bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of differentially expressed genes representing dendritic cell precursors and their progeny
Authors: Wilson Heather L. , O'Neill Helen C. 
Published: May 2003

AbstractThe development of dendritic cells (DCs) from hematopoietic progenitors is not well understood. Using a spleen-derived long-term culture (LTC) system, it has been possible to continuously generate DCs from progenitors maintained in culture. The nonadherent LTC-DC population is composed of 2 major subsets. These are the small LTC-DC or DC precursors and their progeny, the large LTC-DCs that phenotypically resemble immature DCs. In this study, subtracted cDNA libraries were generated containing sequences differentially expressed in small or large LTC-DCs. Differential screening was then used on plated library clones to select genes expressed in either the small or the large cell population. Real-time polymerase chain reaction (PCR) has been used to verify the selection procedure for several genes of particular interest. Known genes isolated from subtracted libraries were related to stages in DC development and supported previous findings regarding the function of small and large LTC-DCs. Large LTC-DCs expressed a number of immunologically important genes encoding CD86, CCR1, osteopontin, and lysozyme. Small LTC-DCs resembled progenitor DCs expressing genes related to the organization of the cytoskeleton, the regulation of antigen processing, and a number of mitochondrial and ribosomal proteins. Novel transcripts were isolated from small and large LTC-DC–subtracted libraries that could encode novel proteins important in DC development. This study describes changes in gene expression related to the development of CD11c+CD11b+ major histocompatibility complex 2 low (MHC2lo) CD8α– DCs from precursors in a stroma-dependent culture system in the absence of exogenous cytokines.
Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1
Authors: Pineault Nicolas , Buske Christian , Feuring-Buske Michaela , Abramovich Carolina , Rosten Patty , Hogge Donna E. , Aplan Peter D. , Humphries R. Keith 
Published: May 2003

Abstract
HOX genes, notably members of the HOXA cluster, and HOX cofactors have increasingly been linked to human leukemia. Intriguingly, HOXD13, a member of the HOXD cluster not normally expressed in hematopoietic cells, was recently identified as a partner of NUP98 in a t(2;11) translocation associated with t-AML/MDS. We have now tested directly the leukemogenic potential of the NUP98-HOXD13 t(2; 11) fusion gene in the murine hematopoietic model. NUP98-HOXD13 strongly promoted growth and impaired differentiation of early hematopoietic progenitor cells in vitro; this effect was dependent on the NUP98 portion and an intact HOXD13 homeodomain. Expression of the NUP98-HOXD13 fusion gene in vivo resulted in a partial impairment of lymphopoiesis but did not induce evident hematologic disease until late after transplantation (more than 5 months), when some mice developed a myeloproliferative-like disease. In contrast, mice transplanted with bone marrow (BM) cells cotransduced with NUP98-HOXD13 and the HOX cofactor Meis1 rapidly developed lethal and transplantable acute myeloid leukemia (AML), with a median disease onset of 75 days. In summary, this study demonstrates that NUP98-HOXD13 can be directly implicated in the molecular process leading to leukemic transformation, and it supports a model in which the transforming properties of NUP98-HOXD13 are mediated through HOX-dependent pathways.
Tetrocarcin-A—induced ER stress mediates apoptosis in B-CLL cells via a Bcl-2—independent pathway
Authors: Anether Gabriele , Tinhofer Inge , Senfter Monika , Greil Richard 
Published: May 2003

AbstractTetrocarcin-A (TC-A), an antibiotic agent isolated from actinomycetes, has recently been described to antagonize Bcl-2 functions, thereby sensitizing tumor cells to cell death signals under control of Bcl-2. In this study, we analyzed the direct proapoptotic effect of TC-A in the B-chronic lymphocytic leukemia (B-CLL) model. We focused on the signal cascade triggered by TC-A in B-CLL cells and identified activated mitochondrial as well as endoplasmatic reticulum (ER) stress signals. The expression levels of known effector molecules mediating mitochondrial signaling, such as Bax and Bid, and the antagonistic molecule Bcl-2 did not influence sensitivity of B-CLL cells to TC-A. Furthermore, the molecular chaperone and sensor of ER stress, HSP70, though significantly up-regulated in B-CLL cells undergoing TC-A—triggered apoptosis, was ineffective to exert its anti-apoptotic function described in multiple cell death pathways. Autologous T cells of B-CLL patients were significantly less sensitive to TC-A as were also T cells from healthy donors when compared with their normal B-cell fraction. Furthermore, sensitivity of B-CLL cells to TC-A treatment in vitro was dependent neither on the expression levels of CD38—a prognostic factor for survival of B-CLL patients as well as for their response to therapy—nor on the clinical stage or pretreatment status of patients. From our data showing that TC-A induced a cell death pathway via ER stress preferentially in B cells and that it acted independently of important markers of drug sensitivity and of clinical markers, we conclude that TC-A might represent an attractive candidate drug for further evaluation in preclinical trials.
Regulation of T-cell receptor Dβ1 promoter by KLF5 through reiterated GC-rich motifs
Authors: Yang Xuexian O. , Doty Raymond T. , Hicks Justin S. , Willerford Dennis M. 
Published: May 2003

AbstractRearrangement of T-cell receptor (TCR) and immunoglobulin genes by a common V(D)J recombination machinery is regulated by developmentally specific chromatin changes at the target locus, a process associated with transcription. At the TCRβ locus, the Eβ enhancer and the Dβ1 promoter regulate germline transcription originating near the TCR Dβ1 gene segment. The Dβ1 promoter contains 3 GC-rich motifs that bind a common set of nuclear proteins from pro–T-cell lines. Mutations that diminish the binding of nuclear proteins also diminish the activity of the Dβ1 promoter in transcriptional reporter assays. Using a yeast one-hybrid approach, 3 Krüppel-like factors—KLF3, KLF5, and KLF6—and a novel zinc finger protein were identified in a thymus library, all of which bound the GC-rich motif in a sequence-specific manner. Of these genes, KLF5 mRNA was expressed in a restricted manner in lymphoid cells and tissues, with highest expression in pro–T-cell lines and Rag-deficient thymocytes. Antibody supershift studies and chromatin immunoprecipitation assay confirmed that KLF5 bound the Dβ1 promoter. In reporter gene assays, KLF5 but not KLF6 efficiently transactivated the Dβ1 promoter, whereas a dominant-negative KLF5 construct inhibited reporter expression. These data suggest that reiterated GC motifs contribute to germline TCRβ transcription through binding of KLF5 and other Krüppel family members and that restricted expression of KLF5 may contribute to lineage-specific regulation of germline TCRβ transcription.
The low-frequency allele of the platelet collagen signaling receptor glycoprotein VI is associated with reduced functional responses and expression
Authors: Joutsi-Korhonen Lotta , Smethurst Peter A. , Rankin Angela , Gray Elaine , IJsseldijk Martin , Onley Catherine M. , Watkins Nicholas A. , Williamson Lorna M. , Goodall Alison H. , de Groot Philip G. , Farndale Richard W. , Ouwehand Willem H. 
Published: May 2003

AbstractInteraction of platelets with collagen under conditions of blood flow is a multi-step process with tethering via glycoprotein IbIXV (GPIbIXV) over von Willebrand factor, adhesion by direct interaction with the integrin GPIaIIa, and signaling via GPVI. GPVI can be specifically agonized by cross-linked collagen-related peptide (CRP-XL), which results in a signaling cascade very similar to that evoked by native collagen. The GPVI gene has 2 common alleles that differ by 3 replacements in the glycosylated stem and 2 in the cytoplasmic domain. We used CRP-XL to elucidate the variation in responses observed in platelet function in different individuals. We observed a 3-fold difference in the response to CRP-XL in platelet aggregation when comparing platelets from 10 high-frequency allele homozygotes with 8 low-frequency ones (2-way analysis of variance [ANOVA], P &lt; .0001). The difference in functional responses was reflected in fibrinogen binding and in downstream signaling events as measured by tyrosine phosphorylation, the expression of P-selectin, and the binding of annexin V and the generation of thrombin on the platelet surface (2-way ANOVA, P &lt; .001). Platelets homozygous for the low-frequency allele tended to be less able to form a thrombus on a collagen surface in flowing whole blood or in the platelet function analyzer–100 (t test, P = .065 and P = .061, respectively). The functional difference was correlated to a difference in total and membrane-expressed GPVI measured by monoclonal and polyclonal antibodies. This study demonstrates for the first time that platelet function may be altered by allelic differences in GPVI.
KRN5500: a novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis
Authors: Byrd John C. , Lucas David M. , Mone Andrew P. , Kitner Joshua B. , Drabick Joseph J. , Grever Michael R. 
Published: May 2003

Abstract
Therapy of B-cell chronic lymphocytic leukemia (CLL) is currently palliative, emphasizing the need for identification of new therapies for this disease. KRN5500 is a novel agent that has a unique sensitivity pattern in the National Cancer Institute cell line screening panel, suggesting a unique mechanism of action. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 11) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC50) at 4 hours, 24 hours, and 4 days at KRN5500 concentrations of 2.50 μM, 0.276 μM, and 0.139 μM, respectively. KRN5500 induced cellular injury via caspase-dependent apoptosis involving the intrinsic mitochondrial (caspase-9) initiating caspase and caspase-3 effector caspase; however, expression of the antiapoptotic mitochondrial membrane protein Bcl-2 was unaffected. These data demonstrate KRN5500 has significant in vitro activity against human CLL cells, thus providing support for introduction of this agent into clinical trials for patients with CLL.
Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial
Authors: Ekstrand Bradley C. , Lucas Jennifer B. , Horwitz Steven M. , Fan Zhen , Breslin Sheila , Hoppe Richard T. , Natkunam Yasodha , Bartlett Nancy L. , Horning Sandra J. 
Published: May 2003

Abstract
Lymphocyte-predominant Hodgkin disease (LPHD) is a unique clinical entity characterized by indolent nodal disease that tends to relapse after standard radiotherapy or chemotherapy. The malignant cells of LPHD are CD20+ and therefore rituximab may have activity with fewer late effects than standard therapy. In this phase 2 trial, 22 patients with CD20+ LPHD received 4 weekly doses of rituximab at 375 mg/m2. Ten patients had previously been treated for Hodgkin disease, while 12 patients had untreated disease. All 22 patients responded to rituximab (overall response rate, 100%) with complete response (CR) in 9 (41%), unconfirmed complete response in 1 (5%), and partial response in 12 (54%). Acute treatment-related adverse events were minimal. With a median follow-up of 13 months, 9 patients had relapsed, and estimated median freedom from progression was 10.2 months. Progressive disease was biopsied in 5 patients: 3 had recurrent LPHD, while 2 patients had transformation to large-cell non-Hodgkin lymphoma (LCL). All 3 patients with recurrent LPHD were retreated with rituximab, with a second CR seen in 1 patient and stable disease in 2. Rituximab induced prompt tumor reduction in each of 22 LPHD patients with minimal acute toxicity; however, based on the relatively short response duration seen in our trial and the concerns about transformation, rituximab should be considered investigational treatment for LPHD. Further clinical trials are warranted to determine the optimal dosing schedule of rituximab, the potential for combination treatment, and the possible relationship of rituximab treatment to the development of LCL.
RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation
Authors: Elagib Kamaleldin E. , Racke Frederick K. , Mogass Michael , Khetawat Rina , Delehanty Lorrie L. , Goldfarb Adam N. 
Published: May 2003

AbstractMegakaryocytic and erythroid lineages derive from a common bipotential progenitor and share many transcription factors, most prominently factors of the GATA zinc-finger family. Little is known about transcription factors unique to the megakaryocytic lineage that might program divergence from the erythroid pathway. To identify such factors, we used the K562 system in which megakaryocyte lineage commitment is dependent on sustained extracellular regulatory kinase (ERK) activation and is inhibited by stromal cell contact. During megakaryocytic induction in this system, the myeloid transcription factor RUNX1 underwent up-regulation, dependent on ERK signaling and inhibitable by stromal cell contact. Immunostaining of healthy human bone marrow confirmed a strong expression of RUNX1 and its cofactor, core-binding factor β (CBFβ), in megakaryocytes and a minimal expression in erythroblasts. In primary human hematopoietic progenitor cultures, RUNX1 and CBFβ up-regulation preceded megakaryocytic differentiation, and down-regulation of these factors preceded erythroid differentiation. Functional studies showed cooperation among RUNX1, CBFβ, and GATA-1 in the activation of a megakaryocytic promoter. By contrast, the RUNX1-ETO leukemic fusion protein potently repressed GATA-1–mediated transactivation. These functional interactions correlated with physical interactions observed between GATA-1 and RUNX1 factors. Enforced RUNX1 expression in K562 cells enhanced the induction of the megakaryocytic integrin proteins αIIb and α2. These results suggest that RUNX1 may participate in the programming of megakaryocytic lineage commitment through functional and physical interactions with GATA transcription factors. By contrast, RUNX1-ETO inhibition of GATA function may constitute a potential mechanism for the blockade of erythroid and megakaryocytic differentiation seen in leukemias with t(8;21).
Central venous line–related thrombosis in children: association with central venous line location and insertion technique
Authors: Male Christoph , Chait Peter , Andrew Maureen , Hanna Kim , Julian Jim , Mitchell Lesley ,   the PARKAA Investigators
Published: May 2003

AbstractVenous thromboembolic events (VTEs) in children are associated with central venous lines (CVLs). The study objective was to assess whether CVL location and insertion technique are associated with the incidence of VTE in children. We hypothesized that VTE would be more frequent with (1) CVL location on the left body side, (2) CVL location in the subclavian vein rather than the jugular vein, and (3) CVL insertion by percutaneous technique rather than venous cut-down. This was a prospective, multicenter cohort study in children with acute lymphoblastic leukemia who had a CVL placed in the upper venous system during induction chemotherapy. Characteristics of CVL were documented prospectively. All children had outcome assessment for VTE by objective radiographic tests, including bilateral venography, ultrasound, echocardiography, and cranial magnetic resonance imaging. Among 85 children, 29 (34%) had VTE; 28 VTEs appeared in the upper venous system, and 1 was sinovenous thrombosis. Left-sided CVL (odds ratio [OR], 2.5; 95% confidence interval, 1.0-6.4; P = .048), subclavian CVL (OR, 3.1; 95% CI, 1.2-8.5; P = .025), and percutaneous CVL insertion (OR, 3.5; 95% CI, 1.3-9.2; P = .011) were associated with an increased incidence of VTE. Interaction occurred between CVL vein location and insertion technique. Subclavian vein CVL inserted percutaneously had an increased incidence (54%) of VTE compared with any other combination (P = .07). For CVL in the upper venous system, CVL placement on the right side and in the jugular vein may reduce the risk for CVL-related VTE. If subclavian vein placement is necessary, CVL insertion by venous cut-down appears preferable over percutaneous insertion.
Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool
Authors: Jensen Peter D. , Jensen Finn T. , Christensen Thorkil , Eiskjær Hans , Baandrup Ulrik , Nielsen Johan L. 
Published: May 2003

Abstract
Evaluation of myocardial iron during iron chelation therapy is not feasible by repeated endomyocardial biopsies owing to the heterogeneity of iron distribution and the risk of complications. Recently, we described a noninvasive method based on magnetic resonance imaging. Here, the method was used for repeated estimation of the myocardial iron content during iron chelation with deferrioxamine in 14 adult nonthalassemic patients with transfusional iron overload. We investigated the repeatability of the method and the relationship between the myocardial iron estimates and iron status. The repeatability coefficient (2sD) was 2.8 μmol/g in the controls (day-to-day) and 4.0 μmol/g in the patients (within-day). Myocardial iron estimates were elevated in 10 of all 14 patients at first examination, but normalized in 6 patients after 6 to 18 months of treatment. If liver iron declined below 350 μmol/g all but one of the myocardial iron estimates were normal or nearly normal. At start (R2 = 0.69, P = .0014) and still after 6 months of iron chelation (R2 = 0.76, P = .001), the estimates were significantly and more closely related to the urinary iron excretion than to liver iron or serum ferritin levels. In conclusion, our preliminary data, which may only pertain to patients with acquired anemias, suggest the existence of a critical liver iron concentration, above which elevated myocardial iron is present, but its extent seems related to the size of the chelatable iron pool, as reflected by the urinary iron excretion. This further supports the concept of the labile iron pool as the compartment directly involved in transfusional iron toxicity.
Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sézary syndrome
Authors: Lundin Jeanette , Hagberg Hans , Repp Roland , Cavallin-Ståhl Eva , Fredén Susanne , Juliusson Gunnar , Rosenblad Eija , Tjønnfjord Geir , Wiklund Tom , Österborg Anders 
Published: May 2003

AbstractThis phase 2 study evaluated the safety and efficacy of alemtuzumab in 22 patients with advanced mycosis fungoides/Sézary syndrome (MF/SS). Most patients had stage III or IV disease, reduced performance status, and severe itching. The overall response (OR) rate was 55%, with 32% of patients in complete remission (CR) and 23% in partial remission (PR). Sézary cells were cleared from the blood in 6 of 7 (86%) patients, and CR in lymph nodes was observed in 6 of 11 (55%) patients. The effect was better on erythroderma (OR, 69%) than on plaque or skin tumors (OR, 40%) and in patients who had received 1 to 2 previous regimens (OR, 80%) than in those who had received 3 or more prior regimens (OR, 33%). Itching, self-assessed on a 0 to 10 visual analog scale, was reduced from a median of 8 before treatment to 2 at end of therapy. Median time to treatment failure was 12 months (range, 5-32+ months). Cytomegalovirus (CMV) reactivation (causing fever without pneumonitis and responding to ganciclovir) occurred in 4 (18%) patients. Six additional patients had suspect or manifest infection (fever of unknown origin, 3; generalized herpes simplex, 1; fatal aspergillosis, 1). One patient had fatal Mycobacterium pneumonia at 10+ months. All serious infectious adverse events (except CMV) occurred in patients who had received 3 or more prior regimens. Progression of squamous cell skin carcinoma was noted in 1 patient. Alemtuzumab shows promising clinical activity and an acceptable safety profile in patients with advanced MF/SS, particularly in patients with erythroderma and severe itching and those who were not heavily pretreated.
Impaired recovery of Epstein-Barr virus (EBV)—specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease
Authors: Meij Pauline , van Esser Joost W. J. , Niesters Hubert G. M. , van Baarle Debbie , Miedema Frank , Blake Neil , Rickinson Alan B. , Leiner Ingrid , Pamer Eric , Löwenberg Bob , Cornelissen Jan J. , Gratama Jan W. 
Published: May 2003

AbstractEpstein-Barr virus (EBV)—specific cytotoxic T lymphocytes are considered pivotal to prevent lymphoproliferative disease (LPD) in allogeneic stem cell transplantation (SCT) recipients. We evaluated the recovery of EBV-specific CD8+ T cells after partially T-cell—depleted SCT and studied the interaction between EBV-specific CD8+ T cells, EBV reactivation, and EBV-LPD. EBV-specific CD8+ T cells were enumerated using 12 class I HLA tetramers presenting peptides derived from 7 EBV proteins. Blood samples were taken at regular intervals after SCT in 61 patients, and EBV DNA levels were assessed by real-time polymerase chain reaction. Forty-five patients showed EBV reactivation, including 25 with high-level reactivation (ie, more than 1000 genome equivalents [geq] per milliliter). Nine of these 25 patients progressed to EBV-LPD. CD8+ T cells specific for latent or lytic EBV epitopes repopulated the peripheral blood at largely similar rates. In most patients, EBV-specific CD8+ T-cell counts had returned to normal levels within 6 months after SCT. Concurrently, the incidence of EBV reactivations clearly decreased. Patients with insufficient EBV-specific CD8+ T-cell recovery were at high risk for EBV reactivation in the first 6 months after SCT. Failure to detect EBV-specific CD8+ T cells in patients with high-level reactivation was associated with the subsequent development of EBV-LPD (P = .048). Consequently, the earlier defined positive predictive value of approximately 40%, based on high-level EBV reactivation only, increased to 100% in patients without detectable EBV-specific CD8+ T cells. Thus, impaired recovery of EBV-specific CD8+ T cells in patients with high-level EBV reactivation may identify a subgroup at very high risk for EBV-LPD and supports that EBV-specific CD8+ T cells protect SCT recipients from progressive EBV reactivation and EBV-LPD.