bluuebunny/crossref_metadata_2025 huggingface dataset:
Coping Style Influences Compliance with Multidisciplinary Pain Management
Authors: Cipher Daisha J. , Fernandez Ephrem , Clifford P. Andrew
Published: July 2003

The treatment of chronic pain disorders has become multifaceted in recognition of the complexities of chronic pain. However, few models have emerged to predict patients’ response to treatment. This study examined a path model of pain treatment outcome, incorporating the variables of coping style and treatment compliance. Results indicated that the suppression of negative emotion was associated with greater treatment compliance, whereas amplification of negative emotion was found to be associated with poorer treatment compliance. An aggressive coping style was found to be associated with poor treatment compliance. In turn, poor compliance predicted poor pre-/post-treatment functional capacity. Moreover, a path model incorporating compliance as a mediator between coping styles and functional impairment revealed an excellent model fit when compared to a path model with no mediators.
Body Image Ideal among Males and Females: Sociocultural Influences and Focus on Different Body Parts
Authors: Stanford Jacqueline N. , Mccabe Marita P.
Published: July 2003

Past research has obtained mixed findings in relation to gender differences and other factors that shape ideal body image. The current study was designed to investigate these differences further, using a digital body image program to assess body image individually. As expected, females desired a body that was smaller than their current size, whereas males were split between wanting a smaller and larger body. The perceived messages from peers and parents were consistent with the individual’s ideal image. Gender differences were also found with ratings of attractiveness and effectiveness. Females rated messages from peers and parents as more important than did males. For both males and females, opposite sex peers were the most important influences, and parents the least important.
The Cognitive Processes by which Perceived Locus of Causality Predicts Participation in Physical Activity
Authors: Chatzisarantis Nikos L. D. , Hagger Martin S. , Biddle Stuart J. H. , Karageorghis Costas
Published: July 2003

The present study examined the cognitive processes by which perceived locus of causality influences participation in leisure time physical activity. Based on the theoretical tenets of self-determination theory, it was hypothesized that deliberative modes of information processing and past behaviour will account for the direct effects of perceived locus of causality on effort and physical activity. Data from self-report questionnaires were analysed using confirmatory factor analysis and path analysis. Results demonstrated that perceived locus of causality influences effort and physical activity participation via attitudes and perceived behavioural control. It was concluded that the addition of perceived locus of causality to the theory of planned behaviour increased the utility of the theory in predicting adherence to physical activity.
Interpretations of Risk and Expectations of Change among Individuals with Types 1 and 2 Diabetes
Authors: Eiser J. Richard , Eiser Christine , Riazi Afsane , Hammersley Suzanne , Tooke John E.
Published: July 2003

Questionnaires to assess expectations of future health were administered to 382 patients with diabetes immediately before and after attending an annual check-up. When considering their future health status and interpreting feedback from clinicians, diabetic control appeared to be a more important criterion for Type 1 than Type 2 patients. Both patients and clinicians briefly recorded the topics they felt had been discussed during the consultation. Comparing the two sets of records revealed significant concordance, within the Type 1 but not the Type 2 sample, between patients and clinicians with respect to whether patients had been given good news. Our findings emphasize the importance of distinguishing Types 1 and 2 diabetes in accounts of patients’ expectations and motivation for self-management.
The Influence of Social Support, Coping and Mood on Sexual Risk Behavior among HIV-Positive Men and Women
Authors: Gore-felton Cheryl , Koopman Cheryl , Turner-cobb Julie M. , Durán Ron , Israelski Dennis , Spiegel David
Published: July 2003

The purpose of this study was to examine the relationships between social support, coping, mood and sexual risk behavior. Participants were 122 HIV-positive adults (60 women and 62 men). All participants were assessed on sexual risk behavior, perceived partner social support, coping with HIV/AIDS and mood. The results showed that sexual risk behavior was associated with male gender, education, perceived support of their partners and the use of emotion-focused coping style to deal with living with HIV and AIDS. Intervening with partners and developing effective coping strategies may decrease risk among HIV-positive men and women. Indeed, effective HIV prevention interventions must consider the social, psychological and cultural context in which sexual risk behavior occurs and develop strategies that intervene on these psychosocial factors.
Risky Sexual Behavior in American White College Women: The Role of Sex Guilt and Sexual Abuse
Authors: Wayment Heidi A. , Aronson Bethany
Published: July 2003

Ninety-five sexually active White American female college students participated in a questionnaire study about their sexual behavior in the past 12 months. A path model was tested in order to assess specific hypothesized predictors of risky sexual behavior. As predicted, participants with greater sex guilt reported using condoms more and having had fewer sexual partners. The findings of this study suggest that White American female college students are at some degree of risk due to risky sexual behavior. Taking into account attitudes about sexuality and past sexual abuse along with the requisite training in condom use self-efficacy may enhance the success of interventions designed to reduce risky sexual behavior among White American female college students.
Seeing Things
Authors: Bradley Richard
Published: July 2003

Recent attempts to problematize archaeological fieldwork have been concerned with excavation at the expense of surface survey, and with questions of procedure more than interpretations of the past. In fact these two kinds of fieldwork offer quite different possibilities and suffer from different constraints. Thought must be given to ways in which they can be combined if they are to make a real contribution to social archaeology. The argument is illustrated by a project carried out at a megalithic cemetery in Scotland.
Nervous Landscapes
Authors: Byrne Denis R.
Published: July 2003

The experience of being on the receiving end of racial segregation has been fundamental to the way generations of Aboriginal people in NSW view the landscape. Racial segregation was and is a spatial system with a plenitude of dividing lines, but the lines were unmarked more than marked, the conventions unvoiced more than spoken. Historically, in the Australian case, it was a system that covered its own tracks and left few marks apart from those it left on the lives of its victims. The colonial, cadastral mapping of land was instrumental in racial separation. In theory, the colonized were gridlocked by the cadastra but there were always ways through it and ways of subverting it.
Archaeological Visions
Authors: Lazzari Marisa
Published: July 2003

It is argued here that the desire to make things visible that under-writes archaeological research is an effect of the Western split between subject and object. This conforms a matrix of `optic knowledge', or the totalizing gaze of an all-knowing subject, that infuses our language and practices with visual metaphors. The critical consideration of visual metaphors is particularly relevant for gender studies in archaeology and their desire to make women visible. However, this desire also enables the re-signification of vision as a connected experience within a field of social and material forces, thus exposing gender, or any other aspect of social difference, as part of a field of relational practices.
Growing Metaphors
Authors: Williams Mike
Published: July 2003

By reviewing the theory of metaphor, it can be shown how metaphors need not solely be linguistic but can include actions and objects. This allows for metaphors to be found and recognized in the archaeological record. Furthermore, some metaphors can be so pervasive and all-encompassing that they can determine the way people think and understand their world. During the later prehistoric period in Britain and north-western Europe, this article suggests that the agricultural cycle formed such a metaphor. Elements of agricultural production can be found in many diverse contexts and an examination of these indicates the way in which people understood and conceptualized their lives. Their aim was to situate social reproduction in the timeless and unchanging cycle of agricultural production. If people could show that they were as permanent as the land upon which they lived then possibly they could claim that land with equal permanence and, there-after, keep it as their own.
Cities of Violence
Authors: Swenson Edward R.
Published: July 2003

Sacrifice and related forms of ritual violence were deeply rooted cultural practices in the Andes, fundamental principles of cosmology that framed conceptions of the natural and social world and phenomena closely connected to the exercise of power. This article explores the intimate relationship between political power and ritual violence by examining the institutionalization of social inequality and the production of urban landscapes in the Andes, focusing principally on the Moche culture (AD 100-750) and earlier polities of central and northern Peru. Drawing on theories of Maurice Bloch, data from Mesoamerica will then be analyzed to illuminate cross-cultural parallels of the significance of sacralized violence in processes of prehistoric urbanization. Ultimately, a comparative approach affords a stronger analytical perspective in deciphering the striking inter-dependence of power and ritual homicide in the prehistory of American urbanism.
Thioguanine offers no advantage over mercaptopurine in maintenance treatment of childhood ALL: results of the randomized trial COALL-92
Authors: Harms Dörthe O. , Göbel Ulrich , Spaar Hans J. , Graubner Ulrike B. , Jorch Norbert , Gutjahr Peter , Janka-Schaub Gritta E. ,   for the COALL Study Group
Published: July 2003

The German cooperative study group for childhood acute lymphoblastic leukemia (COALL-92) was designed to examine the clinical effectiveness of thioguanine (TG) versus mercaptopurine (MP) in maintenance treatment of childhood acute lymphoblastic leukemia (ALL) in a randomized multicenter trial. TG and MP are prodrugs and have to be converted intracellularly to 6-thioguanine nucleotides (TGNs) for cytostatic activity. TG is converted into TGN in fewer steps and has been shown to be more cytotoxic in equimolar doses in vitro compared with 6-MP. Therefore, a higher effectiveness of TG in maintenance treatment was postulated. Of 521 patients enrolled into the protocol, 474 were randomized to receive either MP or TG during maintenance therapy in a daily oral dose. After a median observation time of 6.6 years, the probability of event-free survival was 79% ± 3% for the MP group (238 children) and 78% ± 3% in the TG group (236 patients). In spite of TGN levels, exceeding those of the MP group 7 times, treatment with TG did not improve the outcome but was more complicated to handle due to a specific toxicity profile of prolonged myelosuppression with marked thrombocytopenia. Therefore, MP should remain the preferred drug for maintenance treatment of ALL, unless other studies demonstrate superiority of TG in larger trials or selected patient groups.
A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia
Authors: Fiedler Walter , Mesters Rolf , Tinnefeld Heike , Loges Sonja , Staib Peter , Dührsen Ulrich , Flasshove Michael , Ottmann Oliver G. , Jung Wolfram , Cavalli Franco , Kuse Rolf , Thomalla Joerg , Serve Hubert , O'Farrell Anne M. , Jacobs Mark , Brega Nicoletta M. , Scigalla Paul , Hossfeld Dieter K. , Berdel Wolfgang E.
Published: July 2003

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.
Generation of autologous cytotoxic and helper T-cell responses against the B-cell leukemia–associated antigen HB-1: relevance for precursor B-ALL–specific immunotherapy
Authors: de Rijke Björn , Fredrix Hanny , Zoetbrood Agnes , Scherpen Frank , Witteveen Henry , de Witte Theo , van de Wiel-van Kemenade Elly , Dolstra Harry
Published: July 2003

Tumor relapses in patients with precursor B-cell acute lymphoblastic leukemia (BALL) occur frequently after primary treatment. Therefore, development of additional treatment modalities to eliminate residual tumor cells is needed. Active immunotherapy using dendritic cells (DCs) loaded with tumor-associated antigens is a promising approach to induce specific T-cell immunity in patients with cancer. In previous studies, we described HB-1 as a B-cell lineage-specific antigen that is recognized by donor-derived cytotoxic T lymphocytes (CTLs) on allogeneic B-ALL tumor cells. Here, we investigated the potential use of the HB-1 antigen as an autologous T-cell vaccine target. To determine whether HB-1–specific CTL precursors are present within the T-cell repertoire, we induced expansion of CD8+ T cells using mature monocyte-derived DCs pulsed with the previously identified HB-1.B44 antigenic peptide. In 6 of 8 donors, CD8+ CTL lines have been generated that exert cytotoxicity against target cells exogenously pulsed with peptide or endogenously expressing the HB-1 antigen. From one of these HB-1–specific T-cell lines, we isolated a CD8+ CTL that produces interferon-γ on stimulation with B-ALL tumor cells. Interestingly, the HB-1 antigen also induced CD4+ T-helper responses on activation with protein-loaded mature monocyte-derived DCs. We identified 2 novel epitopes recognized in the context of HLA-DR4 and HLA-DR11 with the use of HB-1–specific CD4+ T-cell clones generated from different donors. These present data, that HB-1 induces both helper and cytotoxic T-cell responses, indicate that the HB-1 antigen is a candidate target to induce T-cell–mediated antitumor immunity in patients.
The scavenger receptor MARCO mediates cytoskeleton rearrangements in dendritic cells and microglia
Authors: Granucci Francesca , Petralia Filippo , Urbano Matteo , Citterio Stefania , Di Tota Francesco , Santambrogio Laura , Ricciardi-Castagnoli Paola
Published: July 2003

Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor expressed in peritoneal macrophages and in a subpopulation of macrophages in the marginal zone of the spleen and in the medullary cord of lymph nodes. By global gene expression analysis, it has been found that the MARCO mRNA was one of the most up-regulated in splenic dendritic cells (DCs) following lipopolysaccharide or bacterial activation and in granulocyte-macrophage colony-stimulating factor (GM-CSF)–treated microglial cells. Here we show that MARCO is expressed on splenic DCs at late time points after activation and that its expression correlates with profound changes in actin cytoskeleton organization in DCs and microglia. During maturation, DCs undergo profound rearrangements of actin cytoskeleton. Immature DCs are adherent with visible actin cables, while fully mature, MARCO-expressing, splenic DCs are nonadherent, round in shape, and have an actin cytoskeleton with a punctate distribution. The simple expression of MARCO was sufficient to induce these cytoskeleton modifications in DCs. MARCO-transfected immature DCs acquired a typical morphology of mature DCs and did not rearrange the actin cytoskeleton following activation. Moreover, DCs in which MARCO was knocked down did not reach the mature phenotype and maintained the typical morphology of transitional DCs. MARCO expression in DCs and microglial cells was also associated with a decrease of antigen internalization capacity. Thus, the MARCO receptor is important for actin cytoskeleton rearrangements and the down-regulation of antigen uptake function during DC and microglial cell maturation.
Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia
Authors: Minami Yosuke , Yamamoto Kazuhito , Kiyoi Hitoshi , Ueda Ryuzo , Saito Hidehiko , Naoe Tomoki
Published: July 2003

An internal tandem duplication (ITD) of the juxtamembrane (JM) domain of FLT3 (FLT3/ITD) has been found in 20% of patients with acute myeloid leukemia (AML) and is correlated with leukocytosis and a poor prognosis. Here, we compared the antiapoptotic effects of wild-type FLT3 (WtFLT3) and FLT3/ITD in terms of the regulation of Bcl-2 family members. In a murine myeloid cell line, 32D, interleukin-3 (IL-3) deprivation induced apoptosis following the down-regulation of Bcl-XL and the dephosphorylation of Bad. However, the expression levels of Bcl-2, Bax, Bak, and Mcl-1 were unchanged. In WtFLT3-transfected 32D (WtFLT3-32D) cells, FLT3 ligand (FL) stimulation did not restore the down-regulation of Bcl-XL but maintained the phosphorylation of Bad. Combined treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, dephosphorylated Bad and induced apoptosis in WtFLT3-32D cells stimulated with FL. Induction of nonphosphorylated Bad induced remarkable apoptosis. These findings suggest that the FL stimulation is associated with antiapoptosis through Bad phosphorylation. On the other hand, FLT3/ITD-transfected 32D (FLT3/ITD-32D) cells survived in an IL-3–or FL-deprived state. Furthermore, the dephosphorylation of Bad using LY294002 and PD98059 was insufficient for apoptosis, and the down-regulation of Bcl-XL using antisense treatment was needed to induce apoptosis. FLT3 kinase inhibitor, AG1296, alone not only dephosphorylated Bad but also down-regulated Bcl-XL, leading FLT3/ITD-32D cells into apoptosis. These findings suggest that the antiapoptotic pathways from FLT3/ITD are more divergent than those from WtFLT3 and may represent targets for drug discovery with the potential of inducing selective cell death of human leukemia cells.
Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells
Authors: Yvon Eric S. , Vigouroux Stephane , Rousseau Raphael F. , Biagi Ettore , Amrolia Persis , Dotti Gianpietro , Wagner Hans-Joachim , Brenner Malcolm K.
Published: July 2003

Graft-versus-host disease (GVHD) represents one of the major complications of allogeneic hematopoietic stem cell transplantation. Techniques to prevent GVHD have included ex vivo T-cell depletion of the graft or prolonged in vivo immunosuppression. Both reduce the frequency and severity of GVHD but also reduce T-cell-mediated graft-versus-malignancy effect, and increase the risk of infection. A major goal in transplantation is to prevent alloreactivity while preserving activity against tumors and infectious agents. We have used activation of the Notch pathway to try to generate T cells able to specifically regulate alloantigen responses. We used allogeneic Epstein-Barr virus lymphoblastoid B cells (EBV-LCLs) as stimulator cells. Such LCLs are excellent (allo) antigen-presenting cells and can be obtained in large numbers even from donors who have received extensive chemo/radiotherapy. We overexpressed a Notch ligand, Jagged-1, in these cells by adenoviral vector transduction. Stimulation of CD45RA+ naive T cells by Jagged-1 EBV-LCL reduces production of interferon-γ, interleukin-2, and interleukin-5, but up-regulates transforming growth factor-β1 synthesis, consistent with induction of a regulatory T-cell phenotype. Transfer of these T cells to fresh lymphocyte cultures inhibits proliferative and cytotoxic immune responses to the priming alloantigens while sparing responses to third-party stimulator cells. Notch activation in the presence of alloantigen-presenting cells may therefore be a means of inducing specific regulatory T cells while preserving other T-cell functionality. (Blood. 2003;102:3815-3821)
IGF-1 down-regulates IFN-γR2 chain surface expression and desensitizes IFN-γ/STAT-1 signaling in human T lymphocytes
Authors: Bernabei Paola , Bosticardo Marita , Losana Giuliana , Regis Gabriella , Di Paola Francesca , De Angelis Stefania , Giovarelli Mirella , Novelli Francesco
Published: July 2003

The ability of insulin-like growth factor-1 (IGF-1) to regulate surface expression of the interferon-γ receptor 2 (IFN-γR2) transducing chain and activation of IFN-γ–induced signal transducer and activator of transcription-1 (STAT-1) in human T cells was analyzed. We show that, especially in the absence of serum (which contains IGF-1), IGF-1 down-regulated surface expression of the IFN-γR2 chain and inhibited both IFN-γ–dependent STAT-1 activation and apoptosis in T-cell lines ST4, Jurkat, and Molt-4. IFN-γR2 down-regulation resulted from its enhanced internalization since IGF-1 completely restored the uptake of anti–IFN-γR2 monoclonal antibody (mAb) in serum-deprived T-cell lines. When the interaction between IGF-1 and its receptor was blocked by anti–IGF-1R mAb, enhancement of IFN-γR2 surface expression, STAT-1 activation, and reinstatement of IFN-γ–induced apoptosis were observed. Enhanced expression of IFN-γR2 was also observed in phytohemagglutinin (PHA)–activated T lymphoblasts cultured in the presence of anti–IGF-1R mAb, whereas IGF-1 or anti–IGF-1R mAb did not modify the high IFN-γR2 expression in B and myeloid cell lines. Both IGF-1 and anti–IGF-1R mAb did not modify the constitutive expression of IFN-γR2 mRNA in T cells as well as the high IFN-γR1 binding chain surface expression in T, B, and myeloid cells. These data indicate that IGF-1 plays a critical role in the desensitization of IFN-γ/STAT-1 signaling in T lymphocytes by delivering a signal for IFN-γR2 internalization.
Vasculin, a novel vascular protein differentially expressed in human atherogenesis
Authors: Bijnens Ann P. J. J. , Gils Ann , Jutten Barry , Faber Birgit C. G. , Heeneman Sylvia , Kitslaar Peter J. E. H. M. , Tordoir Jan H. M. , de Vries Carlie J. M. , Kroon Abraham A. , Daemen Mat J. A. P. , Cleutjens Kitty B. J. M.
Published: July 2003

Recent suppressive subtractive hybridization analysis on human atherosclerotic plaque-derived RNA revealed genes upregulated in plaques with a thrombus versus stable plaques. Clone SSH6, containing part of a putative open reading frame of an unknown protein, was further investigated. Full-length cDNA, coding for a 473–amino acid (aa) protein, was identified in a vascular smooth muscle cell (SMC) cDNA library. Bioinformatics suggested the presence of multiple SSH6 variants due to alternative splicing of exon 3. Multiple-tissue Northern blot analysis demonstrated a differential expression pattern of these variants, as a ubiquitously expressed SSH6 mRNA missing exon 3, was detected apart from a putative vascular SMC–specific form containing exon 3. Western blot analysis indicated a ubiquitous 35-kDa protein (SSH6-β), in addition to a 45-kDa protein (vasculin), detected in the vascular wall and in plasma. Analysis of arteries displaying various stages of atherosclerosis indicated that the vasculin/SSH6-β ratio increases throughout atherogenesis. Immunohistochemical analysis demonstrated cytoplasmic expression of SSH6 gene products in macrophages, endothelial cells, and SMCs. In summary, we identified a novel mRNA/protein, vasculin, in the arterial wall and plasma. The regulated expression of vasculin in plaques suggests a role in atherogenesis. Moreover, its presence in plasma opens perspectives for vasculin as a marker for atherosclerosis.
The mutation Ser511Asn leads to N-glycosylation and increases the cleavage of high molecular weight kininogen in rats genetically susceptible to inflammation
Authors: Isordia-Salas Irma , Pixley Robin A. , Parekh Hemant , Kunapuli Satya P. , Li Fengling , Stadnicki Anthony , Lin Yingzhang , Sartor R. Balfour , Colman Robert W.
Published: July 2003

Crohn disease is immunologically mediated and characterized by intestinal and systemic chronic inflammation. In a rat model, injection of peptidoglycan-polysaccharide complexes into the intestinal wall induced chronic inflammation in Lewis but neither Fischer nor Buffalo rats, indicating a differential genetic susceptibility. Proteolysis of plasma high molecular weight kininogen (HK) yielding bradykinin and cleaved HK (HKa) was faster in Lewis than in Fischer or Buffalo rat plasma. A single point mutation at nucleotide 1586 was found translating from Ser511 (Buffalo and Fisher) to Asn511 (Lewis). The latter defines an Asn-Xaa-Thr consensus sequence for N-glycosylation. We expressed these domains in Escherichia coli and found no differences in the rate of cleavage by purified kallikrein in the 3 strains in the absence of N-glycosylation. We then expressed these domains in Chinese hamster ovary (CHO) cells, which are capable of glycosylation, and found an increased rate of cleavage of Lewis HK. The Lewis mutation is associated with N-glycosylation as evidenced by a more rapid migration after treatment with N-glycosidase F. When CHO cells were cultured in the presence of tunicamycin, the kallikrein-induced cleavage rate of Lewis HK was not increased. This molecular alteration might be one contributing factor resulting in chronic inflammation in Lewis rats.
Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro
Authors: Ochiai Naoya , Uchida Ryo , Fuchida Shin-ichi , Okano Akira , Okamoto Masashi , Ashihara Eishi , Inaba Tohru , Fujita Naohisa , Matsubara Hiroaki , Shimazaki Chihiro
Published: July 2003

Ras gene mutations occur in 30% to 40% of patients with multiple myeloma (MM), and farnesylation is the first and most important step in the posttranslational modification of Ras proteins. R115777 is a newly synthesized potent farnesyl transferase inhibitor (FTI) and has recently demonstrated significant antitumor activities in vitro and in vivo. Therefore, we examined the effect of R115777 on the growth of fresh and cloned myeloma cells in vitro. R115777 inhibited the growth of fresh and cloned myeloma cells dose dependently, and effects were not dependent on the status of N-Ras mutation in fresh myeloma cells. Flow cytometric analysis using annexin V and 7-aminoactinomycin D (7AAD) showed that R115777 induced apoptosis of 2 of 3 myeloma cell lines at a concentration of 1.0 × 10-8 M. R115777 appears to be a potent inducer of apoptosis, and its effects depend on the status of Ras mutation in cloned myeloma cells but not on the status of N-Ras mutation in fresh myeloma cells. This is the first report that demonstrates the relationship between the N-Ras mutation in fresh myeloma cells and the effect of R115777. R115777 might have some benefit in the treatment of myeloma patients.
Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years
Authors: Wong Raymond , Giralt Sergio A. , Martin Thomas , Couriel Daniel R. , Anagnostopoulos Athanasios , Hosing Chitra , Andersson Borje S. , Cano Pedro , Shahjahan Munir , Ippoliti Cindy , Estey Elihu H. , McMannis John , Gajewski James L. , Champlin Richard E. , de Lima Marcos
Published: July 2003

Hematopoietic stem cell transplantation from unrelated donors is an effective treatment for myeloid malignancies, but its use is usually restricted to young patients without comorbidities. The development of reduced-intensity preparative regimens has allowed the extension of this form of treatment to older and medically infirm patients. We assessed the outcomes of patients older than 54 years who received unrelated donor transplants for the treatment of myeloid malignancies in our institution. There were 29 patients (median age, 59 years) with advanced acute myeloid leukemia (n = 13), myelodysplastic syndrome (n = 7), and chronic myeloid leukemia (n = 9) included. With a median follow-up of 27 months, the probability of overall and event-free survival, and nonrelapse mortality at one year were 44%, 37%, and 55%, respectively. Grades II to IV acute graft-versus-host disease (GVHD) occurred in 41% of patients and chronic GVHD developed in 63% of patients surviving more than 100 days. Of the 11 survivors, 9 were interviewed and reported good quality of life after transplantation using the Functional Assessment of Cancer Therapy–Bone Marrow Transplant Scale (FACT-BMT) questionnaire, with high scores in all dimensions. Unrelated donor transplantation is a treatment option for older patients with myeloid malignancies. The results in this cohort of patients are comparable with those reported in younger patients with similarly advanced disease.
New score predicting for prognosis in PML-RARA+, AML1-ETO+, or CBFBMYH11+ acute myeloid leukemia based on quantification of fusion transcripts
Authors: Schnittger Susanne , Weisser Martin , Schoch Claudia , Hiddemann Wolfgang , Haferlach Torsten , Kern Wolfgang
Published: July 2003

To evaluate the prognostic significance of quantitative PML-RARA, AML1-ETO, and CBFB-MYH11 fusion transcript expression, real-time polymerase chain reaction was used to analyze bone marrow samples of 349 such patients at diagnosis and 522 samples of 142 patients also during therapy (total analyses, n = 859; median number of follow-up samples, 4/patient; median duration of assessment, 12 months). Lower expression levels at diagnosis correlated with better overall and event-free survival in all 3 leukemia subtypes. By combining the median expression ratio after consolidation therapy and the 75th percentile of the expression ratio at diagnosis, a new score was established that separates a group with 100% EFS from a significantly worse group (P < .0001) in each of the 3 acute myeloid leukemia subgroups. Eight patients showed increasing levels of expression during follow-up and all had relapse. In conclusion, patients at high risk for treatment failure can be identified by high levels of fusion gene expression at diagnosis or less than 3 logs of tumor reduction during the first 3 to 4 months of therapy. By combining the transcription ratios at these 2 checkpoints, a new powerful prognostic score has been established.
Bone marrow precursor of extranodal T-cell lymphoma
Authors: Gniadecki Robert , Lukowsky Ansgar , Rossen Kristian , Madsen Hans O. , Thomsen Kristian , Wulf Hans Christian
Published: July 2003

The development of extranodal lymphomas is thought to be initiated by the transformation event in peripheral organs. Lymphomatoid papulosis (LyP) is a low-grade cutaneous lymphoma and may progress into the cutaneous anaplastic lymphoma. We identified 2 patients who 3 and 4 years before the development of LyP were treated for an unrelated malignancy (Burkitt lymphoma and small-cell B-cell lymphoma). We analyzed the T-cell receptor (TCR) gene rearrangement pattern in their skin, blood, and bone marrow, including the archival bone marrow sampled years before the development of clinically evident LyP. In all samples we detected the unique monoclonal TCR rearrangements. This observation suggests that the initial malignant transformation in LyP occurred in bone marrow and not, as could be supposed, in the skin. (Blood. 2003;102:3797-3799)
Tec regulates platelet activation by GPVI in the absence of Btk
Authors: Atkinson Ben T. , Ellmeier Wilfried , Watson Steve P.
Published: July 2003

The Tec family kinase Btk plays an important role in the regulation of phospholipase Cγ2 (PLCγ2) downstream of the collagen receptor glycoprotein VI (GPVI) in human platelets. Platelets also express a second member of this family, Tec; however, its function has not been analyzed. To address the role of Tec, we analyzed Btk-/-, Tec-/-, and Btk/Tec double-deficient (Btk-/-/Tec-/-) platelets. Tec-/- platelets exhibit a minor reduction in aggregation to threshold concentrations of collagen or the GPVI-specific agonist collagen-related peptide (CRP), whereas responses to higher concentrations are normal. Tyrosine phosphorylation of PLCγ2 by collagen and CRP is not altered in Tec-/- platelets. However, Btk-/-/Tec-/- platelets exhibit a greater reduction in PLCγ2 phosphorylation than is seen in the absence of Btk, thus revealing an important role for Tec in this situation. Furthermore, Btk-/-/Tec-/- platelets fail to undergo an increase in Ca2+, aggregation, secretion, and spreading in response to collagen or CRP, whereas they aggregate normally to adenosine diphosphate (ADP) and spread on fibrinogen. A residual GPVI signal exists in the Btk-/-/Tec-/- platelets as CRP synergizes with ADP to mediate aggregation. These results demonstrate an essential requirement for Tec and Btk in platelet activation by GPVI and reveal a functional role for Tec in the regulation of PLCγ2 in the absence of Btk. (Blood. 2003;102: 3592-3599)
Minimal residual disease–based role of imatinib as a first-line interim therapy prior to allogeneic stem cell transplantation in Philadelphia chromosome–positive acute lymphoblastic leukemia
Authors: Lee Seok , Kim Dong-Wook , Kim Yoo-Jin , Chung Nak-Gyun , Kim Yoo-Li , Hwang Ji-Yeon , Kim Chun-Choo
Published: July 2003

Fourteen adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) were studied to evaluate the role of imatinib prior to allogeneic stem cell transplantation (SCT). Of these, 12 patients were in complete hematologic response (CHR), and 2 were refractory. Imatinib was administered as an interim schedule after each chemotherapy course. After the first imatinib cycle, 11 patients remained in sustained CHR with a decrease in the BCR-ABL/ABL ratios (0.89 logs), and one refractory patient achieved CHR. Meanwhile, 2 patients were resistant to imatinib. Ten patients receiving a second imatinib cycle following consolidation showed sustained CHR, including 2 molecular CR, with a further decrease in the BCR-ABL/ABL ratios (0.19 logs). Twelve patients underwent SCT in a favorable status, and of these, 11 are still alive in a leukemia-free status at 9 to 28+ months after SCT. First-line imatinib interim therapy appears to be a useful strategy to bridge the time to SCT for patients with Ph+ ALL.
TGF-β signaling–deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro
Authors: Larsson Jonas , Blank Ulrika , Helgadottir Hildur , Björnsson Jon Mar , Ehinger Mats , Goumans Marie-José , Fan Xiaolong , Levéen Per , Karlsson Stefan
Published: July 2003

Studies in vitro implicate transforming growth factor β (TGF-β) as a key regulator of hematopoiesis with potent inhibitory effects on progenitor and stem cell proliferation. In vivo studies have been hampered by early lethality of knock-out mice for TGF-β isoforms and the receptors. To directly assess the role of TGF-β signaling for hematopoiesis and hematopoietic stem cell (HSC) function in vivo, we generated a conditional knock-out model in which a disruption of the TGF-β type I receptor (TβRI) gene was induced in adult mice. HSCs from induced mice showed increased proliferation recruitment when cultured as single cells under low stimulatory conditions in vitro, consistent with an inhibitory role of TGF-β in HSC proliferation. However, induced TβRI null mice show normal in vivo hematopoiesis with normal numbers and differentiation ability of hematopoietic progenitor cells. Furthermore HSCs from TβRI null mice exhibit a normal cell cycle distribution and do not differ in their ability long term to repopulate primary and secondary recipient mice following bone marrow transplantation. These findings challenge the classical view that TGF-β is an essential negative regulator of hematopoietic stem cells under physiologic conditions in vivo.
VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome
Authors: Kienle Dirk , Kröber Alexander , Katzenberger Tiemo , Ott German , Leupolt Elke , Barth Thomas F. E. , Möller Peter , Benner Axel , Habermann Annett , Müller-Hermelink Hans Konrad , Bentz Martin , Lichter Peter , Döhner Hartmut , Stilgenbauer Stephan
Published: July 2003

Immunoglobulin variable heavy chain gene (VH) mutation status and VDJ rearrangement structure were analyzed in 141 patients with mantle cell lymphoma (MCL) and correlated with biologic and clinical characteristics; 29% of the MCLs displayed mutated VH using a 98% germline homology cutoff. Striking differences occurred in the VH mutation subgroups with respect to the use of specific V genes. Rearrangements involving V4-34 and V3-21 were almost exclusively unmutated, whereas rearrangements using V4-59 and V3-23 were typically mutated. Significant association occurred between mutated VH with shorter CDR3 lengths and the use of JH4b. V3-21 and V4-59 were involved in highly characteristic rearrangements, implying that antigen specificity might have been involved in MCL development. There was no evidence for isotype switch recombination or Bcl-6 expression in any MCL. ZAP70 expression was not different in VH-mutated or -unmutated MCL. Although the deletions 11q– and 17p– showed a balanced distribution, an overrepresentation was observed for trisomies +3q, +8q, and tetraploidy in the VH-unmutated subgroup and +12q in the VH-mutated subgroup. Clinically, mutated VH was associated with a higher rate of complete remission, but there was no correlation between VH mutation status and other clinical characteristics or overall survival.
Active amino acids of the Kell blood group protein and model of the ectodomain based on the structure of neutral endopeptidase 24.11
Authors: Lee Soohee , Debnath Asim K. , Redman Colvin M.
Published: July 2003

In addition to its importance in transfusion, Kell protein is a member of the M13 family of zinc endopeptidases and functions as an endothelin-3–converting enzyme. To obtain information on the structure of Kell protein we built a model based on the crystal structure of the ectodomain of neutral endopeptidase 24.11 (NEP). Similar to NEP, the Kell protein has 2 globular domains consisting mostly of α-helical segments. The domain situated closest to the membrane contains both the N- and C-terminal sequences and the enzyme-active site. The outer domain contains all of the amino acids whose substitutions lead to different Kell blood group phenotypes. In the model, the zinc peptidase inhibitor, phosphoramidon, was docked in the active site. Site-directed mutagenesis of amino acids in the active site was performed and the enzymatic activities of expressed mutant Kell proteins analyzed and compared with NEP. Our studies indicate that Kell and NEP use the same homologous amino acids in the coordination of zinc and in peptide hydrolysis. However, Kell uses different amino acids than NEP in substrate binding and appears to have more flexibility in the composition of amino acids allowed in the active site.
CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy
Authors: Pardanani Animesh , Ketterling Rhett P. , Brockman Stephanie R. , Flynn Heather C. , Paternoster Sarah F. , Shearer Brandon M. , Reeder Terra L. , Li Chin-Yang , Cross Nicholas C. P. , Cools Jan , Gilliland D. Gary , Dewald Gordon W. , Tefferi Ayalew
Published: July 2003

Imatinib mesylate is effective in the treatment of hematologic malignancies that are characterized by either abl- or PDGFRβ- activating mutations. The drug is also active in a subset of patients with eosinophilic disorders and systemic mast cell disease (SMCD). Recently, a novel tyrosine kinase that is generated from fusion of the Fip1-like 1 (FIP1L1) and PDGFRα (PDGFRA) genes has been identified as a therapeutic target for imatinib mesylate in hypereosinophilic syndrome (HES). We used fluorescence in situ hybridization (FISH) to detect deletion of the CHIC2 locus at 4q12 as a surrogate for the FIP1L1-PDGFRA fusion. CHIC2 deletion was observed in bone marrow cells for 3 of 5 patients with SMCD associated with eosinophilia. Deletion of this locus and expression of the FIP1L1–platelet-derived growth factor receptor α (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase–polymerase chain reaction (RT-PCR) for one patient. While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not. These observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES. Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD.
Differences in PO2 and PCO2 between arterial and arterialized earlobe samples
Authors: Sauty A , Uldry C , Debetaz LF , Leuenberger P , Fitting JW
Published: July 2003

Arterialized ear lobe blood samples have been described as adequate to gauge gas exchange in acute and chronically ill patients. It is a safe procedure, usually performed by medical technicians. We have conducted a prospective study to verify the validity of this method. One hundred and fifteen consecutive adult patients were studied. Blood samples were drawn simultaneously from arterialized earlobe and radial artery. Values of partial pressure of oxygen (PO2) and of carbon dioxide (PCO2) were measured by means of blood gas electrodes. The correlation coefficients between the two samples were 0.928 for PO2 and 0.957 for PCO2 values. In spite of a highly significant correlation, the limits of agreement between the two methods were wide for PO2. Earlobe values of PO2 were usually lower than arterial values, with larger differences in the range of normal arterial PO2. On the other hand, the error and the limits of agreement were smaller for PCO2. We conclude that, in adult patients, arterialized earlobe blood PO2 is not a reliable mirror of arterial PO2.
Effect of nitric oxide inhalation on respiratory system resistance in chronic obstructive pulmonary disease
Authors: Roger N , Barbera JA , Farre R , Cobos A , Roca J , Rodriguez-Roisin R
Published: July 2003

Nitric oxide (NO) has been identified as a neurotransmitter of nonadrenergic noncholinergic bronchodilator nerves. To investigate whether inhaled NO exerts a bronchodilator effect in patients with chronic obstructive pulmonary disease (COPD), we measured the resistance of the respiratory system, using the forced oscillation technique, while breathing NO. Eight patients with COPD (7 men and 1 woman; aged 66 +/- 7 yrs (mean +/- SD); forced expiratory volume in one second (FEV1) 37 +/- 17% of predicted) and eight healthy subjects (7 men and 1 woman; 33 +/- 4 yrs; FEV1 108 +/- 14% pred) were studied. Nitric oxide, at a concentration of 40 parts per million (ppm) in air, was inhaled for 20 min. Total resistance (Rrs) and reactance (Xrs) of the respiratory system, arterial oxygen saturation, heart rate, tidal volume, and breathing frequency were continuously recorded at baseline, and during and after ceasing NO inhalation. Methaemoglobin levels were additionally measured in healthy subjects. At baseline, patients with COPD showed higher Rrs than healthy subjects (Rrs at 10 Hz (Rrs,10) 4.97 +/- 2.19 vs 2.29 +/- 0.65 hPa.L-1.s). During NO inhalation, no significant change in Rrs or in Xrs was observed. Mean variation in Rrs,10 while breathing NO was negligible and similar in the two groups (-0.10 +/- 0.13 hPa.L-1.s in COPD patients and -0.02 +/- 0.13 hPa.L-1.s in healthy subjects). Moreover, there were no differences in oxygen saturation, heart rate, tidal volume and breathing frequency during NO inhalation. Methaemoglobinaemia increased at the end of NO inhalation (from 0.48 +/- 0.18 to 0.81 +/- 0.16%), and this increment remained 10 min later (0.86 +/- 0.31%). From these results, we conclude that inhaled nitric oxide, at a concentration of 40 ppm, exerts no effect on respiratory system resistance in patients with chronic obstructive pulmonary disease or in healthy subjects.
Changes in the dose of inhaled steroid affect exhaled nitric oxide levels in asthmatic patients
Authors: Kharitonov SA , Yates DH , Chung KF , Barnes PJ
Published: July 2003

An increased concentration of nitric oxide (NO) in the exhaled air of asthmatic patients may reflect inflammation of the airways, and exhaled NO may, therefore, be useful in monitoring asthma control and the optimal use of anti-inflammatory treatment. We have studied the effect of reducing and then increasing the dose of inhaled steroid on exhaled NO, lung function and symptoms in 14 asthmatic patients treated with twice daily budesonide. Baseline measurements were made at the end of a 2 week run-in period, 2 weeks after the daily dose of budesonide was reduced by 200 micrograms daily, and 2 weeks after the dose was then increased by 200 micrograms daily. Exhaled NO increased significantly compared with baseline after the dose was reduced by 200 micrograms daily (from 122 +/- 13 to 246 +/- 52 ppb); whereas, there was no significant decrease in spirometry or change in peak flow variability. There was also a significant increase in symptoms at night, but no change during the day or in the number of rescue doses of inhaled beta 2-agonist. The level of exhaled NO decreased when the dose of inhaled steroids was increased, and this was associated with a reduction in diurnal variability of peak expiratory flow, and in nocturnal symptoms. Our study suggests that exhaled nitric oxide may be a useful means of monitoring control of asthma. Further longitudinal studies in patients of differing asthma severity are now indicated.