bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells
Authors: McAllister Shane C. , Hansen Scott G. , Ruhl Rebecca A. , Raggo Camilo M. , DeFilippis Victor R. , Greenspan Deborah , Früh Klaus , Moses Ashlee V. 
Published: January 2004

Abstract
Kaposi sarcoma (KS) is the most common AIDS-associated malignancy and is characterized by angiogenesis and the presence of spindle cells. Kaposi sarcoma-associated herpesvirus (KSHV) is consistently associated with all clinical forms of KS, and in vitro infection of dermal microvascular endothelial cells (DMVECs) with KSHV recapitulates many of the features of KS, including transformation, spindle cell proliferation, and angiogenesis. To study the molecular mechanisms of KSHV pathogenesis, we compared the protein expression profiles of KSHV-infected and uninfected DMVECs. This comparison revealed that heme oxygenase-1 (HO-1), the inducible enzyme responsible for the rate-limiting step in heme catabolism, was up-regulated in infected endothelial cells. Recent evidence suggests that the products of heme catabolism have important roles in endothelial cell biology, including apoptosis and angiogenesis. Here we show that HO-1 mRNA and protein are up-regulated in KSHV-infected cultures. Comparison of oral and cutaneous AIDS-KS tissues with normal tissues revealed that HO-1 mRNA and protein were also up-regulated in vivo. Increased HO-1 enzymatic activity in vitro enhanced proliferation of KSHV-infected DMVECs in the presence of free heme. Treatment with the HO-1 inhibitor chromium mesoporphyrin IX abolished heme-induced proliferation. These data suggest that HO-1 is a potential therapeutic target for KS that warrants further study. (Blood. 2004;103: 3465-3473)
Donor treatment with pegylated G-CSF augments the generation of IL-10-producing regulatory T cells and promotes transplantation tolerance
Authors: Morris Edward S. , MacDonald Kelli P. A. , Rowe Vanessa , Johnson Diana H. , Banovic Tatjana , Clouston Andrew D. , Hill Geoffrey R. 
Published: January 2004

AbstractWe investigated whether the protection from graft-versus-host disease (GVHD) afforded by donor treatment with granulocyte colony-stimulating factor (G-CSF) could be enhanced by dose escalation. Donor treatment with human G-CSF prevented GVHD in the B6 → B6D2F1 murine model in a dose-dependent fashion, and murine G-CSF provided equivalent protection from GVHD at 10-fold lower doses. Donor pretreatment with a single dose of pegylated G-CSF (peg-G-CSF) prevented GVHD to a significantly greater extent than standard G-CSF (survival, 75% versus 11%, P &lt; .001). Donor T cells from peg-G-CSF-treated donors failed to proliferate to alloantigen and inhibited the responses of control T cells in an interleukin 10 (IL-10)-dependent fashion in vitro. T cells from peg-G-CSF-treated IL-10-/- donors induced lethal GVHD; T cells from peg-G-CSF-treated wild-type (wt) donors promoted long-term survival. Whereas T cells from peg-G-CSF wt donors were able to regulate GVHD induced by T cells from control-treated donors, T cells from G-CSF-treated wt donors and peg-G-CSF-treated IL-10-/- donors did not prevent mortality. Thus, peg-G-CSF is markedly superior to standard G-CSF for the prevention of GVHD following allogeneic stem cell transplantation (SCT), due to the generation of IL-10-producing regulatory T cells. These data support prospective clinical trials of peg-G-CSF-mobilized allogeneic blood SCT. (Blood. 2004;103:3573-3581)
Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication
Authors: Gammaitoni Loretta , Weisel Katja C. , Gunetti Monica , Wu Kai-Da , Bruno Stefania , Pinelli Silvana , Bonati Antonio , Aglietta Massimo , Moore Malcolm A. S. , Piacibello Wanda 
Published: January 2004

Abstract
Telomerase activity, telomere length, stem/progenitor cell production, and function of CD34+ cells from cord blood (CB), bone marrow, and mobilized peripheral blood were evaluated in long-term cultures. CB cells were cultured either on OP-9 stromal cells transduced with an adenovector expressing thrombopoietin (TPO) or stimulated by a cytokine cocktail in the absence of stroma, with, in one method, CD34+ cells reisolated at monthly intervals for passage. Continuous expansion of stem cells as measured by in vitro cobblestone area and secondary colony-forming assays was noted for 18 to 20 weeks and by severe combined immunodeficiency (SCID)-repopulating cells (SRCs), capable of repopulating and serially passage in nonobese diabetic/SCID mice, for 16 weeks. Despite this extensive proliferation, telomere length initially increased and only at late stages of culture was evidence of telomere shortening noted. This telomere stabilization correlated with maintenance of high levels of telomerase activity in the CD34+ cell population for prolonged periods of culture. Cytokine-stimulated cultures of adult CD34+ cells showed CD34+ and SRC expansion (6-fold) for only 3 to 4 weeks with telomere shortening and low levels of telomerase. There is clearly a clinical value for a system that provides extensive stem cell expansion without concomitant telomere erosion. (Blood. 2004;103:4440-4448)
T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease
Authors: Heinonen Krista M. , Nestel Frederick P. , Newell Evan W. , Charette Gabrielle , Seemayer Thomas A. , Tremblay Michel L. , Lapp Wayne S. 
Published: January 2004

AbstractThe deregulation of the immune response is a critical component in inflammatory disease. Recent in vitro data show that T-cell protein tyrosine phosphatase (TC-PTP) is a negative regulator of cytokine signaling. Furthermore, tc-ptp-/- mice display immune defects and die within 5 weeks of birth. We report here that tc-ptp-/- mice develop progressive systemic inflammatory disease as shown by chronic myocarditis, gastritis, nephritis, and sialadenitis as well as elevated serum interferon-γ. The widespread mononuclear cellular infiltrates correlate with exaggerated interferon-γ, tumor necrosis factor-α, interleukin-12, and nitric oxide production in vivo. Macrophages grown from tc-ptp-/- mice are inherently hypersensitive to lipopolysaccharide, which can also be detected in vivo as an increased susceptibility to endotoxic shock. These results identify T-cell protein tyrosine phosphatase as a key modulator of inflammatory signals and macrophage function. (Blood. 2004;103:3457-3464)
Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity
Authors: Rajagopalan Sanjay , Somers Emily C. , Brook Robert D. , Kehrer Christine , Pfenninger Dana , Lewis Emily , Chakrabarti Anjan , Richardson Bruce C. , Shelden Eric , McCune W. Joseph , Kaplan Mariana J. 
Published: January 2004

AbstractWomen with systemic lupus erythematosus (SLE) are at risk for premature atherothrombosis independent of Framingham risk factors. We investigated whether endothelial cell (EC) apoptosis predicts abnormal vasomotor tone and contributes to circulating tissue factor (TF) levels in this disease. Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were determined in women with SLE, healthy control subjects, and subjects with coronary artery disease (CAD) (n = 43/group). Quantification of circulating apoptotic ECs was performed by flow cytometry (CD146+ cells that stained for Annexin V [CD146AnnV+]) and immunofluorescent microscopy. Plasma TF was measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy control and CAD subjects, patients with SLE had higher numbers of circulating CD146AnnV+ cells (10 ± 3, 18 ± 5, and 89 ± 32 cells/mL, respectively, mean ± SEM; P &lt; .01). Increased CD146AnnV+ cells correlated strongly with abnormal vascular function (P = .037). After adjusting for known predictors of endothelial function, CD146AnnV+ was the only variable that predicted FMD (β = –4.5, P &lt; .001). Increased CD146AnnV+ was strongly associated with elevated levels of circulating TF (r = .46, P = .002). Circulating apoptotic ECs are elevated in young women with SLE and strongly correlate with markedly abnormal vascular function and elevated TF levels. Heightened endothelial apoptosis may represent an important mechanism for development of atherothrombosis in SLE.
SCL is required for normal function of short-term repopulating hematopoietic stem cells
Authors: Curtis David J. , Hall Mark A. , Van Stekelenburg Leonie J. , Robb Lorraine , Jane Stephen M. , Begley C. Glenn 
Published: January 2004

AbstractThe stem cell leukemia (SCL) gene is essential for the development of hematopoietic stem cells in the embryo. Here, we used a conditional gene targeting approach to examine the function of SCL in adult hematopoietic stem cells (HSCs). Flow cytometry of bone marrow from SCL-deleted mice demonstrated a 4-fold increase in number of Linneg c-kit+ Sca-1+ cells. Despite this increase in the number of phenotypic HSCs, competitive repopulation assays demonstrated a severe multilineage defect in repopulation capacity by SCL-deleted bone marrow cells. SCL-heterozygous cells also showed a mild repopulation defect, thus suggesting haploinsufficiency of SCL. The transplantation defect of SCL-deleted cells was observed within 4 weeks of transplantation, indicating a defect in a multipotent progenitor or short-term repopulating HSCs. Although the defect persisted in secondary transplants, it remained relatively stable, suggesting that SCL was not required for self-renewal of the HSCs. Generation of SCL-deleted cells within SCL-wild-type mice rescued the early repopulating defect. Together, our results suggest that SCL is required for the normal function of short-term repopulating HSCs. (Blood. 2004;103:3342-3348)
Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection
Authors: Farel Claire E. , Chaitt Doreen G. , Hahn Barbara K. , Tavel Jorge A. , Kovacs Joseph A. , Polis Michael A. , Masur Henry , Follmann Dean A. , Lane H. Clifford , Davey Richard T. 
Published: January 2004

AbstractStudies establishing that intermittent subcutaneous interleukin-2 (IL-2) therapy can lead to substantial CD4 cell increases in many HIV-infected patients have generally been of limited duration. We studied 77 patients participating in active longitudinal studies of subcutaneous IL-2 therapy at our center in order to determine the long-term feasibility of this approach. Following initial induction, patients in each trial were eligible to receive intermittent 5-day cycles of subcutaneous IL-2 treatment at individualized doses and frequencies capable of maintaining CD4 counts at postinduction levels. The mean duration of study participation to date is 5.9 years (range, 1.0-9.3 years). Mean baseline CD4 cell count and CD4 percent values of 0.521 × 109/L (521 cells/μL) and 27% have risen to 1.005 × 109/L (1005 cells/μL) and 38%, respectively, at 90 months. The mean number of subcutaneous IL-2 cycles required to achieve and maintain these increases was 10 cycles (range, 3-29 cycles), and the current mean interval of cycling required to maintain these elevations is 39 months (median, 35 months; range, 2-91 months). We conclude that subcutaneous IL-2 therapy is capable of maintaining CD4 cell increases for an extended period using a remarkably low frequency of intermittent cycling. These observations may contribute to patients' acceptance of subcutaneous IL-2 as a favorable long-term treatment strategy. (Blood. 2004;103:3282-3286)
Proteomics techniques and their application to hematology
Authors: Cristea Ileana M. , Gaskell Simon J. , Whetton Anthony D. 
Published: January 2004

AbstractThe recent sequencing of a number of genomes has raised the level of opportunities for studies on proteins. This area of research has been described with the all-embracing term, proteomics. In proteomics, the use of mass spectrometric techniques enables genomic databases to be used to establish the identity of proteins with relatively little data, compared to the era before genome sequencing. The use of related analytical techniques also offers the opportunity to gain information on regulation, via posttranslational modification, and potential new diagnostic and prognostic indicators. Relative quantification of proteins and peptides in cellular and extracellular material remains a challenge for proteomics and mass spectrometry. This review presents an analysis of the present and future impact of these proteomic technologies with emphasis on relative quantification for hematologic research giving an appraisal of their potential benefits.
SAP mediates specific cytotoxic T-cell functions in X-linked lymphoproliferative disease
Authors: Sharifi Reza , Sinclair Joanna C. , Gilmour Kimberly C. , Arkwright Peter D. , Kinnon Christine , Thrasher Adrian J. , Gaspar H. Bobby 
Published: January 2004

AbstractCytotoxic T cells (CTLs) and natural killer cells play a major role in the immune response to Epstein-Barr virus (EBV) infection. In X-linked lymphoproliferative (XLP) disease, a severe immunodeficiency, immunodysregulatory phenomena are observed following EBV infection, suggesting that defects exist in these effector populations. The gene defective in XLP is SAP (signaling lymphocytic activation molecule [SLAM]–associated protein), an adaptor protein that mediates signals through SLAM and other immunoglobulin superfamily receptors including 2B4. We generated EBV-specific T-cell lines from controls and XLP patients and examined CTL function in response to different stimuli. We show that XLP patients can generate EBV–T-cell lines that are phenotypically similar to those from controls. XLP patient EBV–T-cell lines showed a significant decrease in interferon-gamma (IFN-γ) production in response to 2B4 and autologous EBV-transformed lymphoblastoid cell line (LCL) stimulation but not in response to SLAM. Furthermore, XLP EBV–T-cell lines demonstrated markedly decreased cytotoxic activity against autologous LCLs. By retroviral gene transfer of the SAP gene into XLP EBV–T-cell lines, we show reconstitution of IFN-γ production and of cytotoxic activity confirming SAP-dependent defects. These studies demonstrate that in XLP the lack of SAP affects specific signaling pathways resulting in severe disruption of CTL function.
Bioengineering of coagulation factor VIII for improved secretion
Authors: Miao Hongzhi Z. , Sirachainan Nongnuch , Palmer Lisa , Kucab Phillip , Cunningham Michael A. , Kaufman Randal J. , Pipe Steven W. 
Published: January 2004

AbstractFactor VIII (FVIII) functions as a cofactor within the intrinsic pathway of blood coagulation. Quantitative or qualitative deficiencies of FVIII result in the inherited bleeding disorder hemophilia A. Expression of FVIII (domain structure A1-A2-B-A3-C1-C2) in heterologous mammalian systems is 2 to 3 orders of magnitude less efficient compared with other proteins of similar size compromising recombinant FVIII production and gene therapy strategies. FVIII expression is limited by unstable mRNA, interaction with endoplasmic reticulum (ER) chaperones, and a requirement for facilitated ER to Golgi transport through interaction with the mannose-binding lectin LMAN1. Bioengineering strategies can overcome each of these limitations. B-domain-deleted (BDD)-FVIII yields higher mRNA levels, and targeted point mutations within the A1 domain reduce interaction with the ER chaperone immunoglobulin-binding protein. In order to increase ER to Golgi transport we engineered several asparagine-linked oligosaccharides within a short B-domain spacer within BDD-FVIII. A bioengineered FVIII incorporating all of these elements was secreted 15- to 25-fold more efficiently than full-length FVIII both in vitro and in vivo. FVIII bioengineered for improved secretion will significantly increase potential for success in gene therapy strategies for hemophilia A as well as improve recombinant FVIII production in cell culture manufacturing or transgenic animals. (Blood. 2004;103: 3412-3419)
X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival
Authors: Nishikomori Ryuta , Akutagawa Hiroshi , Maruyama Kyoko , Nakata-Hizume Mami , Ohmori Katsuyuki , Mizuno Kazunori , Yachie Akihiro , Yasumi Takahiro , Kusunoki Takashi , Heike Toshio , Nakahata Tatsutoshi 
Published: January 2004

AbstractX-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID) is an X-linked recessive disease caused by a mutation in the nuclear factor-κB (NF-κB) essential modulator (NEMO). Here we report an XL-EDA-ID patient with atypical features of very few naive-phenotype T cells and defective mitogen-induced proliferation of peripheral blood mononuclear cells (PBMCs). The patient's NEMO defect was diagnosed by flow cytometric analysis of intracellular NEMO staining. Specific cell lineages (monocytes and neutrophils) expressed reduced levels of NEMO, but 2 populations of T, B, and NK cells were detected with normal and reduced expression of NEMO. Genomic analysis revealed that duplication of a 4.4-kb sequence ranging from intron 3 to exon 6 caused the reduced expression of NEMO. Polymorphism analysis showed that the patient's B- and T-cell lines with reduced and normal expression of NEMO had the same X chromosome, indicating that the somatic mosaicism was not due to fetomaternal transfusion but was most likely due to postzygotic reversion. This XLEDA-ID case adds to our understanding of NEMO biology, indicating that NEMO is critical for T-cell development and/or survival in humans as well as in mice. (Blood. 2004;103:4565-4572)
Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions
Authors: Lozanski Gerard , Heerema Nyla A. , Flinn Ian W. , Smith Lisa , Harbison Jennifer , Webb Jennifer , Moran Mollie , Lucas Margaret , Lin Thomas , Hackbarth Marcy L. , Proffitt John H. , Lucas David , Grever Michael R. , Byrd John C. 
Published: January 2004

Abstract
The presence of p53 mutation or deletion predicts for poor response to conventional therapy in chronic lymphocytic leukemia (CLL). We sought to determine whether the humanized anti-CD52 antibody alemtuzumab was effective in this patient group. Thirty-six patients with fludarabine-refractory CLL were treated with alemtuzumab, 15 (42%) of whom had p53 mutations or deletions. Clinical responses in patients with p53 mutations, deletions, or both were noted in 6 (40%) of 15 versus 4 (19%) of 21 of patients without. The median response duration for this subset of patients was 8 months (range, 3-17 months). These data suggest that alemtuzumab may be an effective therapy for patients with CLL with p53 mutations or deletions. (Blood. 2004;103:3278-3281)
Hematopoiesis is severely altered in mice with an induced osteoblast deficiency
Authors: Visnjic Dora , Kalajzic Zana , Rowe David W. , Katavic Vedran , Lorenzo Joseph , Aguila Hector L. 
Published: January 2004

AbstractWe previously reported a transgenic mouse model expressing herpesvirus thymidine kinase (TK) gene under the control of a 2.3-kilobase fragment of the rat collagen α1 type I promoter (Col2.3ΔTK). This construct confers lineage-specific expression in developing osteoblasts, allowing the conditional ablation of osteoblast lineage after treatment with ganciclovir (GCV). After GCV treatment these mice have profound alterations on bone formation leading to a progressive bone loss. In addition, treated animals also lose bone marrow cellularity. In this report we characterized hematopoietic parameters in GCV-treated Col2.3ΔTK mice, and we show that after treatment transgenic animals lose lymphoid, erythroid, and myeloid progenitors in the bone marrow, followed by decreases in the number of hematopoietic stem cells (HSCs). Together with the decrease in bone marrow hematopoiesis, active extramedullary hematopoiesis was observed in the spleen and liver, as measured by an increase in peripheral HSCs and active primary in vitro hematopoiesis. After withdrawal of GCV, osteoblasts reappeared in the bone compartment together with a recovery of medullary and decrease in extramedullary hematopoiesis. These observations directly demonstrate the role of osteoblasts in hematopoiesis and provide a model to study the interactions between the mesenchymal and hematopoietic compartments in the marrow. (Blood. 2004; 103:3258-3264)
Case report: fatal poisoning with Colchicum autumnale
Authors: Brvar Miran , Ploj Tom , Kozelj Gordana , Mozina Martin , Noc Marko , Bunc Matjaz 
Published: January 2004

Abstract
Introduction
Colchicum autumnale, commonly known as the autumn crocus, contains alkaloid colchicine with antimitotic properties.

Case report
A 76-year-old man with a history of alcoholic liver disease and renal insufficiency, who mistakenly ingested Colchicum autumnale instead of wild garlic (Aliium ursinum), presented with nausea, vomiting and diarrhea 12 hours after ingestion. On admission the patient had laboratory signs of dehydration. On the second day the patient became somnolent and developed respiratory insufficiency. The echocardiogram showed heart dilatation with diffuse hypokinesia with positive troponin I. The respiratory insufficiency was further deteriorated by pneumonia, confirmed by chest X-ray and later on by autopsy. Laboratory tests also revealed rhabdomyolysis, coagulopathy and deterioration of renal function and hepatic function. The toxicological analysis disclosed colchicine in the patient's urine (6 μg/l) and serum (9 μg/l) on the second day. Therapy was supportive with hydration, vasopressors, mechanical ventilation and antibiotics. On the third day the patient died due to asystolic cardiac arrest.

Discussion and conclusion
Colchicine poisoning should be considered in patients with gastroenterocolitis after a meal of wild plants. Management includes only intensive support therapy. A more severe clinical presentation should be expected in patients with pre-existing liver and renal diseases. The main reasons for death are cardiovascular collapse, respiratory failure and leukopenia with infection.
Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene
Authors: Burnett Sandra H , Kershen Edward J , Zhang Jiayou , Zeng Li , Straley Susan C , Kaplan Alan M , Cohen Donald A 
Published: January 2004

AbstractTransgenic mice expressing an inducible suicide gene, which allows systemic and reversible elimination of macrophages, were developed. A macrophage-specific c-fms promoter was used to express enhanced green fluorescent protein and a drug-inducible suicide gene that leads to Fas-mediated apoptosis in resting and cycling cells of the macrophage lineage. Transgenic mice were fertile, of normal weight, and showed no abnormal phenotype before drug exposure. The transgene was expressed constitutively in macrophages and dendritic cells (DC) but not significantly in T cells or B cells. Induction of the suicide gene led to depletion of 70–95% of macrophages and DC in nearly all tissues examined. Depletion reduced the ability to clear bacteria from the blood and led to increased bacterial growth in the liver. Depleted mice displayed several abnormalities, including splenomegaly, lymphadenopathy, thymic atrophy, extramedullary hematopoiesis, and development of peritoneal adhesions. This new, transgenic line will be useful in investigating the role of macrophages and DC.