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  • 1
    Electronic Resource
    Electronic Resource
    Evidence for a gelsolin-rich, labile F-actin pool in human polymorphonuclear leukocytes (1992)
    New York, NY : Wiley-Blackwell
    Cell Motility and the Cytoskeleton 21 (1992), S. 25-37 
    Details
    ISSN: 0886-1544
    Keywords: cytoskeleton ; human neutrophils ; actin binding proteins ; cytochalasins ; ultracentrifugation ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Filamentous (F) actin is a major cytoskeletal element in polymorphonuclear leukocytes (PMNs) and other non-muscle cells. Exposure of PMNs to agonists causes polymerization of monomeric (G) actin to F-actin and activates motile responses. In vitro, all purified F-actin is identical. However, in vivo, the presence of multiple, diverse actin regulatory and binding proteins suggests that all F-actin within cells may not be identical. Typically, F-actin in cells is measured by either NBDphallacidin binding or as cytoskeletal associated actin in Triton-extracted cells. To determine whether the two measures of F-actin in PMNs, NBDphallacidin binding and cytoskeletal associated actin, are equivalent, a qualitative and quantitative comparison of the F-actin in basal, non-adherent endo-toxin-free PMNs measured by both techniques was performed. F-actin as NBD-phallacidin binding and cytoskeletal associated actin was measured in cells fixed with formaldehyde prior to cell lysis and fluorescent staining (PreFix), or in cells lysed with Triton prior to fixation (PostFix). By both techniques, F-actin in PreFix cells is higher than in PostFix cells (54.25 ± 3.77 vs. 23.5 ± 3.7 measured as mean fluorescent channel by NBDphallacidin binding and 70.3 ± 3.5% vs. 47.2 ± 3.6% of total cellular actin measured as cytoskeletal associated actin). These results show that in PMNs, Triton exposure releases a labile F-actin pool from basal cells while a stable F-actin pool is resistant to Triton exposure. Further characterizations of the distinct labile and stable F-actin pools utilizing NBDphallacidin binding, ultracentrifugation, and electron microscopy demonstrate the actin released with the labile pool is lost as filament. The subcellular localization of F-actin in the two pools is documented by fluorescent microscopy, while the distribution of the actin regulatory protein gelsolin is characterized by immunoblots with antigelsolin. Our studies show that at least two distinct F-actin pools coexist in endotoxin-free, basal PMNs in suspension: (1) a stable F-actin pool which is a minority of total cellular F-actin, Triton insoluble, resistant to depolymerization at 4°C, gelsolin-poor, and localized to submembranous areas of the cell; and (2) a labile F-actin pool which is the majority of total cellular F-actin, Triton soluble, depolymerizes at 4°C, is gelsolin-rich, and distributed diffusely throughout the cell. The results suggest that the two pools may subserve unique cytoskeletal functions within PMNs, and should be carefully considered in efforts to elucidate the mechanisms which regulate actin polymerization and depolymerization in non-muscle cells.
    Additional Material: 12 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cm.970210104
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  • 2
    Electronic Resource
    Electronic Resource
    Role of tropomyosin, α-actinin, and actin binding protein 280 in stabilizing triton insoluble f-actin in basal and chemotactic factor activated neutrophils (1994)
    New York, NY : Wiley-Blackwell
    Cell Motility and the Cytoskeleton 28 (1994), S. 155-164 
    Details
    ISSN: 0886-1544
    Keywords: microfilamentous cytoskeleton ; actin binding proteins ; formyl peptides ; ionic extraction ; immunoblots ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: F-actin is a major component of the neutrophil (PMN) cytoskeleton. In basal PMNs, F-actin exists in two structurally and functionally distinct pools: Triton insoluble F-actin (TIF)-cold insensitive, not depolymerizable by dilution, and distributed in pseudopods and submembranous locations; and Triton soluble F-actin (TSF)-unstable in cold, diffusely distributed, and gelsolin enriched. The element(s) conferring these unique properties to the Triton insoluble F-actin pool are unknown, but logically include distinct actin regulatory proteins. To study the morphologic and functional determinants of the Triton insoluble F-actin pool, the distribution and quantity of three candidate regulatory proteins, α-actinin, tropomyosin (TM), and actin binding protein (ABP-280), were compared in F-actin (Triton insoluble and Triton soluble) and G-actin pools isolated from basal and chemotactic factor activated human PMNs in suspension, using immunoblots and ionic extraction. F-actin content was measured by NBDphallacidin binding and gel scans. The results show that: (1) α-actinin, actin binding protein 280, and tropomyosin are localized to TIF and excluded from TSF; (2) TM, α-actinin, and ABP 280 are required to stabilize fractions of Triton insoluble F-actin in PMNs; and (3) chemotactic factor activation results in release of a fraction of TM from the Triton insoluble F-actin pool in temporal association with F-actin polymerization in the Triton insoluble F-actin pool. Shifts in ABP 280 or α-actinin do not occur. The results suggest that TM, α-actinin, and ABP 280 provide structure to TIF and that TM release from TIF is involved in chemotactic factor induced actin polymerization in PMNs. © 1994 Wiley-Liss, Inc.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cm.970280207
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  • 3
    Electronic Resource
    Electronic Resource
    Dynamics of triton-insoluble and triton-soluble F-actin pools in calcium-activated human polymorphonuclear leukocytes: Evidence for regulation by gelsolin (1995)
    New York, NY : Wiley-Blackwell
    Cell Motility and the Cytoskeleton 30 (1995), S. 136-145 
    Details
    ISSN: 0886-1544
    Keywords: microfilamentous cytoskeleton ; actin binding proteins ; actin polymerization ; annealing ; non-muscle cells ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Gelsolin, a Ca++ activated, 90 kd actin binding protein, can regulate actin polymerization in polymorphonuclear leukocytes (PMNs) via severing of filaments to dissolve gels or by capping of filament ends to limit polymerization. In Triton-lysed PMNs, 30% of gelsolin is bound to the Triton-soluble F-actin (TSF) pool and none is bound to the Triton-insoluble F-actin (TIF) pool. Calcium-activated PMNs exhibit concurrent temporal and quantitative TIF growth and TSF and total F-actin loss. To determine if gelsolin plays a role in regulating TSF pool size, we monitored gelsolin-actin interactions and TIF, TSF and G-actin content at 5 second intervals in PMNs activated with the calcium ionophore, ionomycin. Actin pools were measured by NBDphallacidin binding and by gel scans and expressed relative to basal; gelsolin-actin interactions were measured as change in the amount of EGTA-resistant gelsolin:actin (G:A) complexes and by immunoblot quantification of gelsolin in actin pools. In basal PMNs, 33% of PMN gelsolin is bound in 1:1 EGTA-resistant G:A complexes and TSF and TIF retain 30% and 0% of PMN gelsolin, respectively. By 20 seconds after ionomycin addition, TSF decreases, TIF increases and a fraction of gelsolin repartitions from the TSF to the TIF pool. At maximum change (60 seconds), total F-actin (TIF + TSF) and TSF decrease and TIF increases by 25%; gelsolin is bound to both TSF and TIF (35% of total gelsolin in each pool), and 1:1 EGTA-resistant G:A complexes increase from 33% to 70%. No changes occur in cells activated by ionomycin in the absence of Ca++. The data show Ca++ activated TIF growth and TSF loss are temporally and quantitatively associated with an increase in the percent of gelsolin bound to actin and the translocation of gelsolin from TSF to TIF. This is unique, since no other PMN activator is known to repartition gelsolin into TIF actin. Further, the Ca++ activated initial increase in TIF concurrent with a fall in TSF without a change in total F-actin or G-actin content suggest that TIF grows initially only by TSF annealing/cross-linking to TIF. Gelsolin may regulate these events. © 1995 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cm.970300205
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  • 4
    Electronic Resource
    Electronic Resource
    A quantitative study of the role of F-actin in producing neutrophil shape (1991)
    New York, NY : Wiley-Blackwell
    Cell Motility and the Cytoskeleton 19 (1991), S. 159-168 
    Details
    ISSN: 0886-1544
    Keywords: cytoskeleton ; morphology ; polymorphonuclear leukocytes ; human neutrophils ; scanning electron microscopy ; cytochalasins ; formyl peptides ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Neutrophils change shape from round to polar and sequentially polymerize/depolymerize actin following chemotactic peptide activation in suspension. To study the relationship between changes in F-actin content and shape we altered the kinetics/extent of actin polymerization and depolymerization with tBOC peptide, cytochalasin D (CD), and low-dose FMLP, and determined the effect of these alterations on the temporal sequence of changes in neutrophil shape. F-actin was measured by FACS analysis of NBDphallacidin-stained cells and expressed as relative fluorescent intensity (RFI) compared to control (RFI = 1.00). Shape was determined by scanning electron microscopy. FMLP causes serial polymerization/depolymerization of actin (RFI = 1.00 ± 0.04, 1.60 ± 0.21, 1.10 ± 0.18, and 1.05 ± 0.14) associated with four distinct shapes (round-smooth, round-ruffled, blebbed, and polar) noted at 0, 30, 90, 300 sec respectively. Since blebbed and polar shapes appear concurrent with depolymerization and following polymerization, we determined whether depolymerization is required for polarization of cells. The kinetics of depolymerization were: (1) accelerated by tBOC addition at 45 sec, and (2) slowed by high concentrations of FMLP (〉10-7 M) (300 sec RFI = 1.46). Neither change altered the time course of shape change. To determine whether duration of actin polymerization defines shape, polymerization was halted by addition of tBOC at 5, 10, 20, 30 sec after FMLP to block actin polymerization and shape was monitored at 300 sec. TBOC added 5-20 sec after FMLP limited neutrophil shape change to the blebbed form, while tBOC addition 30 sec following FMLP resulted in a polar shape at 300 sec. To determine whether the extent of actin polymerization affects the shape change sequence, polymerization was limited by (1) inhibition of polymerization with CD, (2) exposure of cells to low concentrations of FMLP ( 〈 10-9 M), and (3) interruption of polymerization with tBOC. Actin polymerization to RFI 〈 1.35-fold basal results in blebbed shape; polymerization 〉 1.35-fold basal yields polar shape. The data show: (1) the human neutrophil demonstrates intermediate shapes when activated by chemotactic peptide, (2) depolymerization of F-actin does not determine shape, and (3) blebbed shape appears when actin polymerizes for 〉5 sec; polar shape with polymerization ≥30 sec to RFI 〉 1.35-fold basal. The data suggest actin polymerization is required for, and extent of polymerization determines, the shape of human neutrophils.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/cm.970190304
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  • 5
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    The Role of Immune-Response Gene Variants in Inhibitor Development in Black Patients with Hemophilia A. (2009)
    American Society of Hematology
    Details
    Publication Date: 2009-11-20
    Description: Abstract 1301 Poster Board I-323 Background Neutralizing factor VIII (FVIII) alloantibodies (“inhibitors”) develop in about 15% of all patients with hemophilia A following replacement therapy. The pathogenesis of this important treatment-related alloimmune complication is complex and involves both genetic and environmental factors, and likely their interactions. The type of hemophilia-causing FVIII gene (F8) mutation influences the risk of developing inhibitors with large deletions conferring the greatest risk and subtypes of single-base substitution mutations the lowest. Additional genetic factors that include possible transcription-modulating polymorphisms in the promoter regions of the structural loci encoding tumor necrosis factor a (TNFA), interleukin 10 (IL10), and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) were recently found to be associated with alloimmunization risk in the Malmo International Brother Study (MIBS). We recently demonstrated that mismatched FVIII replacement therapy due to the presence of common F8 nonsynonymous-single-nucleotide polymorphisms (ns-SNPs), which result in single amino acid changes in FVIII but do not cause hemophilia, may represent a novel genetic determinant of risk and contribute to the greater frequency of inhibitor development in black compared to white patients with hemophilia A (Viel et al. N Engl J Med. 360:1618-27, 2009). Because the implicated immune response gene variants described above were not controlled for in our initial study, however, we are now evaluating their influence on inhibitor development in this sample of black Americans with hemophilia A. Methods We used PCR and genomic DNA from 78 black hemophilia A patients to genotype a SNP in the TNFA promoter (-308 G〉A) and a CA-dinucleotide repeat polymorphism in the IL10 promoter (IL10G) by direct sequencing and fragment-length analysis, respectively. The inhibitor status, baseline severity, age at enrollment, and biologic relationships of these study subjects were already known as was their hemophilic F8 mutations and the background haplotypes on which they reside. Analyses for genotype-specific associations with inhibitor status were performed with and without controlling for background F8 haplotype. Results Although we found the frequency of the 134bp IL10 risk allele (102bp in our modified assay) to be 20.3%, which is similar to that observed previously in the largely Euro-Caucasian MIBS cohort (26.8%), no obvious association between inhibitor risk and genotypes containing this allele was identified in the black hemophilia A patients studied, even after controlling for the background F8 ns-SNP haplotype. The frequency we identified for the -308A TNFA risk allele (8.8%) was similar to that observed previously in non-hemophilic African Americans (12%), but was far less frequent than observed in the MIBS (32.9%). Analogous to the IL10 results, we identified no association between inhibitor development and TNFA genotypes containing the risk allele (which was only G/A heterozygotes since no homozygous A/A individuals were identified) in this black patient cohort, even after controlling for their ns-SNP haplotypes. Conclusions We found no association between inhibitor development in black Americans with hemohilia A and promoter variants in two immune response genes recently implicated as risk genotypes in the MIBS. While we did not replicate the prior findings, the small sample size of our present study could explain these results if a true functional variant in one of these genes either has a small effect or is in poor linkage disequilibrium with the typed variant in this black patient population. Our findings therefore require confirmation in a larger study, which is currently under way. Disclosures Howard: Haplomics, Inc.: Equity Ownership, Patents & Royalties. Kempton:Biomeasure Inc: Consultancy; CSL Behring Foundation: Research Funding.
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 6
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    Allelically Mismatched Replacement Therapy Due to Common African−Restricted Haplotypes of the Factor (F)VIII Protein May Underlie the Increased Incidence of FVIII Inhibitors Observed in Hemophilia−A Patients of African−Descent. (2006)
    American Society of Hematology
    Details
    Publication Date: 2006-11-16
    Description: Alloantibodies that inhibit the function of wildtype (wt) FVIII molecules constitute the most serious complication of replacement therapy for hemophilia (H)A patients. Although it is not possible to accurately predict which patients will develop inhibitors, ethnicity is a known risk factor as alloimmunization occurs ~2−fold more often in African Americans (AAs) than in Caucasians (Cs). Analysis of data from a resequencing study revealed that the FVIII gene (F8) contains four nonsynonymous−single nucleotide polymorphisms (ns−SNPs) that encode six distinct wt FVIII proteins designated haplotype (H)1−H6. While AAs express all but H6, only H1 and H2, the two recombinant (r)−FVIII proteins used clinically, are expressed by Cs. About 25% of AAs express H3, H4, or H5, proteins that differ structurally from r−FVIII at three ns−SNPs (R484H, D1241E, M2238V), two of which are located in dominant inhibitor epitopes and have AA−restricted minor−alleles. We designed the Pharmacogenetics of Inhibitor Risk (PIR) study to test the hypothesis that these ns−SNPs, when allelically mismatched in replacement therapy, are pharmacogenetic risk factors that contribute to the greater incidence of inhibitor development in patients of African−descent. We enrolled 94 of 223 total AA HA patients from collaborating treatment centers. Table 1 presents characteristics of the first 47 subjects (whose functional F8 regions have been resequenced entirely) including: FVIII haplotype (exposure) − H3/H4/H5 vs H1/H2; inhibitor status (outcome) − yes/no; F8 mutation − high−risk vs low−risk types; other covariates and potential confounders. A preliminary analysis demonstrated an odds ratio of 3.6 for inhibitors developing in the exposed subjects (P=0.10; 95% CI=0.7–17.6). Our finding suggests that pharmacogenetic factors may indeed contribute to the increased incidence of this alloimmune complication in AAs. To increase the power to detect a true association and allow adjustment for confounders, we are currently completing F8 resequencing in the next 47 patients. Table 1. Relevant characteristics of the first 47 African-American hemophilia-A PIR study patients*
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology
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  • 7
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    Phenotypes of Allo- and Autoimmune Antibody Responses to FVIII Characterized by Surface Plasmon Resonance (2013)
    Public Library of Science
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    Publication Date: 2013-05-08
    Electronic ISSN: 1932-6203
    Topics: Medicine , Natural Sciences in General
    Published by Public Library of Science
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  • 8
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    Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors (2017)
    Springer Nature
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    Publication Date: 2017-12-01
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 9
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    Pretreatment and routine echocardiogram monitoring during chemotherapy for anthracycline-induced cardiotoxicity rarely identifies significant cardiac dysfunction or alters treatment decisions (2011)
    Wiley
    Details
    Publication Date: 2011-08-31
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley on behalf of American Cancer Society.
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  • 10
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    Combination chemotherapy with ifosfamide and etoposide is effective in the treatment of central nervous system metastasis of childhood neuroblastoma (1992)
    Wiley
    Details
    Publication Date: 1992-06-15
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley on behalf of American Cancer Society.
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