bluuebunny/crossref_metadata_2025 huggingface dataset:
Dendritic cell potentials of early lymphoid and myeloid progenitors
Authors: Manz Markus G. , Traver David , Miyamoto Toshihiro , Weissman Irving L. , Akashi Koichi
Published: July 2002

It has been proposed that there are at least 2 classes of dendritic cells (DCs), CD8α+ DCs derived from the lymphoid lineage and CD8α− DCs derived from the myeloid lineage. Here, the abilities of lymphoid- and myeloid-restricted progenitors to generate DCs are compared, and their overall contributions to the DC compartment are evaluated. It has previously been shown that primitive myeloid-committed progenitors (common myeloid progenitors [CMPs]) are efficient precursors of both CD8α+ and CD8α− DCs in vivo. Here it is shown that the earliest lymphoid-committed progenitors (common lymphoid progenitors [CLPs]) and CMPs and their progeny granulocyte-macrophage progenitors (GMPs) can give rise to functional DCs in vitro and in vivo. CLPs are more efficient in generating DCs than their T-lineage descendants, the early thymocyte progenitors and pro-T cells, and CMPs are more efficient DC precursors than the descendant GMPs, whereas pro-B cells and megakaryocyte-erythrocyte progenitors are incapable of generating DCs. Thus, DC developmental potential is preserved during T- but not B-lymphoid differentiation from CLP and during granulocyte-macrophage but not megakaryocyte-erythrocyte development from CMP. In vivo reconstitution experiments show that CLPs and CMPs can reconstitute CD8α+ and CD8α− DCs with similar efficiency on a per cell basis. However, CMPs are 10-fold more numerous than CLPs, suggesting that at steady state, CLPs provide only a minority of splenic DCs and approximately half the DCs in thymus, whereas most DCs, including CD8α+ and CD8α− subtypes, are of myeloid origin.
Expression of interferon-α (IFN-α) receptor 2c at diagnosis is associated with cytogenetic response in IFN-α–treated chronic myeloid leukemia
Authors: Barthe Christophe , Mahon François-Xavier , Gharbi Marie-José , Fabères Carole , Bilhou-Nabéra Chrystèle , Hochhaus Andreas , Reiffers Josy , Marit Gérald
Published: July 2002

For the management of chronic myeloid leukemia (CML), prediction or early determination of the response to interferon-alpha (IFN-α) treatment is important for identifying nonresponder patients to whom alternative therapy may be proposed. In this study, the levels of expression of both BCR-ABL and subunit 2c of IFN-α receptor (IFN-αR2c) genes were analyzed at diagnosis in 74 patients with chronic phase CML treated with an IFN-α monotherapy. By using blood samples, real-time quantitative polymerase chain reaction was performed to quantify BCR-ABL, IFN-αR2c, and G6PDH mRNA as external control. The results were compared with hematologic and cytogenetic responses to IFN-α. A wide variation in the BCR-ABL/G6PDH ratio was observed at diagnosis (median, 6.68%; range, 0.18%-41.31%), but no significant association with response to IFN-α was observed. In contrast, the variation of IFN-αR2c/G6PDH ratio at diagnosis was significantly associated with the achievement of major cytogenetic response (MCR; 34% or lower Ph+metaphases). Median values of IFN-αR2c/G6PDH ratio for patients achieving MCR and for those who did not achieve it were 110.75% (range, 9.47%-612.30%) and 64.42% (range, 5.96%-425.40%), respectively (P = .037). In addition, this novel molecular factor, combined with the achievement of complete hematologic response at 3 months, makes it possible to predict MCR achievement with high probability by Kaplan-Meier analysis (91% ± 17% at 24 months; P = .0001).
Expression of nuclear transcription factor interferon consensus sequence binding protein in chronic myeloid leukemia correlates with pretreatment risk features and cytogenetic response to interferon-α
Authors: Schmidt Manuel , Hochhaus Andreas , Nitsche Andreas , Hehlmann Rüdiger , Neubauer Andreas
Published: July 2002

Recently, it was shown that interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor (IRF) family, has a potential role in chronic myeloid leukemia (CML). Deletion of ICSBP gene in mice leads to a CML-like syndrome and samples from CML patients exhibited impaired ICSBP expression. The present study found that ICSBP expression correlated with risk features determined by Sokal score in untreated CML (P = .007 for high versus low risk). In addition, analyzing ICSBP expression during interferon-α (IFN-α) therapy in “good” (n = 27) versus “poor” (n = 15) cytogenetic responders, high ICSBP levels were only observed in “good” responders (P = .0002). Together, these data suggest that ICSBP levels are related to initial presentation of CML and the therapeutic response of CML to IFN-α, indicating an important role of ICSBP in CML.
Activation of protease-activated receptors by gingipains fromPorphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity
Authors: Lourbakos Afrodite , Yuan YuPing , Jenkins Alison L. , Travis James , Andrade-Gordon Patricia , Santulli Rosemary , Potempa Jan , Pike Robert N.
Published: July 2002

The bacterium Porphyromonas gingivalis is a major etiologic agent in the pathogenesis of adult periodontitis in humans. Cysteine proteinases produced by this pathogen, termed gingipains, are considered to be important virulence factors. Among many other potentially deleterious activities, arginine-specific gingipains-R (RgpB and HRgpA) efficiently activate coagulation factors. To further expand knowledge of the interaction between gingipains and the clotting cascade, this study examined their effects on cellular components of the coagulation system. The enzymes induced an increase in intracellular calcium in human platelets at nanomolar concentrations and caused platelet aggregation with efficiency comparable to thrombin. Both effects were dependent on the proteolytic activity of the enzymes. Based on desensitization studies carried out with thrombin and peptide receptor agonists, and immunoinhibition experiments, gingipains-R appeared to be activating the protease-activated receptors, (PAR)-1 and -4, expressed on the surface of platelets. This was confirmed by the finding that HRgpA and RgpB potently activated PAR-1 and PAR-4 in transfected cells stably expressing these receptors. Cumulatively, the results indicate the existence of a novel pathway of host cell activation by bacterial proteinases through PAR cleavage. This mechanism not only represents a new trait in bacterial pathogenicity, but may also explain an emerging link between periodontitis and cardiovascular disease.
Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models
Authors: Denis Cécile V. , Kwack Kyubum , Saffaripour Simin , Maganti Srinivas , André Patrick , Schaub Robert G. , Wagner Denisa D.
Published: July 2002

Interleukin (IL)-11 is a cytokine with thrombopoietic activity that has been shown to increase plasma von Willebrand factor (vWf) in preliminary clinical studies. This led to further evaluation of the effect of recombinant human (rh)IL-11 on vWf and factor VIII (FVIII) secretion. In vitro, rhIL-11 did not increase vWf production by cultured endothelial cells, which suggests an indirect mechanism. Also, in vivo, plasma vWf was not elevated in mice shortly after a single intravenous (IV) bolus injection of 250 or 1000 μg/kg rhIL-11. The effect of continuous exposure to rhIL-11 was accessed by treating wild type mice for 7 consecutive days with subcutaneous 250 μg/kg/d rhIL-11. Platelet counts increased by 25% and 40% after 4 and 7 days, respectively. Plasma vWf and FVIII levels increased 2-fold after 4 and 7 days. Surprisingly, no effect of rhIL-11 on vWf or FVIII messenger RNA was observed, which suggests that the regulation by rhIL-11 occurs after transcription. No increase in soluble P-selectin was observed after rhIL-11 treatment, indicating that platelet activation is not the source of elevated vWf. Similarly to wild type mice, vWf heterozygous mice responded to rhIL-11 treatment by a significant increase in platelet counts and vWf and FVIII levels. Importantly, in vWf-deficient mice, rhIL-11 also induced a significant increase in FVIII independent of vWf and was able to reduce skin bleeding time. These results suggest that a clinical evaluation of the effects of rhIL-11–induced vWf/FVIII elevation in maintaining hemostasis in mild hemophilia A or von Willebrand disease would be worthwhile.
Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia
Authors: Peters David G. , Hoover Russell R. , Gerlach Melissa J. , Koh Eugene Y. , Zhang Haiyan , Choe Kevin , Kirschmeier Paul , Bishop W. Robert , Daley George Q.
Published: July 2002

BCR/ABL, the oncoprotein responsible for chronic myeloid leukemia (CML), transforms hematopoietic cells through both Ras-dependent and -independent mechanisms. Farnesyl protein transferase inhibitors (FTIs) were designed to block mutant Ras signaling, but they also inhibit the growth of transformed cells with wild-type Ras, implying that other farnesylated targets contribute to FTI action. In the current study, the clinical candidate FTI SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice, SCH66336 potently inhibited soft agar colony formation, slowed proliferation, and sensitized cells to apoptotic stimuli. Quantification of activated guanosine triphosphate (GTP)-bound Ras protein and electrophoretic mobility shift assays for AP-1 DNA binding showed that Ras effector pathways are inhibited by SCH66336. However, SCH66336 was more inhibitory than dominant-negative Ras in assays of soft agar colony formation and cell proliferation, suggesting activity against targets other than Ras. Cell cycle analysis of BCR/ABL-BaF3 cells treated with SCH66336 revealed G2/M blockade, consistent with recent reports that centromeric proteins that regulate the G2/M checkpoint are critical farnesylated targets of FTI action. Mice injected intravenously with BCR/ABL-BaF3 cells developed acute leukemia and died within 4 weeks with massive splenomegaly, elevated white blood cell counts, and anemia. In contrast, nearly all mice treated with SCH66336 survived and have remained disease-free for more than a year. Furthermore, SCH66336 selectively inhibited the hematopoietic colony formation of primary human CML cells. As an oral, nontoxic compound with a mechanism of action distinct from that of ABL tyrosine kinase inhibition, FTI SCH66336 shows promise for the treatment of BCR/ABL-induced leukemia.
Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults
Authors: Smith Martyn T. , Wang Yunxia , Kane Eleanor , Rollinson Sara , Wiemels Joseph L. , Roman Eve , Roddam Philippa , Cartwright Raymond , Morgan Gareth
Published: July 2002

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that detoxifies quinones and reduces oxidative stress. A cysteine-to-threonine (C → T) substitution polymorphism at nucleotide 609 of the NQO1 complementary DNA (NQO1 C609T) results in a lowering of NQO1 activity. Individuals homozygous for this mutation have no NQO1 activity, and heterozygotes have low to intermediate activity compared with people with wild type. DNA samples from 493 adult de novo acute leukemia patients and 838 matched controls were genotyped forNQO1 C609T. The majority of cases were diagnosed as acute myeloid leukemia (AML) (n = 420); 67 as acute lymphoblastic leukemia (ALL); and 6 as other forms of acute leukemia. The frequency of cases with low or null NQO1 activity (heterozygote + homozygous mutant) was significantly higher among total acute leukemia case subjects compared with their matched controls (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.17-1.89). Both ALL (OR = 1.93; 95% CI, 0.96-3.87) and AML case subjects (OR = 1.47; 95% CI, 1.13-1.90) exhibited a higher frequency of low or null NQO1genotypes than controls. For de novo AML, the most significant effect of low or null NQO1 activity was observed among the 88 cases harboring translocations and inversions (OR = 2.39; 95% CI, 1.34-4.27) and was especially high for those harboring inv(16) (OR = 8.13; 95% CI, 1.43-46.42). These findings were confirmed in a second group of 217 de novo AML cases with known cytogenetics. Thus, inheritance ofNQO1 C609T confers an increased risk of de novo acute leukemia in adults, implicating quinones and related compounds that generate oxidative stress in producing acute leukemia.
Activation and priming of neutrophil nicotinamide adenine dinucleotide phosphate oxidase and phospholipase A2 are dissociated by inhibitors of the kinases p42ERK2and p38SAPK and by methyl arachidonyl fluorophosphonate, the dual inhibitor of cytosolic and calcium-independent phospholipase A2
Authors: Mollapour Elahe , Linch David C. , Roberts Pamela J.
Published: July 2002

Arachidonic acid (AA) generated by phospholipase A2(PLA2) is thought to be an essential cofactor for phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Both enzymes are simultaneously primed by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor–α (TNF-α). The possibility that either unprimed or cytokine-primed responses of PLA2 or NADPH oxidase to the chemotactic agents formyl-methionyl-leucyl-phenylalanine (FMLP) and complement factor 5a (C5a) could be differentially inhibited by inhibitors of the mitogen-activated protein (MAP) kinase family members p42ERK2 (PD98059) and p38SAPK(SB203580) was investigated. PD98059 inhibited the activation of p42ERK2 by GM-CSF, TNF-α, and FMLP, but it did not inhibit FMLP-stimulated superoxide production in either unprimed or primed neutrophils. There was no significant arachidonate release from unprimed neutrophils stimulated by FMLP, and arachidonate release stimulated by calcium ionophore A23187 was not inhibited by PD98059. In contrast, PD98059 inhibited both TNF-α– and GM-CSF–primed PLA2 responses stimulated by FMLP. On the other hand, SB203580 inhibited FMLP-superoxide responses in unprimed as well as TNF-α– and GM-CSF–primed neutrophils, but failed to inhibit TNF-α– and GM-CSF–primed PLA2 responses stimulated by FMLP, and additionally enhanced A23187-stimulated arachidonate release, showing that priming and activation of PLA2 and NADPH oxidase are differentially dependent on both the p38SAPK and p42ERK2 pathways. Studies using C5a as an agonist gave similar results and confirmed the findings with FMLP. In addition, methyl arachidonyl fluorophosphonate (MAFP), the dual inhibitor of c and iPLA2 enzymes, failed to inhibit superoxide production in primed cells at concentrations that inhibited arachidonate release. These data demonstrate that NADPH oxidase activity can be dissociated from AA generation and indicate a more complex role for arachidonate in neutrophil superoxide production.
Protection from lethal murine graft-versus-host disease without compromise of alloengraftment using transgenic donor T cells expressing a thymidine kinase suicide gene
Authors: Drobyski William R. , Morse Herbert C. , Burns William H. , Casper James T. , Sandford Gordon
Published: July 2002

Donor T cells play a pivotal role in facilitating alloengraftment but also cause graft-versus-host disease (GVHD). Ex vivo T-cell depletion (TCD) of donor marrow is the most effective strategy for reducing GVHD but can compromise engraftment. This study examined an approach whereby donor T cells are selectively eliminated in vivo after transplantation using transgenic mice in which a thymidine kinase(TK) suicide gene is targeted to the T cell using a CD3 promoter/enhancer construct. Lethally irradiated B10.BR mice transplanted with major histocompatibility complex (MHC)–incompatible TCD C57BL/6 (B6) bone marrow (BM) plus TK+ T cells were protected from GVHD after treatment with ganciclovir (GCV) in a schedule-dependent fashion. To examine the effect of GCV treatment on alloengraftment, sublethally irradiated AKR mice underwent transplantation with TCD B6 BM plus limiting numbers (5 × 105) of B6 TK+ T cells. Animals treated with GCV had comparable donor engraftment but significantly reduced GVHD when compared with untreated mice. These mice also had a significantly increased number of donor splenic T cells when assessed 4 weeks after bone marrow transplantation. Thus, the administration of GCV did not render recipients T-cell deficient, but rather enhanced lymphocyte recovery. Adoptive transfer of spleen cells from GCV-treated chimeric mice into secondary AKR recipients failed to cause GVHD indicating that donor T cells were tolerant of recipient alloantigens. These studies demonstrate that administration of TKgene–modified donor T cells can be used as an approach to mitigate GVHD without compromising alloengraftment.
Influence of the hematopoietic stem cell source on early immunohematologic reconstitution after allogeneic transplantation
Authors: Lapierre Valérie , Oubouzar Nadia , Aupérin Anne , Tramalloni Dominique , Tayebi Hakim , Robinet Eric , Kuentz Matthieu , Blaise Didier , Hartmann Olivier , Hervé Patrick , Tiberghien Pierre
Published: July 2002

Several acute hemolysis episodes, sometimes lethal, have been recently described after transplantation of allogeneic peripheral blood hematopoietic stem cells (PBHSCs). Hemolysis resulted from the production of donor-derived antibodies (Abs) directed at ABO antigens (Ags) present on recipient red blood cells (RBCs). A multicenter randomized phase III clinical study comparing allogeneic PBHSC transplantation (PBHSCT) versus bone marrow hematopoietic stem cell transplantation (BMHSCT) has been conducted in France. In the course of this study, serum anti-A and/or anti-B Ab titers were compared before the conditioning regimen and on day +30 after transplantation in 49 consecutive evaluable PBHSCT (n = 21) or BMHSCT (n = 28) recipients. PBHSCT resulted in a higher frequency of increased anti-A and/or anti-B Ab titers 30 days after transplantation as compared to BMHSCT: 8 (38%) of 21 versus 3 (11%) of 28 (P = .04). In PBHSCT recipients, increased titers were observed mostly after receiving a minor ABO mismatch transplant: 5 of 7 versus 3 of 14 in the absence of any minor ABO mismatch (P = .05), whereas this was not the case after BMHSCT: 1 of 8 versus 2 of 20. Anti-A and/or anti-B serum Abs detectable at day +30 after PBHSCT were always directed against A and/or B Ags absent both on donor and recipient RBCs. Finally, 3 of 21 PBHSCT versus 0 of 28 BMHSCT recipients developed anti-allogeneic RBC Abs other than ABO (P = .07). Overall, the data strongly suggest that immunohematologic reconstitution differs significantly after granulocyte colony-stimulating factor–mobilized PBHSCT when compared to BMHSCT. Such a difference could contribute to the acute hemolysis described after PBHSCT as well as to distinct alloreactivity after PBHSCT.
Iron transport in a lymphoid cell line with the hemochromatosis C282Y mutation
Authors: Chitambar Christopher R. , Wereley Janine P.
Published: July 2002

The gene for hemochromatosis (HFE) is expressed in a variety of cells, including those not thought to be affected by this disease. The impact of HFE on iron transport was examined in B-lymphoid cell lines developed from a patient with hemochromatosis with the HFE C282Y mutation (C282Y cells) and an individual with the wild-type HFE gene (WT cells). Whereas both cell lines expressed HFE protein, C282Y cells displayed less HFE protein at the cell surface. Transferrin receptor (TfR) number was 2- to 3-fold greater in WT cells than in C282Y cells, while TfR affinity for transferrin (Tf) was slightly lower in C282Y cells. TfR distribution between intracellular and cell-surface compartments was similar in both cell lines. Iron uptake per cell was greater in WT cells but was not increased proportional to TfR number. When considered relative to cell-surface TfR number, however, iron uptake and Tf internalization were actually greater in C282Y cells. Surprisingly, Tf-independent iron uptake was also significantly greater in C282Y cells than in WT cells. The ferritin content of C282Y cells was approximately 40% that of WT cells. Exposure of cells to pro-oxidant conditions in culture led to a greater inhibition of proliferation in C282Y cells than in WT cells. Our results indicate that in this B-lymphoid cell line, the HFE C282Y mutation affects both Tf-dependent and -independent iron uptake and enhances cell sensitivity to oxidative stress. The role of HFE in iron uptake by B cells may extend beyond its known interaction with the TfR.
Plasmodium falciparum erythrocyte membrane protein 1 functions as a ligand for P-selectin
Authors: Senczuk Anna M. , Reeder John C. , Kosmala Magda M. , Ho May
Published: July 2002

The malarial protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a parasite protein that is exported to the surface of the infected erythrocyte, where it is inserted into the red cell cytoskeleton in the second half of the parasite life cycle. The surface expression of PfEMP1 coincides with the occurrence of the adhesion of infected erythrocytes to vascular endothelium. This protein has been shown to interact with CD36, intercellular adhesion molecule-1 (ICAM-1) and chondroitin sulfate A (CSA). In this study, it is demonstrated by affinity purification and western blot analysis that PfEMP1 also functions as a cell surface ligand for P-selectin, an adhesion molecule that has been shown to mediate the rolling of infected erythrocytes under physiologic flow conditions, leading to a significant increase in adhesion to CD36 on activated platelets and microvascular endothelium.
The cytoplasmic domain of FcγRIIA (CD32) participates in phagolysosome formation
Authors: Worth Randall G. , Mayo-Bond Laura , Kim Moo-Kyung , van de Winkel Jan G. J. , Todd Robert F. , Petty Howard R. , Schreiber Alan D.
Published: July 2002

Signaling motifs located within the cytoplasmic domain of certain receptors contribute to lysosome fusion. Most studies have described lysosome fusion with respect to endocytic receptors. Phagolysosome fusion has not been extensively studied. To test the hypothesis that the tail of FcγRIIA participates in phagolysosomal fusion, a “reverse” genetic complementation system was used. It was previously shown that complement receptor type 3 (CR3) can rescue the phagocytic activity of a mutant FcγRIIA lacking its cytoplasmic domain (tail-minus form). This system has allowed us to study Fcγ receptor–dependent phagocytosis and phagolysosome fusion in the presence and absence of the cytoplasmic domain of FcγRIIA. Fluorescent dextran was used to label lysosomes. After target internalization, wild-type FcγRIIA–mediated phagolysosome formation was observed as indicated by colocalization of fluorescent dextran and the phagosome. In addition, when studying mutants of FcγRIIA containing a full-length cytoplasmic tail with the 2 ITAM tyrosines mutated to phenylalanine, (1) phagocytosis was abolished, (2) CR3 restored phagocytosis, and (3) lysosomal fusion was similar to that observed with the wild-type receptor. In contrast, in the presence of CR3 and the tail-minus form of FcγRIIA, internalized particles did not colocalize with dextran. Electron microscopy revealed that the lysosomal enzyme acid phosphatase colocalized with immunoglobulin G–coated targets internalized by wild-type FcγRIIA but not by tail-minus FcγRIIA and CR3. Thus, the tail of FcγRIIA contributes to phagolysosome fusion by a mechanism that does not require a functional ITAM sequence.
Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide
Authors: Westervelt Peter , Brown Randy A. , Adkins Douglas R. , Khoury Hanna , Curtin Peter , Hurd David , Luger Selina M. , Ma Margaret K. , Ley Timothy J. , DiPersio John F.
Published: July 2002

Arsenic trioxide has been shown to be effective in treating acute promyelocytic leukemia (APL), with minimal overall toxicity reported to date. A phase I/II study was initiated in June 1998 using arsenic trioxide for relapsed APL to determine the maximum tolerated or minimal effective dose and to determine the efficacy of treatment at that dose. Ten patients received 1 to 4 monthly cycles of treatment with 0.1 mg/kg per day intravenous arsenic trioxide. Six of 7 patients evaluable for response achieved cytogenetic or molecular complete remission. However, 3 patients died suddenly during the first cycle of treatment. Autopsies obtained on 2 of these failed to identify a cause of sudden death, despite evidence of pulmonary hemorrhage in one. A third patient, for whom an autopsy was not performed, became asystolic and died while on continuous cardiac telemetry. These observations suggest that arsenic trioxide may be significantly or even fatally toxic at doses currently used and that caution is warranted in its use.
Identification of myelodysplastic syndrome–specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction
Authors: Miyazato Akira , Ueno Shuichi , Ohmine Ken , Ueda Masuzu , Yoshida Koji , Yamashita Yoshihiro , Kaneko Takashi , Mori Masaki , Kirito Keita , Toshima Masaki , Nakamura Yuichi , Saito Kenji , Kano Yasuhiko , Furusawa Shinpei , Ozawa Keiya , Mano Hiroyuki
Published: July 2002

Myelodysplastic syndrome (MDS) is a slowly progressing hematologic malignancy associated with a poor outcome. Despite the relatively high incidence of MDS in the elderly, differentiation of MDS from de novo acute myeloid leukemia (AML) still remains problematic. Identification of genes expressed in an MDS-specific manner would allow the molecular diagnosis of MDS. Toward this goal, AC133 surface marker–positive hematopoietic stem cell (HSC)-like fractions have been collected from a variety of leukemias in a large-scale and long-term genomics project, referred to as “Blast Bank,” and transcriptome of these purified blasts from the patients with MDS were then compared with those from AML through the use of oligonucleotide microarrays. A number of genes were shown to be expressed in a disease-specific manner either to MDS or AML. Among the former found was the gene encoding the protein Delta-like (Dlk) that is distantly related to the Delta-Notch family of signaling proteins. Because overexpression of Dlk may play a role in the pathogenesis of MDS, the disease specificity of Dlk expression was tested by a quantitative “real-time” polymerase chain reaction analysis. Examination of the Blast Bank samples from 22 patients with MDS, 31 with AML, and 8 with chronic myeloid leukemia confirmed the highly selective expression of the Dlk gene in the individuals with MDS. Dlk could be the first candidate molecule to differentiate MDS from AML. The proposal is made that microarray analysis with the Blast Bank samples is an efficient approach to extract transcriptome data of clinical relevance for a wide range of hematologic disorders.
Efficient identification of HLA-A*2402–restricted cytomegalovirus-specific CD8+ T-cell epitopes by a computer algorithm and an enzyme-linked immunospot assay
Authors: Kuzushima Kiyotaka , Hayashi Naomi , Kimura Hiroshi , Tsurumi Tatsuya
Published: July 2002

Antigenic peptides recognized by virus-specific cytotoxic T lymphocytes (CTLs) are useful tools for studying the CTL responses exclusively among those who own the major histocompatibility complex (MHC) class I molecules that present the peptides. For widening the application, an efficient strategy to determine such epitopes in the context of a given MHC is highly desirable. A rapid and efficient strategy is presented for the determination of CTL epitopes in the context of given MHC molecules of interest through multiple screenings consisting of a computer-assisted algorithm and MHC stabilization and enzyme-linked immunospot assays. A major cytomegalovirus (CMV)–specific CTL epitope, QYDPVAALF, in the amino acid sequence of its lower matrix 65 kd phosphoprotein (pp65) presented by HLA-A*2402 molecules was identified from 83 candidate peptides. The results indicate that the CMV-specific CTL response is highly focused to pp65 in the context of HLA-A*2402. Endogenous processing and presentation was confirmed using a peptide-specific CD8+ T-cell clone as the effectors and autologous fibroblast cells infected with recombinant vaccinia virus expressing pp65 gene or CMV as antigen-presenting cells. Flow cytometric analysis of intracellular interferon-γ production revealed 0.04% to 0.27% of CD8+ T cells in peripheral blood of HLA-A24+ and CMV-seropositive donors to be specific for the peptide. The tetrameric MHC-peptide complexes specifically bound to the reactive T-cell clone and 0.79% of CD8+ T cells in peripheral blood from a seropositive donor. The peptide could be a useful reagent to study CTL responses to CMV among populations positive for HLA-A*2402.
Adoptive transfer of simian immunodeficiency virus (SIV) naı̈ve autologous CD4+ cells to macaques chronically infected with SIV is sufficient to induce long-term nonprogressor status
Authors: Villinger Francois , Brice Gary T. , Mayne Ann E. , Bostik Pavel , Mori Kazuyasu , June Carl H. , Ansari Aftab A.
Published: July 2002

Adoptive transfer of autologous preinfection-collected peripheral blood mononuclear cells (PBMCs) or activated CD4+ T cells was performed in simian immunodeficiency virus (SIVmac239)–infected monkeys following short-term antiviral therapy with PMPA (9-R-[2-phosphonylmethoxypropyl] adenine). Short-term chemotherapy alone led to a transient decrease in plasma and cellular proviral DNA loads and transient rescue of gag/pol and env cytotoxic T-lymphocyte precursors (pCTLs). However, cessation of therapy allowed for SIV infection to resume its clinical course. PMPA chemotherapy coupled with infusions of either autologous pre-SIV infection–collected PBMCs or activated CD4+ T cells led to extended control of plasma and cellular proviral DNA loads after infusion, in spite of the fact that the transfused cells were not primed against SIV. However, qualitatively different antiviral defenses were induced by infusion of unfractionated and unmanipulated PBMCs versus purified and activated CD4+ T cells: PBMC infusions significantly favored development of SIVenv-specific pCTLs, neutralizing antibodies, and secretion of soluble noncytotoxic suppressor factors of SIV replication. In contrast, activated CD4+ T cells predominantly promoted CTL responses to SIVgag/pol and SIVenv. In addition, infusion of influenza-primed activated CD4+ T cells markedly enhanced influenza-specific pCTL responses, whereas infusion of similarly influenza-primed unfractionated PBMCs enhanced such pCTL responses only modestly, suggesting that the predominant immune defect after SIV infection lies in the T helper cell compartment rather than the effector cell compartment. Thus, adoptive immunotherapy with autologous “SIV naı̈ve” CD4+ lymphocytes was sufficient to rescue cell-mediated immune responses and induce long-term anti-SIV control and immune responses in the absence of continued antiviral chemotherapy.
Macrophage functional maturation and cytokine production are impaired in C/EBPε-deficient mice
Authors: Tavor Sigal , Vuong Peter T. , Park Dorothy J. , Gombart Adrian F. , Cohen Arthur H. , Koeffler H. Phillip
Published: July 2002

Members of the CCAAT/enhancer-binding protein (C/EBP) family are involved in the regulation of cellular differentiation and function of many tissues. Unlike the other members of the family, C/EBPε expression is restricted to granulocytes, macrophages, and lymphocytes. C/EBPε is highly conserved between human and rodents and is essential for terminal granulopoiesis in both species. To study the role that C/EBPε plays in macrophages, wild-type and C/EBPε–deficient (−/−) murine macrophages obtained from thioglycollate-elicited peritoneal lavages and differentiated bone marrow cells were compared. Although macrophage development occurred in both types of mice, the C/EBPε−/− cells had a lower expression of macrophage markers and a morphologic and ultrastructural appearance of immaturity. Phagocytic function, measured by calculating the percentage of internalized opsonized fluorescein isothiocyanate (FITC)–labeled yeast, was significantly impaired in the C/EBPε−/− macrophages compared with their wild-type counterparts. Furthermore, the differential expression of 26 macrophage-specific genes between wild-type and C/EBP−/− mice was analyzed. A subset of genes involved in differentiation, immune, and inflammatory responses was found down-regulated in the C/EBP−/− macrophages. Taken together, this study implicates theC/EBPε gene as an important transcription factor required for normal function and development of macrophages.
Acute Oxaliplatin-Induced Peripheral Nerve Hyperexcitability
Authors: Wilson Richard H. , Lehky Tanya , Thomas Rebecca R. , Quinn Mary G. , Floeter Mary Kay , Grem Jean L.
Published: July 2002

PURPOSE: Oxaliplatin is a novel platinum compound with clinical activity in several malignancies. Neurotoxicity is dose-limiting and occurs in two distinct forms, an acute neurologic symptom complex that occurs within hours or days of therapy and a chronic, cumulative sensory neuropathy.

PATIENTS AND METHODS: Patients were treated in a phase I study designed to establish the maximum-tolerated dose of capecitabine given with oxaliplatin. Because of the unusual neurosensory toxicity of oxaliplatin, detailed neurologic examination, needle electromyography (EMG), and nerve conduction studies (NCS) were performed before and the day after oxaliplatin in a subset of 13 patients. Carbamazepine therapy was tried in 12 additional patients to determine whether the neurologic effects might be relieved.

RESULTS: All patients experienced acute, reversible neurotoxicities with oxaliplatin. Symptoms included paresthesias, dysesthesias, cold hypersensitivity, jaw pain, eye pain, pain in the arm used for drug infusion, ptosis, leg cramps, and visual and voice changes. Serial EMG and NCS revealed striking signs of hyperexcitability in motor nerves after oxaliplatin. In patients who achieved therapeutic levels, carbamazepine did not alter the clinical or electromyographic abnormalities.

CONCLUSION: The acute neurotoxicity seen with oxaliplatin is characterized by peripheral-nerve hyperexcitability, and the findings are similar to the clinical manifestations of neuromyotonia. Carbamezepine, which provides symptomatic relief in acquired neuromytonia, did not seem to be beneficial. Efforts to identify a successful neuroprotectant strategy would have a major impact on improving patient quality of life and the ability to deliver full doses of oxaliplatin.
Methylphenidate and Atomoxetine in Pregnancy and Possible Adverse Fetal Outcomes
Authors: di Giacomo Ester , Confalonieri Veronica , Tofani Fabio , Clerici Massimo
Published: November 2024

Importance

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders, and it afflicts about 7% of young people. As a consequence, many young women might be pregnant while taking medication for ADHD, but data about safety have not yet been strictly examined.

Objective

To examine adverse effects in offspring of mothers receiving treatment with atomoxetine and methylphenidate during pregnancy.

Data Sources

Electronic databases (PubMed, Embase, and PsycINFO) were searched for articles published through December 31, 2023, with the following search terms: (atomoxetine OR methylphenidate) AND (pregnancy).

Study Selection

Observational studies (eg, cohort studies, case-control studies, case-crossover studies, cross-sectional studies, and registry-based studies) that reported offspring outcomes in pregnancy with atomoxetine and/or methylphenidate and in mothers with ADHD but unexposed to ADHD treatment during pregnancy or from the general population were included. Ten studies of 656 records satisfied criteria.

Data Extraction and Synthesis

Two independent reviewers performed data extraction according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses were conducted based on reported odds ratios (ORs) and corresponding 95% CIs using a linear random effects model. Each study was inversely weighted by the reported variance of the estimators. Risk of publication bias and analysis of heterogeneity through univariate and multivariate metaregressions were also rated. Data were analyzed from January to March 2024.

Main Outcomes and Measures

Study outcomes included miscarriages and congenital anomalies.

Results

Ten studies involving 16 621 481 pregnant women, 30 830 of them affected by ADHD, were included. Congenital anomalies or miscarriages were not more frequent in offspring of mothers receiving treatment with methylphenidate or atomoxetine during pregnancy compared with unexposed offspring (OR, 1.14; 95% CI, 0.83-1.55; P = .41; I2 = 8% for congenital anomalies; OR, 1.01; 95% CI, 0.70-1.47; P = .96; I2 = 0% for miscarriages) or compared with the general population (OR, 1.19; 95% CI, 0.93-1.53; P = .16; I2 = 74% for congenital anomalies; OR, 1.05, 95% CI, 0.81-1.37; P = .70; I2 = 0% for miscarriage).

Conclusions and Relevance

Evidence from this meta-analysis, which involves a substantial sample of pregnant women with and without ADHD, suggests the maintenance of methylphenidate or atomoxetine during pregnancy is safe, given that congenital anomalies and miscarriages did not appear to significantly increase. Further studies are recommended to support and confirm these findings.
COVID‐19, Environmental Impacts of
Authors: Swanson Emily , Mook Anne
Published: November 2024

In 2020 the COVID‐19 pandemic struck, spreading disease and death across the globe. The presence of this novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) changed life for people worldwide, bringing abrupt upheaval in daily life patterns and behaviors as well as causing immense fear and anxiety. Strategies to reduce the number of infections included use of personal protection equipment such as masks, increased ordering of goods online, and, for many, working and studying from home. As human behaviors changed, so did the impacts on the natural environment. This entry reviews the short‐lived positive and negative environmental impacts of the pandemic, focusing on medical waste and emissions, and concludes with a brief summary of these two examples of environmental impact of the pandemic, how the pandemic affected environmental concerns among the public, and a call for action to increase environmental research and improve environmental policy.
Death and Dying
Authors: Bray Rebecca Scott
Published: November 2024

This entry considers sociological attention to death and dying. It provides a historical overview of early sociological theorizing around the denial of death in the context of urbanization, professionalization, and bureaucratization. It charts how movements such as those around hospice care and natural death resisted the institutional control of death and sought to reclaim agency for dying individuals and their families. Central to agency at the end of life is the issue of a “good death” and what constitutes dying well. The tussle around agency has extended into the landscape of disposition choices and postdeath rituals in contemporary societies. The entry considers key topics of concern, and details the evolution of the interdisciplinary study of death and dying, before surveying the expanding field of death studies with its diverse current concerns and future research directions.
Immigrant Families
Authors: Wall Karin , Gaytán Marie Sarita
Published: November 2024

Sociologists have studied the effects of immigration policies and practices on immigrant families, and advanced our understanding of family reunification, the settlement of families, and integration challenges across different historical periods. More recent work on how gender and sexuality shape migrants' lives and rationales has shown that going beyond normative assumptions about the nuclear family can add crucial insights into the decision to migrate. The political climate of all destination communities has repercussions that can exacerbate vulnerabilities for immigrant families, immigrant adults, and immigrant youth. Possible directions for new research include the migration experiences of queer and trans chosen families, refugees, and asylum‐seekers.
Milk, Harvey (1930–1978)
Authors: Royce Tracy , Hidalgo Danielle Antoinette
Published: November 2024

Harvey Milk was the first out gay candidate to be elected to major political office in the state of California. Though his political career was tragically cut short when he was assassinated, Milk accomplished much during the final 11 months of his life, while serving as the first openly gay supervisor for San Francisco's District 5. He was a fierce advocate of disclosing one's sexual identity, or “coming out of the closet,” and sponsored a civil rights bill, signed into law by Mayor George Moscone, protecting employees from discrimination based on disclosure of sexual orientation. Milk actively opposed Proposition 6, the Briggs Initiative, which, had it passed, would have entailed the firing of gay and lesbian teachers in California. He also facilitated the creation of an enduring symbol of gay pride when he recruited the activist and flag‐maker Gilbert Baker to design the rainbow flag. In practice, Milk embraced a coalitional politics, advocating for gay men and lesbians, feminists, people of color, and others to work together to achieve social justice. Milk's life and achievements continue to inspire sociologists and others engaged with social movements, social change, and lesbian, gay, bisexual, transgender, and queer (LGBTQ+) studies.
Public Opinion
Authors: Beamish Rob
Published: November 2024

“Public opinion” is a contested term that is difficult to define. There is a central tension running through the study of public opinion. One side is captured by Charles Horton Cooley's view that public opinion is an organic process, the other by F.H. Allport's position that public opinion measures the statistical distributions of individuals' responses to opinion surveys. Jacques Necker, in 1789, was the first to popularize the term which came to represent the political views of the nascent middle class as it emerged in Europe and the pressures it created for the absolutist state. Today, public opinion and polling are seen as two sides of the same coin, although this changes the ontological status of “the public” and the epistemological understanding of “opinion.” Despite its contested nature, the conceptual tensions that run through its definition, identification, and critical assessment, public opinion remains a critical concept for understanding contemporary society.
Student Movements
Authors: Rootes Christopher
Published: November 2024

Student movements are social movements composed wholly or mainly of students, especially university or college students. They have attracted the interest of sociologists primarily since the emergence of student protests in the 1960s. Student movements appear across modern societies, engaging in political action through protest and campaigning, and have flourished whenever and wherever there has been an absence of effective political opposition to regimes or policies considered immoral or illegitimate. They are common in nondemocratic states in the process of political development, and unusual in fully democratic states. The confluence of demographic change, economic conditions, the development of higher education, and compelling political issues were conducive to the exceptional eruption of student movements in economically developed liberal democratic states in the 1960s and 1970s. Student protests that spring from narrowly sectional grievances are less likely to attract wide support or to effect political change than those that are driven by moral concerns. Student movements have an important place in the development of social movement theory.
Urban Poverty
Authors: Hyde Zachary
Published: November 2024

The study of urban poverty focuses on the origins and impacts of inequality in cities. From early works such as W.E.B. Du Bois's investigation of the spatial patterns of racism and segregation in the USA, researchers have used a range of methods to understand how economic, political, and social changes have led to changing patterns of poverty at the neighborhood level. In recent years, studies of urban poverty have focused on investigating issues of housing, eviction, and gentrification that are currently impacting cities, as well as incorporating an international comparative perspective.
Exploring the Intracellular Distribution of Se Compounds Delivered by Biodegradable Polyelectrolyte Capsules Using X‐Ray Fluorescence Imaging
Authors: Skiba Marvin , Reszegi Rebeka R. , Huang Yalan , Roy Sathi , Han Jili , Brückner Dennis , Sanchez‐Cano Carlos , Zhao Ying , Hassan Moustapha , Feliu Neus , Falkenberg Gerald , Parak Wolfgang J.
Published: November 2024

Selenium (Se) compounds hold promise as potential therapeutics for cancer due to their diverse biological functions and redox‐regulating properties. In this study, the encapsulation of a hydrophobic selenium compound inside 5 µm sized biodegradable polyelectrolyte capsules consisting of poly‐L‐arginine and dextran is investigated. While the encapsulated form of the compound showed comparable cellular uptake and cytotoxicity as the free drug, e.g. no improved anti‐cancer efficacy is achieved, the investigation yielded crucial insights. Utilizing subcellular resolution synchrotron X‐ray fluorescence imaging (XFI), the intracellular location of the Se compound is successfully visualized by demonstrating the degradation of the capsules and the following redistribution of the compound, without exogenous labeling. By applying a quantitative fitting approach, the intracellular Se mass is determined to be 0.09 ± 0.01 pg after degradation of the carrier. This highlights the potential of XFI as a powerful tool for tracking intracellular dynamics of metal‐based drugs, which may facilitate drug development in the clinic.
Highly Parallel and High‐Throughput Nanoliter‐Scale Liquid, Cell, and Spheroid Manipulation on Droplet Microarray
Authors: Urrutia Gómez Joaquin E. , Zhou Meijun , Mandsberg Nikolaj K. , Serna Julian A. , von Padberg Julius , Liu Sida , Reischl Markus , Levkin Pavel A. , Popova Anna A.
Published: November 2024

The droplet microarray (DMA) platform is a powerful tool for high‐throughput biological and chemical applications, enabling miniaturization and parallelization of experimental processes. Capable of holding hundreds of nanoliter droplets, it facilitates the screening and analysis of samples, such as cells, bacteria, embryos, and spheroids. Handling thousands of small volumes in parallel presents significant challenges. In this study, we utilize the open format of the DMA for controlled, parallel high‐throughput liquid manipulations using the sandwich technique. We demonstrate high‐throughput medium replacement at nanoliter‐scale, maintaining high cell viability on DMA for up to 7 days; for HeLa‐CLL2 cells (adherent) and SU‐DHL4 cells (suspension), and up to 14 days for HEK293 spheroids. Additionally, we achieve highly parallel aliquot uptake from nanoliter droplets, enabling non‐destructive cell viability assessments. Furthermore, the presented method enables the parallel transfer of cell spheroids between different DMAs, allowing transfer and pooling of spheroids in seconds without damage. These advances significantly enhance the capabilities of the DMA platform, enabling long‐term cell culture in nanoliter droplets and parallel sampling for high‐throughput cell or spheroid manipulation. This broadens the scope of DMA's potential applications in fields such as cell‐based high‐throughput screening, formation of complex 3D cell models for drug screening, and microtissue engineering.