bluuebunny/crossref_metadata_2025 huggingface dataset:
Expansion of cytolytic CD8+ natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon γ production
Authors: Baker Jeanette , Verneris Michael R. , Ito Maki , Shizuru Judith A. , Negrin Robert S.
Published: July 2002

T cells with natural killer cell phenotype and function (NKT cells) have been described in both human and murine tissues. In this study, culture conditions were developed that resulted in the expansion of CD8+ NKT cells from bone marrow, thymus, and spleen by the timed addition of interferon-γ (IFN-γ), interleukin 2 (IL-2), and anti-CD3 monoclonal antibody. After 14 to 21 days in culture, dramatic expansion of CD3+, CD8+, αβT-cell receptor+ T cells resulted with approximately 20% to 50% of the cells also expressing the NK markers NK1.1 and DX5. The CD8+ NKT cells demonstrated lytic activity against several tumor target cells with more than 90% lysis by day 14 to day 21 of culture. Cytotoxicity was observed against both syngeneic and allogeneic tumor cell targets with the greatest lytic activity by the cells expressing either NK1.1 or DX5. The expanded CD8+ NKT cells produce TH1-type cytokines with high levels of IFN-γ and tumor necrosis factor α. Expansion of the CD8+ NKT cells was independent of CD1d. Ly49 molecules were expressed on only a minority of cells. A single injection of expanded CD8+ NKT cells was capable of protecting syngeneic animals from an otherwise lethal dose of Bcl1 leukemia cells. Expanded CD8+ NKT cells produced far less graft-versus-host disease (GVHD) than splenocytes across major histocompatibility barriers, even when 10 times the number of CD8+ NKT cells as compared to splenocytes were injected. This reduction in GVHD was related to IFN-γ production since cells expanded from IFN-γ knock-out animals caused acute lethal GVHD, whereas cells expanded from animals defective in fas ligand, fas, IL-2, and perforin did not. These data indicate that CD8+ NKT cells expanded in this fashion could be useful for preserving graft-versus-leukemia activity without causing GVHD.
Hypoxia induces lytic replication of Kaposi sarcoma–associated herpesvirus
Authors: Davis David A. , Rinderknecht Andrea S. , Zoeteweij J. Paul , Aoki Yoshiyasu , Read-Connole Elizabeth L. , Tosato Giovanna , Blauvelt Andrew , Yarchoan Robert
Published: July 2002

There is substantial evidence that Kaposi sarcoma–associated herpesvirus (KSHV) plays an important role in the pathogenesis of all forms of Kaposi sarcoma (KS). It has been noted that KS commonly occurs in locations, such as the feet, where tissue may be poorly oxygenated. On the basis of this observation, the potential role of hypoxia in the reactivation of KSHV replication was explored by studying 2 KSHV-infected primary effusion lymphoma B-cell lines (BC-3 and BCBL-1) latently infected with KSHV. Acute and chronic exposure of these cells to hypoxia (1% O2) induced KSHV lytic replication, as indicated by an increase in intracellular lytic protein expression and detection of virus in cell supernatants by Western immunoblotting. In addition, hypoxia increased the levels of secreted viral interleukin-6. Moreover, hypoxia enhanced the lytic replication initiated by the viral inducer 12-O-tetradecanoylphorbol-13-acetate. Desferoxamine and cobalt chloride, 2 compounds that increase the intracellular levels of hypoxia-inducible factor 1, were also able to induce KSHV lytic replication. These studies suggest that hypoxia is an inducer of KSHV replication. This process may play an important role in the pathogenesis of KS.
Induction of stable prenatal tolerance to β-galactosidase by in utero gene transfer into preimmune sheep fetuses
Authors: Tran Nam D. , Porada Christopher D. , Almeida-Porada Graça , Glimp Hudson A. , Anderson W. French , Zanjani Esmail D.
Published: July 2002

The successful transduction of hematopoietic stem cells and long-term (28 months) transgene expression within the hematopoietic system following the direct injection of high-titer retroviral vectors into preimmune fetal sheep was previously demonstrated. The present studies extended these analyses for 40 months postinjection and evaluated whether the longevity of transgene expression in this model system was the result of induction of prenatal tolerance to the transgene product. The intraperitoneal injection of retroviral vectors into preimmune sheep fetuses transduces thymic epithelial cells thought to present antigen and thus define self during immune system development. To directly demonstrate induction of tolerance, postnatal sheep were boosted with purified β-galactosidase and showed that the peripheral blood lymphocytes from in utero–transduced sheep exhibited significantly lower stimulation indices to transduced autologous cells than did control animals and that the in utero–transduced sheep had a reduced ability to mount an antibody response to the vector-encoded β-galactosidase protein compared with control sheep. Collectively, our results provide evidence that the direct injection of retroviral vectors into preimmune sheep fetuses induces cellular and humoral tolerance to the vector/transgene products and provide an explanation for the duration and stability of transgene expression seen in this model. These results also suggest that even relatively low levels of gene transfer in utero may render the recipient tolerant to the exogenous gene and thus potentially permit the successful postnatal treatment of the recipient.
Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin
Authors: Wagner Klaus F. , Katschinski Dörthe M. , Hasegawa Jo , Schumacher Dunja , Meller Birgit , Gembruch Ulrich , Schramm Uda , Jelkmann Wolfgang , Gassmann Max , Fandrey Joachim
Published: July 2002

The most common cause of an increase of the hematocrit is secondary to elevated erythropoietin levels. Erythrocytosis is assumed to cause higher blood viscosity that could put the cardiovascular system at hemodynamic and rheological risks. Secondary erythrocytosis results from tissue hypoxia, and one can hardly define what cardiovascular consequences are caused by chronic erythrocytosis or hypoxia. Herein, a novel transgenic (tg) mouse line is characterized that is erythrocytotic because of chronic overexpression of the human erythropoietin gene. These mice grow up well, reaching a hematocrit of about 0.80 in adulthood. Blood volume of adult tg mice was markedly increased by 75%. Unexpectedly, blood pressure was not elevated and cardiac output was not decreased. Still, the adult tg mice showed features of cardiac dysfunction with increased heart weight. In vivo, high-frequency echocardiography revealed marked ventricular dilatation that was confirmed by histologic examination. Furthermore, by transmission electron microscopy, a prominent intracellular edema of the cardiomyocytes was seen. Exercise performance of the tg mice was dramatically reduced, unmasking the severity of their compromised cardiovascular function. In addition, life expectancy of the tg mice was significantly reduced to 7.4 months. Our findings suggest that severe erythrocytosis per se results in cardiac dysfunction and markedly reduced life span.
Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress–mediated vasodilation
Authors: Belhassen Laurent , Pelle Gabriel , Sediame Saı̈d , Bachir Dora , Carville Claudine , Bucherer Catherine , Lacombe Catherine , Galacteros Frederic , Adnot Serge
Published: July 2002

Interactions between the endothelium and erythrocytes may contribute to the vascular complications of sickle cell disease (SCD). Endothelium-derived nitric oxide (NO) plays a major role in the regulation of vasomotor tone in response to wall shear stress (WSS) variations and pharmacologic stimuli. However, little is known about endothelial NO production in patients with steady-state SCD. We investigated endothelial NO production in response to flow or vasoactive agonists in 16 homozygous patients with steady-state SCD and 15 controls. Flow-mediated dilation (FMD), arterial diameter changes in response to 100% oxygen inhalation, blood viscosity, and calculated WSS were determined in all patients and controls. At baseline, WSS was higher in SCD patients than in controls, whereas arterial diameter was similar. In patients with SCD, FMD was impaired (1.73% ± 0.44% vs 3.97% ± 0.24% in the controls, P < .001) and vasoconstriction in response to 100% oxygen was abolished. Using venous occlusion plethysmography, forearm blood flow (FBF) was evaluated in response to acetylcholine, nitro-monomethyl-L-arginine (L-NMMA), and sodium nitroprusside (SNP) in subgroups of 9 controls and 7 patients with SCD. Acetylcholine induced a significantly greater FBF increase in the patients (9.7 ± 2.9 mL/min/100 mL of forearm volume vs 2.5 ± 1.5 mL/min/100 mL in the controls,P < .001), whereas responses to L-NMMA and SNP were similar. These results suggest that endothelial dysfunction may prevent the arterial diameter of patients with SCD from adapting to chronic or acute shear stress elevations. This may contribute to the pathophysiology of vaso-occlusive crisis in patients with SCD.
Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation
Authors: Maertens Johan , Verhaegen Jan , Lagrou Katrien , Van Eldere Johan , Boogaerts Marc
Published: July 2002

The diagnosis of invasive aspergillosis (IA) in patients with hematologic disorders is not straightforward; lack of sensitive and specific noninvasive diagnostic tests remains a major obstacle for establishing a precise diagnosis. In a series of 362 consecutive high-risk treatment episodes that were stratified according to the probability of IA based on recently accepted case definition sets, the potential for diagnosis of serial screening for circulating galactomannan (GM), a major aspergillar cell wall constituent was validated. After incorporating postmortem findings to allow a more accurate final analysis, this approach proved to have a sensitivity of 89.7% and a specificity of 98.1%. The positive and negative predictive values equaled 87.5% and 98.4%, respectively. False-positive reactions occurred at a rate of 14%, although this figure might be overestimated due to diagnostic uncertainty. More or less stringent criteria of estimation could highly influence sensitivity, which ranged from 100% to 42%; the impact on other test statistics was far less dramatic. All proven cases of IA, including 23 cases confirmed after autopsy only, had been detected before death, although serial sampling appeared to be necessary to maximize detection. The excellent sensitivity and negative predictive value makes this approach suitable for clinical decision making. Unfortunately, given the species-specificity of the assay, some emerging non-Aspergillus mycoses were not detected. In conclusion, serial screening for GM, complemented by appropriate imaging techniques, is a sensitive and noninvasive tool for the early diagnosis of IA in high-risk adult hematology patients.
Apolipoprotein A-I inhibits the production of interleukin-1β and tumor necrosis factor-α by blocking contact-mediated activation of monocytes by T lymphocytes
Authors: Hyka Nevila , Dayer Jean-Michel , Modoux Christine , Kohno Tadahiko , Edwards Carl K. , Roux-Lombard Pascale , Burger Danielle
Published: July 2002

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), essential components in the pathogenesis of immunoinflammatory diseases, are strongly induced in monocytes by direct contact with stimulated T lymphocytes. This study demonstrates that adult human serum (HS) but not fetal calf or cord blood serum displays inhibitory activity toward the contact-mediated activation of monocytes by stimulated T cells, decreasing the production of both TNF-α and IL-1β. Fractionation of HS and N-terminal microsequencing as well as electroelution of material subjected to preparative electrophoresis revealed that apolipoprotein A-I (apo A-I), a “negative” acute-phase protein, was the inhibitory factor. Functional assays and flow cytometry analyses show that high-density lipoprotein (HDL)-associated apo A-I inhibits contact-mediated activation of monocytes by binding to stimulated T cells, thus inhibiting TNF-α and IL-1β production at both protein and messenger RNA levels. Furthermore, apo A-I inhibits monocyte inflammatory functions in peripheral blood mononuclear cells activated by either specific antigens or lectins without affecting cell proliferation. These results demonstrate a new anti-inflammatory activity of HDL-associated apo A-I that might have modulating functions in nonseptic conditions. Therefore, because HDL has been shown to bind and neutralize lipopolysaccharide, HDL appears to play an important part in modulating both acute and chronic inflammation. The novel anti-inflammatory function of apo A-I reported here might lead to new therapeutic approaches in inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and atherosclerosis.
RELT, a new member of the tumor necrosis factor receptor superfamily, is selectively expressed in hematopoietic tissues and activates transcription factor NF-κB
Authors: Sica Gabriel L. , Zhu Gefeng , Tamada Koji , Liu Ding , Ni Jian , Chen Lieping
Published: July 2002

The members of tumor necrosis factor receptor (TNFR) superfamily have been designated as the “guardians of the immune system” due to their roles in immune cell proliferation, differentiation, activation, and death (apoptosis). This study reports the cloning of a new member of the TNFR superfamily, RELT (ReceptorExpressed in Lymphoid Tissues). RELT is a type I transmembrane glycoprotein with a cysteine-rich extracellular domain, possessing significant homology to other members of the TNFR superfamily, especially TNFRSF19, DR3, OX40, and LTβ receptor. The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-κB pathway and selectively binds tumor necrosis factor receptor-associated factor 1. Although the soluble form of RELT fusion protein does not inhibit the one-way mixed lymphocyte reaction, immobilized RELT is capable of costimulating T-cell proliferation in the presence of CD3 signaling. These results define a new member of the TNFR superfamily that may be a potential regulator of immune responses.
A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations
Authors: Levis Mark , Tse Kam-Fai , Smith B. Douglas , Garrett Elizabeth , Small Donald
Published: July 2002

Internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 have been found in 20% to 30% of patients with acute myeloid leukemia (AML). These mutations constitutively activate the receptor and appear to be associated with a poor prognosis. Recent evidence that this constitutive activation is leukemogenic renders this receptor a potential target for specific therapy. In this study, dose-response cytotoxic assays were performed with AG1295, a tyrosine kinase inhibitor active against FLT3, on primary blasts from patients with AML. For each patient sample, the degree of cytotoxicity induced by AG1295 was compared to the response to cytosine arabinoside (Ara C) and correlated with the presence or absence of a FLT3/ITD mutation. AG1295 was specifically cytotoxic to AML blasts harboring FLT3/ITD mutations. The results suggest that these mutations contribute to the leukemic process and that the FLT3 receptor represents a therapeutic target in AML.
T-cell–depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect
Authors: Alyea Edwin , Weller Edie , Schlossman Robert , Canning Christine , Webb Iain , Doss Deborah , Mauch Peter , Marcus Karen , Fisher David , Freeman Andrea , Parikh Bijal , Gribben John , Soiffer Robert , Ritz Jerome , Anderson Kenneth
Published: July 2002

Previous trials of allogeneic bone marrow transplantation (BMT) in patients with multiple myeloma (MM) have demonstrated high response rates but also high transplantation-related mortality (TRM) and high relapse rates. Exploitation of this strategy remains of interest because donor lymphocyte infusions (DLIs) can induce a potent graft-versus-myeloma (GVM) effect. CD6 T-cell–depleted allogeneic BMT was combined with prophylactic CD4+ DLI administered 6 to 9 months after BMT in an effort to reduce TRM and to induce a GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy-sensitive disease underwent BMT. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host disease (GVHD) prophylaxis. GVHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II GVHD. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% of patients developed acute (≥ II) or extensive chronic GVHD. Two-year estimated overall survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 months with no GVHD and did not receive DLI (41%) (P = .13). Although this study suggests that prophylactic DLI induces significant GVM responses after allogeneic BMT, only 58% of patients were able to receive DLI despite T-cell–depleted BMT. Therefore, less toxic transplantation strategies are needed to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after transplantation.
Localized reduction of atherosclerosis in von Willebrand factor–deficient mice
Authors: Methia Nassia , André Patrick , Denis Cécile V. , Economopoulos Maria , Wagner Denisa D.
Published: July 2002

To examine the role of the platelet adhesion molecule von Willebrand factor (vWf) in atherogenesis, vWf-deficient mice (vWf−/−) were bred with mice lacking the low-density lipoprotein receptor (LDLR−/−) on a C57BL/6J background. LDLR−/−vWf+/+ and LDLR−/−vWf−/− mice were placed on a diet rich in saturated fat and cholesterol for different lengths of time. The atherogenic diet stimulated leukocyte rolling in the mesenteric venules in both genotypes, indicating an increase in P-selectin–mediated adhesion to the endothelium. After 8 weeks on the atherogenic diet, the fatty streaks formed in the aortic sinus of LDLR−/−vWf−/− mice of either sex were 40% smaller and contained fewer monocytes than those in LDLR−/−vWf+/+ mice. After 22 weeks on the atherogenic diet (early fibrous plaque stage), the difference in lesion size in the aortic sinus persisted. Interestingly, the lesion distribution in the aortas of LDLR−/−vWf−/− animals was different from that of LDLR−/− vWf+/+ animals. In vWf-positive mice, half of all lesions were located at the branch points of the renal and mesenteric arteries, whereas lesions in this area were not as prominent in the vWf-negative mice. These results indicate that the absence of vWf primarily affects the regions of the aorta with disturbed flow that are prone to atherosclerosis. Thus, vWf may recruit platelets/leukocytes to the lesion in a flow-dependent manner or may be part of the mechano-transduction pathway regulating endothelial response to shear stress.
Platelet endothelial cell adhesion molecule-1 is a negative regulator of platelet-collagen interactions
Authors: Jones Karen L. , Hughan Sascha C. , Dopheide Sacha M. , Farndale Richard W. , Jackson Shaun P. , Jackson Denise E.
Published: July 2002

The functional importance of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in platelets is unclear. Because PECAM-1 represents a newly assigned immunoglobulin–ITIM superfamily member expressed on the surface of platelets, it was hypothesized that it may play an important regulatory role in modulating ITAM-bearing receptors such as collagen (GP)VI receptor and FcγRIIA. To examine the functional role of PECAM-1 in regulating platelet-collagen interactions, 2 different approaches were applied using recombinant human PECAM-1–immunoglobulin chimeras and platelets derived from PECAM-1–deficient mice. Stimulation of platelets by collagen-, (GP)VI-selective agonist, collagen-related peptide (CRP)–, and PECAM-1–immunoglobulin chimera induced tyrosine phosphorylation of PECAM-1 in a time- and dose-dependent manner. Activation of PECAM-1 directly through the addition of soluble wild-type PECAM-1–immunoglobulin chimera, but not mutant K89A PECAM-1–immunoglobulin chimera that prevents homophilic binding, was found to inhibit collagen- and CRP-induced platelet aggregation. PECAM-1–deficient platelets displayed enhanced platelet aggregation and secretion responses on stimulation with collagen and CRP, though the response to thrombin was unaffected. Under conditions of flow, human platelet thrombus formation on a collagen matrix was reduced in a dose-dependent manner by human PECAM-1–immunoglobulin chimera. Platelets derived from PECAM-1–deficient mice form larger thrombi when perfused over a collagen matrix under flow at a shear rate of 1800 seconds−1 compared to wild-type mice. Collectively, these results indicate that PECAM-1 serves as a physiological negative regulator of platelet-collagen interactions that may function to negatively limit growth of platelet thrombi on collagen surfaces.
Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation
Authors: Chung Brile , Barbara-Burnham Lucia , Barsky Lora , Weinberg Kenneth
Published: July 2002

Interleukin-7 (IL-7) is the major thymopoietic cytokine. Injections of IL-7 after murine bone marrow transplantation (BMT) correct defects in thymic differentiation, including thymic hypocellularity, abnormal differentiation of CD3− CD4−CD8− (triple-negative [TN]) thymocytes into CD4+ CD8+ (double-positive [DP]) cells, and antigen-specific mature T-lymphocyte proliferation. To determine whether IL-7 production is decreased in BMT recipients, BMT was performed with congenic murine donor-recipient strains and escalating doses of pre-BMT conditioning. Increasing doses of radiation resulted in decreased thymic cellularity and maturation from the TN to the DP stage. Quantitative reverse transcription–polymerase chain reaction analyses demonstrated that intrathymic production of IL-7 was significantly decreased in irradiated mice than in nonirradiated controls. Decline in IL-7 transcript levels was correlated with the dose of radiation administered. Analyses of the numbers of CD45− major histocompatibility complex class II+ thymic stromal cells suggested that the mechanism for the decreased IL-7 production was loss of IL-7–producing thymic stromal cells. Experiments indicated that pre-BMT conditioning with radiation led to decreased stromal production of IL-7 and consequent blocks in the maturation of thymocytes. They provided a mechanism for both the abnormal thymopoiesis observed after BMT and the previously observed beneficial effects of IL-7 administration in murine models. Impaired production of IL-7 by thymic stroma may be a general model for the clinically observed adverse effects of cytotoxic therapy on thymopoiesis.
Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor
Authors: Monneret Guillaume , Gravel Sylvie , Diamond Michael , Rokach Joshua , Powell William S.
Published: July 2002

Prostaglandin D2 (PGD2) is released following exposure of asthmatics to allergen and acts via the adenylyl cyclase–coupled receptor for PGD2 (DP receptor). In this study, it is reported that human eosinophils possess this receptor, which would be expected to inhibit their activation. In contrast, it was found that prostaglandin D2 is a potent stimulator of eosinophil chemotaxis, actin polymerization, CD11b expression, and L-selectin shedding. These responses are specific for eosinophils, as neutrophils display little or no response to prostaglandin D2. They were not due to interaction with receptors for other prostanoids, as prostaglandins E2 and F2α, U46619 (a thromboxane A2 analogue), and carbaprostacyclin (a prostacyclin analogue) displayed little or no activity. Furthermore, they were not shared by the selective DP receptor agonist BW245C and were not prevented by the selective DP receptor antagonist BWA868C, indicating that they were not mediated by DP receptors. In contrast, the prostaglandin D2 metabolite 13,14-dihydro-15-oxoprostaglandin D2 induced eosinophil activation but did not stimulate DP receptor–mediated adenosine 3′,5′–cyclic monophosphate (cAMP) formation. These results indicate that in addition to the classic inhibitory DP1 receptor, eosinophils possess a second, novel DP2 receptor that is associated with PGD2-induced cell activation. These 2 receptors appear to interact to regulate eosinophil responses to PGD2, as blockade of DP1 receptor–mediated cAMP production by BWA868C resulted in enhanced DP2receptor–mediated stimulation of CD11b expression. The balance between DP1 and DP2 receptors could determine the degree to which prostaglandin D2 can activate eosinophils and may play a role in eosinophil recruitment in asthma.
Decorin inhibits macrophage colony-stimulating factor proliferation of macrophages and enhances cell survival through induction of p27Kip1 and p21Waf1
Authors: Xaus Jordi , Comalada Mònica , Cardó Marina , Valledor Annabel F. , Celada Antonio
Published: July 2002

Decorin is a small proteoglycan that is ubiquitous in the extracellular matrix of mammalian tissues. It has been extensively demonstrated that decorin inhibits tumor cell growth; however, no data have been reported on the effects of decorin in normal cells. Using nontransformed macrophages from bone marrow, results of this study showed that decorin inhibits macrophage colony-stimulating factor (M-CSF)–dependent proliferation by inducing blockage at the G1 phase of the cell cycle without affecting cell viability. In addition, decorin rescues macrophages from the induction of apoptosis after growth factor withdrawal. Decorin induces the expression of the cdk inhibitors p21Waf1 and p27Kip1. Using macrophages from mice where these genes have been disrupted, inhibition of proliferation mediated by decorin is related to p27Kip1 expression, whereas p21Waf1expression is necessary to protect macrophages from apoptosis. Decorin also inhibits M-CSF–dependent expression of MKP-1 and extends the kinetics of ERK activity, which is characteristic when macrophages become activated instead of proliferating. The effect of decorin on macrophages is not due to its interaction with epidermal growth factor or interferon-γ receptors. Furthermore, decorin increases macrophage adhesion to the extracellular matrix, and this may be partially responsible for the expression of p27Kip1 and the modification of ERK activity, but not for the increased cell survival.
Forced expression of the Ikaros 6 isoform in human placental blood CD34+ cells impairs their ability to differentiate toward the B-lymphoid lineage
Authors: Tonnelle Cécile , Bardin Florence , Maroc Christine , Imbert Anne-Marie , Campa Fanny , Dalloul Ali , Schmitt Christian , Chabannon Christian
Published: July 2002

Studies in mice suggest that the Ikaros (Ik) gene encodes several isoforms and is a critical regulator of hematolymphoid differentiation. Little is known on the role of Ikaros in human stem cell differentiation. Herein, the biological consequences of the forced expression of Ikaros 6 (Ik6) in human placental blood CD34+ progenitors are evaluated. Ik6 is one of the isoforms produced from the Ikaros premessenger RNA by alternative splicing and is thought to behave as a dominant negative isoform of the gene product because it lacks the DNA binding domain present in transcriptionally active isoforms. The results demonstrate that human cord blood CD34+ cells that express high levels of Ik6 as a result of retrovirally mediated gene transfer have a reduced capacity to produce lymphoid B cells in 2 independent assays: (1) in vitro reinitiation of human hematopoiesis during coculture with the MS-5 murine stromal cell line and (2) xenotransplantation in nonobese diabetic–severe combined immunodeficient mice. These results suggest that Ikaros plays an important role in stem cell commitment in humans and that the balance between the different isoforms is a key element of this regulatory system; they support the hypothesis that posttranscriptional events can participate in the control of human hematopoietic differentiation.
A novel CBFA2 single-nucleotide mutation in familial platelet disorder with propensity to develop myeloid malignancies
Authors: Buijs Arjan , Poddighe Pino , van Wijk Richard , van Solinge Wouter , Borst Eric , Verdonck Leo , Hagenbeek Anton , Pearson Peter , Lokhorst Henk
Published: July 2002

Hereditary mutations associated with hematologic malignancies are rare. Heterozygous mutations affecting the hematopoietic transcription factor CBFA2 (also AML1/RUNX1) were recently reported to be associated with familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML, MIM 601399). A new 3-generation family with FPD/AML with a novel CBFA2 mutation is described. In this family, AML was diagnosed in a second-generation male. After allogeneic stem cell transplantation from his human leukocyte antigen–identical sister, a donor-derived, genetically identical leukemia developed in the recipient and the donor. Sequencing analysis identified a G-to-T transition within the CBFA2 gene, which involves codon 198, encoding a conserved aspartic acid within the DNA- binding Runt domain. Three of 5 siblings affected with the FPD/AML trait harbored the mutation in a heterozygous form. This experience underscores the necessity of performing mutation analysis of the CBFA2 gene before sibling allogeneic transplantation in families with FPD/AML.
Deep‐towed gravity surveys in the southern California Continental Borderland
Authors: Ridgway Jeff R. , Zumberge Mark A.
Published: July 2002

We surveyed two sites in the southern California continental borderland with a newly developed instrument, a towed deep ocean gravimeter—a gravity sensor that can be towed a few tens of meters above the sea floor. During its development phase, we used the instrument to survey two regions off the coast of southern California. The first was along two tracks in the San Diego Trough. The second was over a seamount‐like feature named Emery Knoll. Results of the trough survey reveal a basin with a geometry consistent with seismic data. We observed no significant density contrast across the San Diego Trough fault in the near‐surface sediments. The survey of Emery Knoll shed light on the question of the origin of this structure; modeling the knoll to determine its bulk density suggested a nearly uniform structure surrounded by sedimentary basins with a more massive central intrusive body. Derived densities of 2850 kg/m3for the knoll and 3050 kg/m3for the central intrusion assume that no deep unmodeled sources exist directly underneath the knoll. The gravity data favor a model of metamorphic basement rock uplifted and containing igneous intrusives.
Offset and angle‐domain common image‐point gathers for shot‐profile migration
Authors: Rickett James E. , Sava Paul C.
Published: July 2002

Prestack depth migration of shot profiles by downward continuation is a practical imaging algorithm that is especially cost‐effective for sparse‐shot wide‐azimuth geometries. The interpretation of offset as the displacement between the downward‐propagating (shot) wavefield and upward‐propagating (receiver) wavefield enables us to extract offset‐domain common image‐point (CIP) gathers during shot‐profile migration. The offset‐domain gathers can then be transformed to the angle domain with a radial‐trace mapping originally introduced for shot‐geophone migration. The computational implications of this procedure include both the additional cost of multioffset imaging and an implicit transformation from shot‐geophone to midpoint‐offset coordinates. Although this algorithm provides a mechanism for imaging angle‐dependent reflectivity via shot‐profile migration, for sparse‐shot geometries the fundamental problem of shot‐aliasing may severely impact the quality of CIP gathers.
Seismic data mapping and reconstruction
Authors: Stolt Robert H.
Published: July 2002

Seismic data mapping uses data at source and receiver locations one actually has to create or simulate data at the locations one desires to have. The process is similar to seismic migration, though less demanding in that only data relatively near to the desired output point need be employed. Basic data mapping adjusts phase and amplitude of the data to conform to the geometry at the output location under the assumption that reflectivity does not change with angle of incidence. Full seismic data reconstruction goes beyond basic data mapping by also allowing reflection coefficients to change with incident angle. In the straight‐raypath approximation, both data mapping and full data reconstruction are Kirchhoff‐like operations of small integration aperture, with data mapping the simpler of the two. Operating on moveout‐corrected data, they are (up to a point) velocity independent. The operators can map or continue data from one offset to another [dip moveout (DMO) being a special case of data mapping] or from one source or receiver location to another. Both 2‐D and 3‐D versions of the operators can be constructed. The 2‐D mapping and reconstruction operators apply when input and output offset azimuths are aligned. The 3‐D operators are equivalent, at least in principle, to two passes of the corresponding 2‐D operators: the first pass a DMO to zero offset, the second an inverse DMO to the desired location. Potential uses for data mapping and reconstruction include filling in missing data, regularizing a data set, consolidating to a smaller data set, removing acquisition footprints, and so on.
Breast Cancer Screening in Women Previously Treated for Hodgkin’s Disease: A Prospective Cohort Study
Authors: Diller Lisa , Nancarrow Cheryl Medeiros , Shaffer Kitt , Matulonis Ursula , Mauch Peter , Neuberg Donna , Tarbell Nancy J. , Litman Heather , Garber Judy
Published: July 2002

PURPOSE: Young women who are exposed to chest irradiation for Hodgkin’s disease (HD) are at increased risk of breast cancer; this study investigated patient awareness of breast cancer risk and patient screening behavior and assessed the utility of mammographic screening in HD survivors.

PATIENTS AND METHODS: This is a prospective cohort study of 90 female long-term survivors of HD who had been treated ≥ 8 years previously with mantle irradiation (current age, 24 to 51 years). Participants completed surveys of their perceptions of breast cancer risk and screening behaviors and received written recommendations for breast examinations and mammography. Annual follow-up was conducted through medical records, telephone, and/or mailed questionnaires.

RESULTS: At baseline, women were often unaware of their increased risk of breast cancer; 40% (35 of 87) reported themselves to be at equal or lower risk than women of the same age. Only 47% (41 of 87) reported having had a mammogram in the previous 24 months. Women who had received information from an oncologist were more likely to assess correctly their risk than women who received information from other sources (P < .001). Ten women developed 12 breast cancers (ductal carcinoma-in-situ [n = 2], invasive ductal carcinoma [n = 10]) during the study; two were diagnosed at study entry, and 10 during follow-up (median, 3.1 years). All cancers were evident on mammogram, and eight of 10 invasive cancers were node negative.

CONCLUSION: Practitioners who care for women after HD therapy need to educate patients regarding their risks and begin early screening. Screening by mammography can detect small, node-negative breast cancers in these patients.
ZD1839, a Selective Oral Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial
Authors: Ranson Malcolm , Hammond Lisa A. , Ferry David , Kris Mark , Tullo Andrew , Murray Philip I. , Miller Vince , Averbuch Steve , Ochs Judy , Morris Charles , Feyereislova Andrea , Swaisland Helen , Rowinsky Eric K.
Published: July 2002

PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors.

PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed.

RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non–small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for ≥ 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for ≥ 6 months.

CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.
Absolute and Functional Iron Deficiency in the US, 2017-2020
Authors: Tawfik Yahya M. K. , Billingsley Hayley , Bhatt Ankeet S. , Aboelsaad Iman , Al-Khezi Omar S. , Lutsey Pamela L. , Buckley Leo F.
Published: September 2024

Importance

The prevalence of absolute and functional iron deficiency among adults in the US is unknown.

Objective

To estimate the prevalence of absolute and iron deficiency and iron supplement use in the US across age, sex, and comorbidity categories.

Design, Setting, and Participants

This cross-sectional study analyzed data from the National Health and Nutritional Examination Survey (NHANES) 2017 to 2020 prepandemic cycle. Participants included noninstitutionalized, civilian women and men aged 18 years or older who had available serum ferritin, iron, and unsaturated iron binding capacity measurements. Data analysis was performed from March 21, 2023, to July 5, 2024.

Exposure

Absolute iron deficiency and functional iron deficiency.

Main Outcomes and Measures

Absolute iron deficiency was defined as serum ferritin less than 30 ng/mL regardless of transferrin saturation. Functional iron deficiency was defined as serum ferritin greater than or equal to 30 ng/mL with transferrin saturation less than 20%. The prevalence of absolute and functional iron deficiency was estimated among all adults in the US and separately among women and men according to age category (>18 years to <50 years, 50-65 years, and ≥65 years) using recommended sample weights and sampling design factors to provide estimates representative of the national, noninstitutionalized civilian population. The 95% CIs were calculated using the Korn-Graubard method.

Results

A total of 8021 US adults (mean age, 48 years; 95% CI, 47-49 years; 52% [95% CI, 50%-53%] female) were included in this analysis. An estimated 14% (95% CI, 13%-15%) of adults in the US met the criteria for absolute iron deficiency, and an estimated 15% (95% CI, 14%-17%) met the criteria for functional iron deficiency. Among US adults without anemia, heart failure, chronic kidney disease, or current pregnancy, the estimated prevalence of absolute iron deficiency was 11% (95% CI, 10%-11%), and that of functional iron deficiency was 15% (95% CI, 14%-17%). The prevalence of functional iron deficiency exceeded that of absolute iron deficiency in all US adults except women younger than 50 years. Iron supplement use ranged from 22% (95% CI, 12%-37%) to 35% (95% CI, 29%-42%) of women with iron deficiency and 12% (95% CI, 5%-21%) to 18% (95% CI, 8%-32%) of men with iron deficiency depending on age.

Conclusions and Relevance

These findings suggest that absolute and functional iron deficiency affect a large proportion of American adults even in the absence of anemia, heart failure, or chronic kidney disease. Further research on the role of functional iron deficiency in adverse health outcomes and on iron deficiency screening strategies is needed.
Hybrid Additive Manufacturing for Site‐Specific Tensile Response in 316L Stainless Steel
Authors: Mithal Abeer , Maharjan Niroj , Chew Youxiang , Idapalapati Sridhar
Published: September 2024

Herein, an alternative way of achieving site‐specific mechanical properties is explored—the hybridization of a directed energy deposition technology with a secondary deformation process (hammer peening (HP)) which acts between deposited layers. By applying the peening in a selective manner, microstructure and hence mechanical properties can be locally varied. Microstructural characterization reveals recrystallization in the HP‐induced deformation zone. The columnar grains of as‐built regions with a grain size of ≈26 μm are transformed into a recrystallized zone with equiaxed grains having a size of ≈8 μm. There is also a highly strain‐hardened region below this recrystallized zone where the dislocation density is more than two times higher than in the as‐built condition. Subsequent tensile testing reveals that these microstructural zones corresponded to local enhancement in tensile strength normal to the build direction. The strengthening mechanisms are identified as Hall–Petch and dislocation (Taylor) strengthening, and their relative contributions are studied. The local strength enhancement comes at the expense of ductility in the build direction, which is studied via finite element modeling and attributed to strain localization into non‐strengthened areas. The results from this work show the possibility of achieving site‐specific properties via interlayer processing.
Ti3C2Tx‐MXene‐Based Color‐Indicative All‐Organic Electrochromic Supercapacitors
Authors: Sahu Bhumika , Singh Mayank K. , Bansal Love , Rath Deb Kumar , Rai Dhirendra K. , Kumar Rajesh
Published: September 2024

An all‐organic multifunctional solid‐state electrochromic supercapacitor has been designed by utilizing 2D‐MXene and a combination of viologen and polythiophene. The 2D MXene is synthesized using selective etching method and properly characterized; afterward, it is doped in ethyl viologen (EV) and a solid‐state electrochromic supercapacitor device is prepared having poly‐3‐hexylthiophene (P3HT) as complementary electrode. The prepared device gives high optical contrast (OC) (≈85%) and coloration efficiency (CE) (≈340 cm2 C−1) with ≈1 s of switching time in the visible spectrum at 515 nm. A similar color modulation is observed in NIR region also. Along with high electrochromic properties, the device takes almost 23.1 s for discharging and 6.7 s for charging, giving high Columbic efficiency due to the pseudocapacitor‐type charge storage property providing necessary electrons for the redox reaction to occur. The current study proposes a new MXene‐based recipe for designing multifunctional electrochromic supercapacitors with a promise for practical use.
Microstructure Evolution and Mechanical Properties of In Situ TiB2/Al–Zn–Mg–Cu Composites by Electropulsing‐Assisted Solution Treatment
Authors: Chen Jian , Luo Xianhui , Geng Jiwei , Chen Dong , Li Yugang , Xia Peikang , Wang Haowei
Published: September 2024

The traditional solution treatment is not completely applicable for in situ TiB2/Al–Zn–Mg–Cu composite due to the influence of TiB2 particles. This study investigates the impact of the electropulsing‐assisted solution (EAS) process on the microstructure evolution and mechanical properties of TiB2/Al–Zn–Mg–Cu composites. The nonuniform microstructure evolution related to the difference in temperature and current density is supported by simulative and experimental results. EAS treatment significantly enhances the degree of supersaturation, allowing phases surrounding TiB2 particles to dissolve without extensive overburning, unlike traditional solution treatments. This improvement is attributed to the reduced thermodynamic barrier and accelerated atomic diffusion, facilitated by both localized and average Joule heating effects and enhanced thermal electron/phonon scattering. Meanwhile, grain size remains stable during the temperature rise induced by EAS treatment. Furthermore, the mechanical properties of composites increase, among which the increase in strength is mainly ascribed to solid–solution strengthening, and the increase in elongation is related to multiple factors referring to TiB2 particles fracture and interface crack between the undissolved phases and matrix. This study provides an approach to achieve an efficient dissolution of phases aggregated with particles and without widespread overburning in particle‐reinforced Al matrix composites via electropulsing techniques.
One‐Step Fabrication of Nanofiber/Nanosphere Composite Membranes by Airflow/Electrostatic Method
Authors: Zheng Wenxing , Zhang Zuojun , Liu Kecheng
Published: September 2024

A fabrication technology and equipment for nanofiber/nanosphere composite membranes (NNCMs) is proposed and named as the airflow/electrostatic method (AEM). AEM uses both air flow and induced electric field to stretch the jets. The AEM working mechanisms are proposed and verified. The electric field laws of AEM are obtained by finite‐element simulation and theoretical deduction. Compared with the airflow method (AM), the average fiber diameter, standard deviation of fiber diameter, and NNCMs, porosity of AEM can be reduced by 38.8%, 71.1%, and 87.3%, respectively. AEM can also overcome the shortcoming of the AM that cannot receive nanospheres. Compared with the electrostatic method (EM), AEM can not only fabricate NNCMs with randomly distributed nanofibers and nanospheres in one step, but also greatly improve the yield. The injection speeds of solution X and solution Y of AEM can be increased by 24 000% and 1920%, respectively, compared with that of EM. The diameters of AEM nanospheres and nanofibers increase with the increase of injection speed of solution X and solution Y, respectively. The distance between needle and receiver has little effect on the diameters of nanofibers and nanospheres. AEM NNCMs with excellent quality and high yield will be widely used in many fields.