13 results on '"Ladon, Dariusz"'
Search Results
2. Unraveling facets of MECOM-associated syndrome: somatic genetic rescue, clonal hematopoiesis, and phenotype expansion.
- Author
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Venugopal P, Arts P, Fox LC, Simons A, Hiwase DK, Bardy PG, Swift A, Ross DM, van Vulpen LFD, Buijs A, Bolton KL, Getta B, Furlong E, Carter T, Krapels I, Hoeks M, Al Kindy A, Al Kindy F, de Munnik S, Evans P, Frank MSB, Bournazos AM, Cooper ST, Ha TT, Jackson MR, Arriola-Martinez L, Phillips K, Brennan Y, Bakshi M, Ambler K, Gao S, Kassahn KS, Kenyon R, Hung K, Babic M, McGovern A, Rawlings L, Vakulin C, Dejong L, Fathi R, McRae S, Myles N, Ladon D, Jongmans M, Kuiper RP, Poplawski NK, Barbaro P, Blombery P, Brown AL, Hahn CN, and Scott HS
- Subjects
- Humans, Mutation, Syndrome, Clonal Hematopoiesis, Phenotype
- Published
- 2024
- Full Text
- View/download PDF
3. TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms.
- Author
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Shah MV, Tran ENH, Shah S, Chhetri R, Baranwal A, Ladon D, Shultz C, Al-Kali A, Brown AL, Chen D, Scott HS, Greipp P, Thomas D, Alkhateeb HB, Singhal D, Gangat N, Kumar S, Patnaik MM, Hahn CN, Kok CH, Tefferi A, and Hiwase DK
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Alleles, Mutation, Prognosis, Retrospective Studies, Gene Frequency, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes therapy, Tumor Suppressor Protein p53 genetics
- Abstract
Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53
mut ) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut . We analyzed 488 t-MN patients for TP53mut . At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt ) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt . Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status., (© 2023. Crown.)- Published
- 2023
- Full Text
- View/download PDF
4. TP53 mutation in therapy-related myeloid neoplasm defines a distinct molecular subtype.
- Author
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Hiwase D, Hahn C, Tran ENH, Chhetri R, Baranwal A, Al-Kali A, Sharplin K, Ladon D, Hollins R, Greipp P, Kutyna M, Alkhateeb H, Badar T, Wang P, Ross DM, Singhal D, Shanmuganathan N, Bardy P, Beligaswatte A, Yeung D, Litzow MR, Mangaonkar A, Giri P, Lee C, Yong A, Horvath N, Singhal N, Gowda R, Hogan W, Gangat N, Patnaik M, Begna K, Tiong IS, Wei A, Kumar S, Brown A, Scott H, Thomas D, Kok CH, Tefferi A, and Shah MV
- Subjects
- Humans, Mutation, Tumor Suppressor Protein p53 genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Myeloproliferative Disorders genetics
- Published
- 2023
- Full Text
- View/download PDF
5. A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program.
- Author
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Rice S, Jackson T, Crump NT, Fordham N, Elliott N, O'Byrne S, Fanego MDML, Addy D, Crabb T, Dryden C, Inglott S, Ladon D, Wright G, Bartram J, Ancliff P, Mead AJ, Halsey C, Roberts I, Milne TA, and Roy A
- Subjects
- Animals, CRISPR-Cas Systems, DNA-Binding Proteins, Female, Gene Editing, Histone-Lysine N-Methyltransferase, Humans, Liver, Mice, Myeloid-Lymphoid Leukemia Protein metabolism, Oncogene Proteins, Fusion metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Transcriptional Elongation Factors, Fetus, Gene Expression Regulation, Neoplastic, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Proteins, Fusion genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism
- Abstract
Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Using the most common MLL-r in infant-ALL, MLL-AF4, as a disease model, we show that fetal-specific gene expression programs are maintained in MLL-AF4 infant-ALL but not in MLL-AF4 childhood-ALL. We use CRISPR-Cas9 gene editing of primary human fetal liver hematopoietic cells to produce a t(4;11)/MLL-AF4 translocation, which replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data support the hypothesis that fetal-specific gene expression programs cooperate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL., (© 2021. The Author(s).)
- Published
- 2021
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- View/download PDF
6. Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott - Aldrich Syndrome.
- Author
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Rai R, Romito M, Rivers E, Turchiano G, Blattner G, Vetharoy W, Ladon D, Andrieux G, Zhang F, Zinicola M, Leon-Rico D, Santilli G, Thrasher AJ, and Cavazza A
- Subjects
- Animals, Blood Platelets metabolism, CRISPR-Cas Systems genetics, Cell Lineage, Codon genetics, Female, Genetic Loci, HEK293 Cells, Hematopoietic Stem Cell Transplantation, High-Throughput Nucleotide Sequencing, Humans, Macrophages metabolism, Male, Mice, Mutagenicity Tests, Myeloid Cells metabolism, T-Lymphocytes metabolism, Wiskott-Aldrich Syndrome pathology, Wiskott-Aldrich Syndrome Protein genetics, Gene Editing, Genetic Therapy, Hematopoietic Stem Cells metabolism, Wiskott-Aldrich Syndrome genetics, Wiskott-Aldrich Syndrome therapy
- Abstract
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with severe platelet abnormalities and complex immunodeficiency. Although clinical gene therapy approaches using lentiviral vectors have produced encouraging results, full immune and platelet reconstitution is not always achieved. Here we show that a CRISPR/Cas9-based genome editing strategy allows the precise correction of WAS mutations in up to 60% of human hematopoietic stem and progenitor cells (HSPCs), without impairing cell viability and differentiation potential. Delivery of the editing reagents to WAS HSPCs led to full rescue of WASp expression and correction of functional defects in myeloid and lymphoid cells. Primary and secondary transplantation of corrected WAS HSPCs into immunodeficient mice showed persistence of edited cells for up to 26 weeks and efficient targeting of long-term repopulating stem cells. Finally, no major genotoxicity was associated with the gene editing process, paving the way for an alternative, yet highly efficient and safe therapy.
- Published
- 2020
- Full Text
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7. DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study.
- Author
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Pickles JC, Fairchild AR, Stone TJ, Brownlee L, Merve A, Yasin SA, Avery A, Ahmed SW, Ogunbiyi O, Gonzalez Zapata J, Peary AF, Edwards M, Wilkhu L, Dryden C, Ladon D, Kristiansen M, Rowe C, Kurian KM, Nicoll JAR, Mitchell C, Bloom T, Hilton DA, Al-Sarraj S, Doey L, Johns PN, Bridges LR, Chakrabarty A, Ismail A, Rathi N, Syed K, Lammie GA, Limback-Stanic C, Smith C, Torgersen A, Rae F, Hill RM, Clifford SC, Grabovska Y, Williamson D, Clarke M, Jones C, Capper D, Sill M, von Deimling A, Pfister SM, Jones DTW, Hargrave D, Chalker J, and Jacques TS
- Subjects
- Biomarkers, Tumor genetics, Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms therapy, Child, Humans, Retrospective Studies, Telomerase, Central Nervous System Neoplasms diagnosis, DNA Methylation physiology, Gene Expression Regulation, Neoplastic physiology, Molecular Targeted Therapy
- Abstract
Background: Marked variation exists in the use of genomic data in tumour diagnosis, and optimal integration with conventional diagnostic technology remains uncertain despite several studies reporting improved diagnostic accuracy, selection for targeted treatments, and stratification for trials. Our aim was to assess the added value of molecular profiling in routine clinical practice and the impact on conventional and experimental treatments., Methods: This population-based study assessed the diagnostic and clinical use of DNA methylation-based profiling in childhood CNS tumours using two large national cohorts in the UK. In the diagnostic cohort-which included routinely diagnosed CNS tumours between Sept 1, 2016, and Sept 1, 2018-we assessed how the methylation profile altered or refined diagnosis in routine clinical practice and estimated how this would affect standard patient management. For the archival cohort of diagnostically difficult cases, we established how many cases could be solved using modern standard pathology, how many could only be solved using the methylation profile, and how many remained unsolvable., Findings: Of 484 patients younger than 20 years with CNS tumours, 306 had DNA methylation arrays requested by the neuropathologist and were included in the diagnostic cohort. Molecular profiling added a unique contribution to clinical diagnosis in 107 (35%; 95% CI 30-40) of 306 cases in routine diagnostic practice-providing additional molecular subtyping data in 99 cases, amended the final diagnosis in five cases, and making potentially significant predictions in three cases. We estimated that it could change conventional management in 11 (4%; 95% CI 2-6) of 306 patients. Among 195 historically difficult-to-diagnose tumours in the archival cohort, 99 (51%) could be diagnosed using standard methods, with the addition of methylation profiling solving a further 34 (17%) cases. The remaining 62 (32%) cases were unresolved despite specialist pathology and methylation profiling., Interpretation: Together, these data provide estimates of the impact that could be expected from routine implementation of genomic profiling into clinical practice, and indicate limitations where additional techniques will be required. We conclude that DNA methylation arrays are a useful diagnostic adjunct for childhood CNS tumours., Funding: The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
8. Long Terminal Repeat CRISPR-CAR-Coupled "Universal" T Cells Mediate Potent Anti-leukemic Effects.
- Author
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Georgiadis C, Preece R, Nickolay L, Etuk A, Petrova A, Ladon D, Danyi A, Humphryes-Kirilov N, Ajetunmobi A, Kim D, Kim JS, and Qasim W
- Subjects
- Animals, Antigens, CD19 immunology, Disease Models, Animal, Gene Order, Genetic Vectors genetics, Humans, Immunophenotyping, Immunotherapy, Adoptive methods, In Situ Hybridization, Fluorescence, Lentivirus genetics, Leukemia genetics, Leukemia immunology, Leukemia therapy, RNA, Guide, CRISPR-Cas Systems, Receptors, Chimeric Antigen, Treatment Outcome, Xenograft Model Antitumor Assays, Clustered Regularly Interspaced Short Palindromic Repeats, Gene Editing, Receptors, Antigen, T-Cell genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, Terminal Repeat Sequences
- Abstract
Gene editing can be used to overcome allo-recognition, which otherwise limits allogeneic T cell therapies. Initial proof-of-concept applications have included generation of such "universal" T cells expressing chimeric antigen receptors (CARs) against CD19 target antigens combined with transient expression of DNA-targeting nucleases to disrupt the T cell receptor alpha constant chain (TRAC). Although relatively efficient, transgene expression and editing effects were unlinked, yields variable, and resulting T cell populations heterogeneous, complicating dosing strategies. We describe a self-inactivating lentiviral "terminal" vector platform coupling CAR expression with CRISPR/Cas9 effects through incorporation of an sgRNA element into the ΔU3 3' long terminal repeat (LTR). Following reverse transcription and duplication of the hybrid ΔU3-sgRNA, delivery of Cas9 mRNA resulted in targeted TRAC locus cleavage and allowed the enrichment of highly homogeneous (>96%) CAR
+ (>99%) TCR- populations by automated magnetic separation. Molecular analyses, including NGS, WGS, and Digenome-seq, verified on-target specificity with no evidence of predicted off-target events. Robust anti-leukemic effects were demonstrated in humanized immunodeficient mice and were sustained longer than by conventional CAR+ TCR+ T cells. Terminal-TRAC (TT) CAR T cells offer the possibility of a pre-manufactured, non-HLA-matched CAR cell therapy and will be evaluated in phase 1 trials against B cell malignancies shortly., (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
9. Report from the European Myeloma Network on interphase FISH in multiple myeloma and related disorders.
- Author
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Ross FM, Avet-Loiseau H, Ameye G, Gutiérrez NC, Liebisch P, O'Connor S, Dalva K, Fabris S, Testi AM, Jarosova M, Hodkinson C, Collin A, Kerndrup G, Kuglik P, Ladon D, Bernasconi P, Maes B, Zemanova Z, Michalova K, Michau L, Neben K, Hermansen NE, Rack K, Rocci A, Protheroe R, Chiecchio L, Poirel HA, Sonneveld P, Nyegaard M, and Johnsen HE
- Subjects
- Humans, In Situ Hybridization, Fluorescence methods, Practice Guidelines as Topic, In Situ Hybridization, Fluorescence standards, Multiple Myeloma diagnosis
- Abstract
The European Myeloma Network has organized two workshops on fluorescence in situ hybridization in multiple myeloma. The first aimed to identify specific indications and consensus technical approaches of current practice. A second workshop followed a quality control exercise in which 21 laboratories analyzed diagnostic cases of purified plasma cells for recurrent abnormalities. The summary report was discussed at the EHA Myeloma Scientific Working Group Meeting 2010. During the quality control exercise, there was acceptable agreement on more than 1,000 tests. The conclusions from the exercise were that the primary clinical applications for FISH analysis were for newly diagnosed cases of MM or frank relapse cases. A range of technical recommendations included: 1) material should be part of the first draw of the aspirate; 2) samples should be sent at suitable times to allow for the lengthy processing procedure; 3) most importantly, PCs must be purified or specifically identified; 4) positive cut-off levels should be relatively conservative: 10% for fusion or break-apart probes, 20% for numerical abnormalities; 5) informative probes should be combined to best effect; 6) in specialist laboratories, a single experienced analyst is considered adequate; 7) at least 100 PC should be scored; 8) essential abnormalities to test for are t(4;14), t(14;16) and 17p13 deletions; 9) suitable commercial probes should be available for clinically relevant abnormalities; 10) the clinical report should be expressed clearly and must state the percentage of PC involved and the method used for identification; 11) a retrospective European based FISH data bank linked to clinical data should be generated; and 12) prospective analysis should be centralized for upcoming trials based on the recommendations made. The European Myeloma Network aims to build on these recommendations to establish standards for a common European data base to define subgroups with prognostic significance.
- Published
- 2012
- Full Text
- View/download PDF
10. Mott cells in CD20-positive myeloma.
- Author
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Ramasamy K, Ladon D, Salisbury J, and Ireland R
- Subjects
- Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 14 genetics, Female, Humans, Inclusion Bodies pathology, Middle Aged, Multiple Myeloma genetics, Multiple Myeloma immunology, Translocation, Genetic, Antigens, CD20 analysis, Multiple Myeloma pathology, Plasma Cells pathology
- Published
- 2011
- Full Text
- View/download PDF
11. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study.
- Author
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Schey SA, Morgan GJ, Ramasamy K, Hazel B, Ladon D, Corderoy S, Jenner M, Phekoo K, Boyd K, and Davies FE
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols toxicity, Cyclophosphamide administration & dosage, Cyclophosphamide toxicity, Dexamethasone administration & dosage, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Hematologic Diseases chemically induced, Humans, Lenalidomide, Male, Maximum Tolerated Dose, Middle Aged, Survival Analysis, Thalidomide administration & dosage, Thalidomide analogs & derivatives, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Multiple Myeloma drug therapy
- Abstract
We report the results of a Phase I/II dose escalation study to determine the maximum tolerated dose (MTD) of cyclophosphamide when combined with lenalidomide and dexamethasone in relapsed/refractory myeloma. Thirty-one patients were enrolled in cohorts of 3, at five dose levels of cyclophosphamide to a maximum of 700 mg on days 1 and 8 of a 28-d cycle. Patients received lenalidomide 25 mg days 1-21 and dexamethasone 20 mg orally days 1-4 and 8-11. The MTD was 600 mg cyclophosphamide, days 1 and 8. Grade 3/4 haematological complications occurred in 26% of patients, grade 3/4 infection in 3% (both at 700 mg cyclophosphamide), with thromboembolic complications in 6% of patients. Overall complete response (CR) rate was 29%, very good partial response rate 7% and partial response rate 45% giving an overall response rate of 81%. After 21 months median follow-up, projected 2-year progression-free survival was 56%, with 80% overall survival at 30 months. Ten further patients were treated at MTD with a 40% CR rate. No dose reductions for any study drugs or deaths occurred during cycles 1-9. Lenalidomide, cyclophosphamide and dexamethasone is a safe, effective combination in relapsed myeloma inducing a high response rate, warranting further investigation in phase III trials.
- Published
- 2010
- Full Text
- View/download PDF
12. Genotoxic effects of particles of surgical cobalt chrome alloy on human cells of different age in vitro.
- Author
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Papageorgiou I, Yin Z, Ladon D, Baird D, Lewis AC, Sood A, Newson R, Learmonth ID, and Case CP
- Subjects
- Apoptosis drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Chromosome Aberrations chemically induced, Chromosome Painting, Cytogenetics, DNA Damage, Gene Expression drug effects, Humans, In Vitro Techniques, Mitochondria drug effects, Mitochondria metabolism, Reverse Transcriptase Polymerase Chain Reaction, Cellular Senescence drug effects, Cellular Senescence genetics, Chromium Alloys toxicity, Mutagens toxicity
- Abstract
Humans are exposed to metals from industry, the environment and from wear debris from worn orthopaedic joint replacements. Patients exposed to worn cobalt chrome hip replacements show an increase of chromosome aberrations in the bone marrow adjacent to the implant and an increase of chromosome translocations and aneuploidy in the peripheral blood. This study has tested whether particles of surgical cobalt chrome alloy are able to induce similar DNA damage and chromosome aberrations in human cells in vitro. Because increasingly young patients are receiving hip replacements it has also tested whether the response is altered at different cellular age in vitro. Primary human fibroblasts, were tested at different pre senescent population doublings (PD10 (young) and PD35 (older)) to particles of cobalt chrome alloy for up to 15 days. As in patients there was an increase of aneuploidy, chromosome translocations and DNA damage after exposure to the cobalt chrome particles in vitro. The overall level of DNA damage and numerical and structural aberrations was approximately the same in young and older cells. However, the cellular reaction to the DNA damage was different. Older cells showed a greater loss of viability and induction of senescence and a lesser rate of mitosis and cell growth than young cells. They showed less change in transcription, particularly of p38 and caspase 10 mRNA levels, than young cells. They showed more complex aneuploidy in association with unseparated or prematurely separated chromatids. This study suggests that at least part of the chromosome changes in patients with worn implants may be due to direct effects of the metal wear particles from the implant. It would be of interest to test whether the altered reaction of the human cells at different in vitro age might correspond with a different incidence of chromosome aberrations in patients at different ages.
- Published
- 2007
- Full Text
- View/download PDF
13. Changes in metal levels and chromosome aberrations in the peripheral blood of patients after metal-on-metal hip arthroplasty.
- Author
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Ladon D, Doherty A, Newson R, Turner J, Bhamra M, and Case CP
- Subjects
- Aged, Aged, 80 and over, Aneuploidy, Arthroplasty, Replacement, Hip adverse effects, Chromium blood, Cobalt blood, Humans, Middle Aged, Molybdenum blood, Prospective Studies, Prosthesis Design, Prosthesis Failure, Translocation, Genetic, Chromosome Aberrations, Hip Prosthesis adverse effects, Metals blood
- Abstract
A prospective study was performed to investigate changes in metal levels and chromosome aberrations in patients within 2 years of receiving metal-on-metal hip arthroplasties. There was a statistically significant increase of cobalt and chromium concentrations, with a small increase in molybdenum, in whole blood at 6, 12, and 24 months after surgery. There was also a statistically significant increase of both chromosome translocations and aneuploidy in peripheral blood lymphocytes at 6, 12, and 24 months after surgery. The changes were generally progressive with time, but the change in aneuploidy was much greater than in chromosome translocations. No statistically significant correlations were found in secondary analyses between chromosome translocation indices and cobalt or chromium concentration in whole blood. Although the clinical consequences of these changes, if any, are unknown, future epidemiological studies could usefully include direct comparisons of patients with implants of different composition.
- Published
- 2004
- Full Text
- View/download PDF
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