1/scl-induced tumor growth. (Blood. 2003;102:2593-2596)
Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax
Authors: Cao Xuefang , Deng Xingming , May W. Stratford 
Published: June 2003

AbstractBax is cleaved by calpain at aspartate 33 (Asp33) to yield p18 Bax during stress-induced apoptosis. To assess the role of p18 Bax in apoptosis, an ecdysone-inducible expression system was generated. Similar levels of wild-type (WT) and noncleavable Asp33Ala (Asp→Ala) Bax are induced in 293 cells while expression of N-terminal-deleted p18 (Δ1-33) Bax remains low (20% of full-length p21 Bax) due to a reduced half-life (2 hours versus 12 hours for p21 Bax) resulting from increased sensitivity to cathepsin-like proteolytic degradation. Expression of p18 Bax is enhanced to levels comparable to p21 Bax when induction is carried out in the presence of cathepsin inhibitors, Z-Phe-Gly-NHO-Bz or N-Acetyl-Leu-Leu-Met-CHO. Compared with WT Bax, expression of similar levels of p18 Bax and, surprisingly, Asp33Ala Bax more potently induces apoptosis as indicated by increased cytochrome c release, caspase-9/-3 activation, and DNA fragmentation, potentially due to their increased homo-oligomerization in mitochondrial membranes. Studies in A-549, U-937, K-562, and HL-60 cells confirm that inhibition of Bax cleavage results in 25% to 35% reduction of drug-induced apoptosis, while inhibition of p18 Bax degradation enhances apoptosis by 25% to 40%. Results indicate that although cleavage to p18 Bax is not required for Bax to initiate apoptosis, p18 Bax potently accelerates the apoptotic process. (Blood. 2003;102:2605-2614)
Disruption of the β3 663-687 disulfide bridge confers constitutive activity to β3 integrins
Authors: Butta Nora , Arias-Salgado Elena G. , González-Manchón Consuelo , Ferrer Milagros , Larrucea Susana , Ayuso Matilde S. , Parrilla Roberto 
Published: June 2003

AbstractThe platelet fibrinogen receptor, integrin αIIbβ3, is a noncovalent heterodimer of glycoproteins IIb and IIIa. This work was aimed at elucidating the role played by the carboxy-terminal extracellular, trans-membrane, and cytoplasmic regions of the glycoprotein β3 in the formation of functional complexes with α subunits. Progressive carboxy-terminal deletions of β3 revealed that surface exposure of αIIbβ3 or αvβ3 could not occur in the absence of the transmembrane domain of β3. In contrast, internal deletions 616 to 690 of the carboxy-terminal regions of the β3 ectodomain led to surface exposure of constitu tive active receptors in CHO cells, as indicated by the enhanced rate of cell adhesion to immobilized ligands and spontaneous binding to soluble fibrinogen or activation-dependent antibody PAC-1. The functional analysis of cysteine mutations within the 616 to 690 region of β3 or chimeric β3-β7 subunits revealed that disruption of the C663-C687 disulfide bridge endows constitutive activity to the αIIbβ3 receptor. It is concluded that the carboxy-terminal tail of the β3 ectodomain, so-called β tail domain (βTD), is not essential for cell surface expression of β3 receptors. However, a basal, nonactivated, low ligand-affinity state of the β3 integrins demands a normal conformation of this domain. (Blood. 2003;102:2491-2497)
NVP-LAQ824 is a potent novel histone deacetylase inhibitor with significant activity against multiple myeloma
Authors: Catley Laurence , Weisberg Ellen , Tai Yu-Tzu , Atadja Peter , Remiszewski Stacy , Hideshima Teru , Mitsiades Nicholas , Shringarpure Reshma , LeBlanc Richard , Chauhan Dharminder , Munshi Nikhil C. , Schlossman Robert , Richardson Paul , Griffin James , Anderson Kenneth C. 
Published: June 2003

AbstractHistone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM. (Blood. 2003;102:2615-2622)
CD94 transcripts imply a better prognosis in nasal-type extranodal NK/T-cell lymphoma
Authors: Lin Chung-Wu , Chen Yu-Hua , Chuang Yi-Chun , Liu Ting-Yun , Hsu Su-Ming 
Published: June 2003

AbstractTranscription of natural killer (NK) cell antigen receptors (NKRs), such as CD94, NKG2, and killer immunoglobulin-like receptors (KIRs), is developmentally regulated and clonally distributed. We have shown a restricted KIR repertoire (rKIR-R) without monoclonal T-cell receptor rearrangement (mTCR-R) supports a NK lineage in nasal-type extranodal NK/T-cell lymphoma (NTENL) but does not correlate with clinical outcomes. Developing NK cells express first CD94, then NKG2A, NKG2E, and finally NKG2C. This sequence suggests an immature CD94- and a mature CD94+ subtype of NTENL. Using a rKIR-R without a mTCR-R as a criterion in 25 cases of NTENL, we confirmed a true NK lineage in 19 cases, including 10 CD94+ and 9 CD94- patients by reverse transcriptase-polymerase chain reaction (RT-PCR). Eight of the 10 CD94+ patients but only 2 of the 9 CD94- patients survived beyond 1 year (median survival, 60 months versus 10 months by Meier-Kaplan survival analysis, P = .026 by Cox F test). The remaining 6 patients had a rKIR-R plus a mTCR-R, suggesting mixed NK/T differentiation. They were CD94- by RT-PCR, found predominantly in young women, and had a median survival of 35 months. Thus, on the basis of the transcripts of NKRs, a division of NTENLs into CD94+, CD94-, and mixed NK/T types reflects a true biologic divergence with different clinical behaviors. (Blood. 2003;102:2623-2631)
Rituximab in relapsed or refractory hairy cell leukemia
Authors: Thomas Deborah A. , O'Brien Susan , Bueso-Ramos Carlos , Faderl Stefan , Keating Michael J. , Giles Francis J. , Cortes Jorge , Kantarjian Hagop M. 
Published: June 2003

AbstractThe purpose of this study was to investigate the efficacy and safety of the monoclonal antibody, rituximab, in relapsed or refractory hairy cell leukemia (HCL). Fifteen patients with relapsed or primary refractory HCL after nucleoside analogs received rituximab 375 mg/m2 weekly for a total of 8 planned doses. An additional 4 doses could be administered to responders who had not achieved complete response (CR). The overall response rate was 80%. Eight patients (53%) achieved CR, 2 (13%) attained CR by hematologic parameters with residual marrow disease (1% to 5% marrow hairy cells), and 2 (13%) had a partial response. Of the 12 responders followed for a median of 32 months (range, 8 to 45+ months), 5 patients (42%) had progression of disease 8, 12, 18, 23, and 39 months from the start of therapy. Three patients failed to respond (after 4, 6, or 8 doses). Reductions in serum interleukin-2 receptor (sIL-2R) levels correlated with response. Toxicity was minimal, and no infectious episodes were observed. Rituximab has significant activity and minimal toxicity in HCL and warrants further study. Rituximab should be explored further in HCL with regard to eradication of minimal residual disease and in combination with nucleoside analogs.
Tie-2–dependent activation of RhoA and Rac1 participates in endothelial cell motility triggered by angiopoietin-1
Authors: Cascone Ilaria , Audero Enrica , Giraudo Enrico , Napione Lucia , Maniero Fabrizio , Philips Mark R. , Collard John G. , Serini Guido , Bussolino Federico 
Published: June 2003

AbstractAngiopoietin-1 is implicated in the maturation and remodeling of the vascular network during embryo development and in adult life. Through its tyrosine kinase receptor Tie-2 it stimulates endothelial cells to migrate and change shape. Here we show that angiopoietin-1 elicits chemokinesis of endothelial cells by a phosphoinositide 3-OH kinase/son of sevenless-dependent modulation of Rac1 and RhoA. The resulting temporal events are associated with cytoskeletal rearrangements and occur in discrete zones of the cell. Endothelial cells carrying dominant-negative mutants of RhoA and Rac1 or treated with LY294002, an inhibitor of phosphoinositide 3-OH kinase, dramatically decrease their chemokinetic velocity. Taken together, these results further expand our understanding of angiopoietin-1-mediated endothelial cell motility during vascular network assembly and angiogenesis. (Blood. 2003;102:2482-2490)
Clinical and molecular characterization of 6 patients affected by severe deficiency of coagulation factor V: broadening of the mutational spectrum of factor V gene and in vitro analysis of the newly identified missense mutations
Authors: Montefusco Maria Claudia , Duga Stefano , Asselta Rosanna , Malcovati Massimo , Peyvandi Flora , Santagostino Elena , Mannucci Pier Mannuccio , Tenchini Maria Luisa 
Published: June 2003

AbstractSevere factor V (FV) deficiency is a rare bleeding disorder, whose genetic bases have been characterized only in a limited number of cases. We investigated 6 unrelated patients with extremely reduced plasma FV levels, associated with a bleeding tendency ranging from moderately severe to severe. Clinical manifestations were substantially concordant with the previously established spectrum of hemorrhagic symptoms of the disease. Molecular analysis of FV gene identified 9 different mutations, 7 hitherto unknown, and 2 previously reported (Arg712ter and Tyr1702Cys). Four of 6 analyzed patients were compound heterozygotes, indicating the high allelic heterogeneity of this disease. Among novel mutations, 5 led to premature termination codons, because of nonsense (Arg1002ter, Arg1606ter, and Trp1854ter), or frameshift mutations (5127-5128insA and 6122-6123insAACAG). The remaining 2 were missense mutations (Cys472Gly and Val1813Met), located in FV A2 and A3 domains. Their effect on FV expression was studied by transient transfection experiments, demonstrating that the presence of each mutation impaired FV secretion. These data increase the number of severe FV deficiency–causing mutations by about 50%. The high number of “private” mutations identified in FV-deficient families indicates that full mutational screening of FV gene is still required for molecular diagnosis.
Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group
Authors: Gringeri Alessandro , Mantovani Lorenzo G. , Scalone Luciana , Mannucci Pier Mannuccio ,   the COCIS Study Group
Published: June 2003

AbstractInhibitors in patients with hemophilia are a rare complication of a rare disease causing pain and disability in patients and impairment to the quality of their lives. Recent advances in treatment have brought improvements, but they have done so by absorbing larger amounts of financial resources. This study involved 52 Italian patients with hemophilia with high-responding inhibitors who were longitudinally observed for 18 months to evaluate concomitantly cost of care and quality of life. Overall, 0.6 bleeding episodes per patient per month were recorded. This frequency of events was lower than that reported in other cohorts of patients with hemophilia who were not taking inhibitors. The average monthly cost of care was, in euros, €18 000 (US $18 000) per patient, mainly because of treatment products. Recombinant activated factor VII, mostly used for orthopedic surgery, represented 50% of the expenses. Quality of life, measured through validated questionnaires, was similar to that of patients with severe hemophilia without inhibitors. In particular, physical quality of life was similar to that in patients with diabetes and on dialysis, whereas mental quality of life was comparable to that in the general population. This study shows that hemophilia complicated by inhibitors, a prototype of rare disease, requires high amounts of resources for management that provides a satisfactory quality of life. (Blood. 2003;102:2358-2363)
ALK-positive plasmablastic B-cell lymphoma with expression of the NPM-ALK fusion transcript: report of 2 cases
Authors: Onciu Mihaela , Behm Frederick G. , Downing James R. , Shurtleff Sheila A. , Raimondi Susana C. , Ma Zhigui , Morris Stephan W. , Kennedy Wren , Jones Sandra C. , Sandlund John T. 
Published: June 2003

AbstractWhile most anaplastic lymphoma kinase (ALK)-positive non-Hodgkin lymphomas (NHLs) are of T-cell lineage, a small number of B-lineage tumors with plasmablastic morphology and expression of the full-length ALK protein have been described in the literature. All of these reported tumors lacked the NPM-ALK fusion transcript. There is controversy regarding the existence of ALK fusion-positive B-cell NHL, with many investigators contending that ALK fusions are expressed uniquely in T- or null-cell lymphomas. Here we describe 2 well-characterized cases of ALK-positive B-cell lymphoma expressing the NPM-ALK fusion. Both tumors occurred in pediatric patients and showed poor response to chemotherapy. Each had plasmablastic morphology, showed immunoglobulin A restriction, and was ALK positive and CD30- by immunohistochemistry. One tumor showed the t(2;5)(p23;q35) chromosomal translocation by conventional cytogenetics. Both were positive for NPM-ALK by reverse transcriptase-polymerase chain reaction. Thus, ALK-positive plasmablastic B-cell lymphomas are more heterogeneous at the molecular level than previously recognized. (Blood. 2003;102:2642-2644)
Stable and developmental optionality in native and non-native Hungarian grammars
Authors: Papp Szilvia 
Published: June 2003

The existence of optionality is well attested in natural languages. It can be defined as the coexistence of two variants of a given construction with identical Logical Form (LF) representations within the same grammatical system. The existence of optionality within both stable (native and non-native) and developing grammars seems to contradict the fundamental claim of the Minimalist Program (MP). In the MP, syntactic optionality is excluded within the computational system because of economy principles which require an ‘optimal realization of interface conditions' (Chomsky, 1995: 171).As a result, movement is possible only if it is necessary. Movement which is possible but not necessary (i.e., truly optional) is not permitted. Thus, at the level of competence, optionality may occur precisely because neither alternative qualifies as a unique optimal realization of interface conditions. This article presents evidence from the grammaticality intuitions of native speakers and English-speaking second language (L2) learners of Hungarian about optional and categorical constructions. It is argued that while often observed, stable native optionality is highly restricted and difficult to capture. This might be due to the fact that developmental L1 optionality disappears when the input that children receive is sufficient and/or sufficiently robust. Where the input is not sufficient, optionality lingers on, creating fuzzy grammars and borderline cases in grammaticality. However, such stable native optionality may eventually be resolved by categorization (one alternative is expunged from the grammar) or by semantic differentiation (leading to quasi-optionality). While stable native optionality is unpredictable, developmental optionality is relatively predictable in both early and end-state non-native grammars. The nature of early L2 optionality depends on the characteristics of the initial state. Advanced and end-state non-native optionality persists only if the target language input is non-robust or parametrically ambiguous. Therefore the resolution of optionality at ultimate attainment depends not only on the L2 initial state but also on the intrinsic nature of the primary linguistic data that the learners are exposed to. It is well known that the evidence L2 learners receive is qualitatively different from that obtained by first language (L1) acquirers, and quantitatively limited compared to it. This, in conjunction with the hypotheses created initially, may lead to non-native-like representations that are nonoptimal realizations of the interface conditions. In the face of non-robust and parametrically ambiguous data, L2 learners are either found to fall back on L1 values or resort to general learning strategies, thus ultimately exhibiting divergent representations in end-state grammars.