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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1373-1381
Epstein-Barr Virus (EBV) in Endemic Burkitt's Lymphoma:
Molecular Analysis of Primary Tumor Tissue
By
Qian Tao,
Keith D. Robertson,
Angela Manns,
Allan Hildesheim, and
Richard F. Ambinder
From the Oncology Center, Johns Hopkins Medical Institutions,
Baltimore, MD, and the National Institutes of Health, Rockville, MD.
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ABSTRACT |
Many aspects of Epstein-Barr virus (EBV) and tumor biology have been
studied in Burkitt's lymphoma (BL)-derived cell lines. However, in
tissue culture, patterns of gene expression and CpG
methylation often change and viral strain selection may occur. In this
report, 10 cases of snap-frozen endemic BL tumors are characterized in
terms of viral gene expression, promoter usage, methylation, and viral
strain. EBNA1 and BamHI-A rightward transcripts (BART) were
detected in 7 of 7 and LMP2A transcripts in 5 of 7 tumors with
well-preserved RNA. Transcripts for the other EBNAs and for LMP1 were
not detected in any tumor. These tumors differ from BL cell lines in
that they lack a variety of lytic cycle transcripts. This pattern of
viral gene expression in endemic BL is similar to that reported in
peripheral blood mononuclear cells (PBMCs) from healthy
EBV-seropositive individuals. EBNA1 transcripts originated from the Q
promoter (Qp) but not C, W, or F promoters that drive transcription of
EBNA1 in other circumstances. Whereas Cp has been previously shown to
be entirely CpG methylated in BL, bisulfite genomic sequencing showed
virtually no methylation in Qp. Type-A EBV was detected in 6 of 10 and
type B in 4 of 10 cases. A previously reported 30bp deletion variant in
the carboxyl terminal of LMP1 gene was detected in 5 of 10 cases. The
association with both A and B strains contrasts with EBV-associated
Hodgkin's disease, nasopharyngeal carcinoma, and post-transplant
lymphoproliferative disease, which are much more consistently
associated with A strain virus.
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INTRODUCTION |
DENNIS BURKITT CALLED attention to the
rapidly growing tumor in African children, that now bears his name, in
1958.1 The endemic form of Burkitt's lymphoma (eBL) that
he described affects children in malarial areas of equatorial Africa
and is consistently associated with Epstein-Barr virus
(EBV).2-4 Elsewhere in the world the association with EBV
is less consistent ranging from 20% to 80%.4-9
Studies of Burkitt's-derived cell lines have led to a variety of
important advances, among them the identification of EBV itself, the
initial characterization of the viral requirements for B-cell
immortalization, and mapping of the c-myc locus to chromosome 8 (reviewed by I. Magrath1). EBV transcription and replication have been studied extensively in these cell lines. In fact,
the three different types of EBV latent gene expression were also
recognized first in Burkitt's cell lines.10-12 However, these studies have also underscored the inherent limitations of cell
line research. Introduction of tumor cells into culture initiates a
series of phenotypic and genetic changes. In early passage BL cell
lines EBNA1 is the only nuclear antigen transcribed, whereas in late
passage BL cell lines, the whole family of EBNAs is transcribed. The
promoter driving EBNA1 expression is also different in some early and
late passage cell lines. In early passage cell lines the Q promoter
(Qp) is used, whereas in late passage cell lines the C promoter (Cp)
can be used.13 In some circumstances the F promoter (Fp) or
W promoter (Wp) may be used. Promoter switching can happen quite
rapidly in culture. EBNA expression in newly infected B cells is
initially driven by the Wp but within hours changes to
Cp.14 Similarly, patterns of methylation change in culture.
Thus, the study of cell lines, even early passage cell lines, cannot
provide definitive information with regard to promoter usage or
methylation status in vivo.
Whereas patterns of viral transcription have been studied directly in
Hodgkin's disease (HD), nasopharyngeal carcinoma (NPC), peripheral
T-cell lymphoma, nasal natural killer-(NK) and T-cell lymphoma, and
other tumors,15-21 patterns of expression in Burkitt's tumors have only been studied in cell lines or by
immunohistochemistry.3,6,22 Similarly, whereas studies of
viral strain in NPC, HD, and other tumors have been carried out
directly on tumor tissue, surveys of strain association with BL have
been mainly carried out on cultured cell lines. The hazards of
inference about strain on the basis of cultured cell lines is
illustrated by studies of lymphocyte immortalization that show that
A-strain virus is much more efficient at immortalization than B-strain
virus, and thus will be more readily detected in lymphocyte
immortalization assays.23 To characterize various aspects
of EBV infection in eBL, we have studied DNA and RNA extracted directly
from a collection of snap-frozen BL specimens from Ghana, Africa.
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MATERIALS AND METHODS |
Tumor samples and cell lines.
Ten BL tumor specimens were from the National Cancer Institute's BL
tumor project at the University of Ghana at Accra, Ghana. BL1-5 have
been described in an earlier report.24 NPC biopsy specimens
from Taiwanese patients and post-transplant lymphoproliferative disease
(PTLD) from patients at Johns Hopkins (Baltimore, MD) served as controls for EBV gene expression. The EBV-negative B-cell line, BJAB, was used as negative control for reverse-transcription polymerase chain reaction (RT-PCR). All cell lines were cultivated at
37°C in RPMI 1640 supplemented with 10% fetal bovine serum, 1 mmol/L glutamine, 100 U/mL penicillin and streptomycin. 5-azacytidine treatment for the Rael cell line (Rael-AzaC) was performed as previously described.25
RT-PCR for EBV transcripts.
The sequences of RT-PCR primers and internal probes are listed in
Table 1. Total RNA was extracted from
frozen BL tumors and cell line pellets by using TriZol (GIBCO BRL,
Gaithersburg, MD). RT-PCR was performed by using random
hexamers and the GeneAmp RNA PCR kit (Perkin Elmer-Cetus, Norwalk,
CT). The PCR reaction involved an initial denaturation at
95°C for 3 minutes, followed by 40 cycles consisting of 94°C
for 30 seconds, optimal annealing temperature for 1 minute, 72°C
for 1 minute, and a final extension at 72°C for 10 minutes. The
RT-PCR product was electrophoresed on a 1.8% agarose gel and alkali
transferred with 0.4 mol/L NaOH onto HyBond N(+) membrane. The membrane
was hybridized using 32P-labeled internal oligonucleotide
probe and the Rapid-Hyb buffer system (Amersham, Arlington Heights,
IL) at 52°C for 2 hours. The membrane was then washed
and autoradiographed. The strength of the RT-PCR signal after Southern
hybridization was graded as: ++ (strong signal after 1 hour exposure), + (strong signal after overnight exposure), and +/ (weak signal after
overnight exposure).
Bisulfite genomic sequencing.
DNA was treated with bisulfite as previously
described.25,26 Briefly, the DNA was digested with EcoRI,
denatured with NaOH, precipitated, and incubated with 3.1 mol/L sodium
bisulfite (Sigma Chemical Co, St. Louis, MO) at 50°C
for 16 hours in darkness. After the reaction, DNA was desalted and
purified. The DNA was then alkaline treated with 0.3 mol/L NaOH and
recovered. The bisulfite-treated DNA was PCR amplified with
strand-specific primers (for the bottom strand): 5 -AACTAACCTAACTA
AAAATAAAAC (corresponding to EBV coordinate 62179-62202),
5-AATGTAAGGATAGTATGTATTATT (corresponding to EBV coordinate
62481-62458). The PCR products were electrophoresed, excised, purified,
and then cloned into the pCR2.1-TA cloning vector (Invitrogen,
Carlsbad, CA). Four to six colonies were analyzed for each
DNA sample. Plasmid DNA was then extracted and sequenced.
Genotyping for EBNA3C and LMP1 gene deletion.
EBV subtypes (A, B) were determined with PCR by using primers spanning
the EBNA3C region.27 Analysis of the previously reported 30bp deletion at the carboxyl terminus of LMP1 gene was performed by
PCR.28,29 Primers were as follows: 5-CCGCTGCCTCATAGCCC (168408-168392), 5-TTAGCTGAACTGGGCCG (168174-168190). B95-8
was used as the control for type-A strain and wild-type LMP1
gene, whereas AG876 was the control for type-B EBV and the deleted LMP1 gene.
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RESULTS |
EBV gene expression in eBL.
Tissue RNA was well preserved in seven BL cases. RT-PCR for EBV
transcripts showed EBNA1 transcript originating in Qp in all seven BL
tumors (Fig 1). In one tumor, weak
Cp/Wp-initiated EBNA1 and EBNA2 transcripts were also detected. No
Fp-initiated EBNA1 transcript and no LMP1 transcripts were detected in
any tumor. LMP2A but not LMP2B transcript was detected in five of seven
cases. BamHI-A rightward transcripts (BART) were expressed in
all seven cases. Weak lytic and latent BHRF1 transcripts, whose encoded protein is a Bcl-2 homolog, were detected in four cases. Lytic BLLF1
transcript that encodes a viral envelope glycoprotein gp220 was
detected in three cases. These results are summarized in
Table 2.
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| Fig 1.
Autoradiography showing representative Southern blot
hybridization of RT-PCR products for eBL tumors and BL cell lines.
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EBV gene expression in BL cell lines.
The patterns of gene expression in BL cell lines differed from those
observed in BL tumors. Although similar to eBL, type-I cell lines
(Rael, Akata, Chep) differed in that lytic transcripts (BZLF1, BHRF1,
BLLF1) generally not detected in eBL tumor tissue were expressed. Cell
lines (Wan, Wewak, and Namalwa) differed from eBL in expressing the
LMP1 transcript and also differed from latency II tumors (NPC, HD, and
nasal lymphoma) in that the Cp/Wp-initiated YUK transcript for EBNA1
was detected. Expression of EBNA2 and EBNA3C transcripts was also
detected in these cell lines. The Wan cell line has been previously
classified as type I/II.12 As expected, all viral
transcripts studied were expressed in type-III BL cell lines
(Rael-AzaC, Raji and AG876) and lymphoblastoid cell lines (LCL).
Methylation status of Qp.
Because Qp is the only promoter used for EBNA1 in eBL, the methylation
status of its CpG sites was studied in eight cases. Twenty CpG sites in
the minimal Qp and adjacent sequences were studied.30-32
Among these CpG sites, all 16 CpG sites downstream of the Fp initiation
site that include the whole Qp region were unmethylated in virtually
all eBL samples studied (Fig 2). These sites were also unmethylated in the Rael cell line. However, the 4 CpG
sites upstream of the initiation site of Fp were variably methylated in
eBL and Rael cell line (Fig 3). Treatment
with 5-azacytidine led to the disappearance of methylation at these 4 sites in Rael and an increase in Fp activity.
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| Fig 2.
Summary of the methylation status of CpG sites in
Qp region in eBL tumors. The top panel shows the structure of Qp and
Fp. The region from CpG sites #8 to #15 corresponds to the minimal region required for Qp function.30-32 The CAAT and TATA box
for Fp and an inverted CCAAT box for Qp are labeled. The transcription initiation sites of Qp (EBV coordinate 62422) and Fp (EBV coordinate 62230) are indicated. The binding sites for EBNA1 are shown by boxes.
(m) indicates methylated CpG sites, (-) indicates unmethylated CpG
sites.
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| Fig 3.
Genomic sequencing for bisulfite-treated DNA from eBL
tumors for Qp. For bisulfite sequencing, the unmethylated C residue (or
G at the opposite strand) within a CpG site will be converted to T (or
A) in sequencing gel, whereas the methylated C residue is not changed.
CpG sites 1 to 8 were sequenced from one direction, whereas CpG sites 9 to 20 were sequenced from another direction. All 16 CpG sites
immediately downstream of the initiation site of Fp were unmethylated
in BL1 and BL2. However, the 4 CpG sites upstream of the initiation
site of Fp were methylated in BL2. Dark arrows indicate unmethylated
CpG dinucleotides and open arrows indicate methylated CpG
dinucleotides.
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EBV genotyping.
PCR amplification of the EBNA3C region yields a 153-bp band for type-A
and a 246-bp band for type-B EBV. Six of 10 eBL cases harbored type-A
virus, whereas 4 of 10 cases harbored type-B EBV (Fig 4). In 1 case (BL1), a strong type-A
band and a very weak type-B band were both detected consistent with
dual infection. PCR amplification of the carboxyl terminal region of
LMP1 gene yields a 235-bp band for the wild-type LMP1 gene but a 205-bp band for the deleted type. The presence of the 30bp deletion was shown
in 5 of 10 cases (Fig 4). There was no apparent relationship between
the EBV strain and the presence or absence of the LMP1 carboxyl
terminal deletion (Table 3).
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| Fig 4.
Genotyping for EBNA3C subtypes and LMP1 gene
deletion by PCR in eBL tumors and BL cell lines. A 153-bp band for
type-A EBV and a 246-bp band for type B virus are shown.
A 30-bp deletion at the carboxyl terminus of LMP1 gene is shown by the
shorter PCR product of 205-bp, rather than a 235-bp band for the
wild-type LMP1 gene.
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DISCUSSION |
By RT-PCR, we have characterized the pattern of EBV gene expression in
eBL tumors. In many regards the pattern of transcription corresponds to
the latency I pattern, ie, EBNA1 is expressed from Qp whereas most of
the rest of the genome is silent.10,11 However, both the
BART and LMP2A transcripts were also detected in eBL tumors. This viral
expression pattern is similar to that reported in peripheral blood
mononuclear cells (PBMCs) isolated from healthy EBV-seropositive
individuals. EBNA1 and LMP2A transcripts have been detected in
PBMCs.33-35 Recently, BART transcripts have also been
detected in PBMCs from a healthy individual (H.L. Chen, personal communication, June 1997). Although BL tumors are actively
proliferating with a very high mitotic index while PBMCs, which are the
locus of latent EBV infection in healthy seropositive individuals, are resting,36,37 these findings highlight the parallels in
patterns of viral gene expression between the two situations.
The expression level of LMP2A RNA as detected by RT-PCR in eBL is
similar to what we have observed in NPC and as reported by
others,15,17 and is also similar to that reported in nasal lymphoma,20 HD,16 and T-cell
lymphoma.18 Because immunologic reagents are not yet
generally available to reliably detect the LMP2 antigen in tumor
specimens, we do not know whether LMP2A protein is expressed in all
tumor cells or just in a small percentage of them and what the protein
expression level is. Although LMP2A RNA thus appears to be almost
ubiquitous in EBV-infected cells, its role in the EBV life cycle
remains ill defined. It appears not to be required for lymphocyte
immortalization, because a mutant virus lacking functional LMP2A gene
is able to infect and immortalize B cells.38 However, a
recent study showed that the transforming ability of a mini-EBV
without the LMP2A gene is greatly impaired and suggests a role for this
protein in enhancing the transforming efficiency of EBV.39
A role for LMP2A in protecting against lytic activation has also been
suggested.40
Rightward transcripts (BART) originating in the BamHI-A region
of the EBV genome were first recognized in 1989 in a nude mice-passaged NPC tumor, C15,41 and have since been detected in all
EBV-associated tumors and cell lines.16-18,20,42,43
Burkitt's tumor tissue has not been previously studied for this
transcript, but in this tumor as in others that have been studied, BART
transcripts are abundant. These transcripts are heavily spliced and the
functional open-reading frames have yet to be fully
defined.44,45 Recently, a new membrane protein encoded by
one open-reading frame of BART, BARF0, has been identified, and its
expression in one BL tumor biopsy has been shown by
immunoblot.46
We also detected weak expression of other latent transcripts
(Cp/Wp-initiated EBNA1 and EBNA2 transcripts) in one of the cases, and
lytic transcripts (BHRF1 and BLLF1) in four cases. These weakly expressed transcripts may derive from a drift in viral gene expression in rare tumor cells, or the presence of EBV-infected tumor
infiltrating lymphocytes.16,20,47 One of the limitations of
RT-PCR as opposed to in situ detection techniques is that tissues with
potentially heterogeneous patterns of gene expression are homogenized
before characterization, sometimes allowing detection of transcripts expressed in rare cells. Unfortunately, the tumors studied here were
snap-frozen in such a way as to preclude in situ analysis. Similarly,
other investigators have reported heterogeneity in rare tumor cells in
Burkitt's tumor specimens by immunohistochemical techniques.3,6
The major difference between patterns of EBV gene expression in type-I
BL cell lines and eBL tumors was the higher level of expression of
lytic cycle transcripts (BZLF1, BHRF1, BLLF1, and Fp transcripts) in BL
cell lines. Tissue culture may permit drift toward lytic cycle
expression that is prevented in patients by cytotoxic T-cell-mediated
immune surveillance. Fp-initiated EBNA1 transcripts, first identified
as latency transcripts in a type-I BL cell line (Rael) are now believed
to be more appropriately characterized as lytic
transcripts.48-50 In eBL tumors, Fp-initiated EBNA1
transcripts are absent and there is little evidence of ongoing lytic
cycle gene expression as assessed by the absence or weak expression of
BZLF1 and BLLF1 transcripts, respectively.
Transcription in EBV tumor cells appears to be regulated through CpG
methylation. An inverse association between the activity of Cp, Wp,
LMP1, EBER, and BHRF1 promoters, and CpG methylation has been noted
previously and we have presented evidence that Cp methylation directly
inhibits its transcription.25,51-56 The Cp, which drives
EBNA expression, is active and hypomethylated in type-III BL cell lines
and LCL,13,51 whereas it is silent and hypermethylated in
BL tumors,24,56 type-I and -II BL cell lines,13,25 and other EBV-associated tumors with type-I
and -II latency.24,57 Qp is the only active promoter for
EBNA1 in eBL. Our bisulfite sequencing results showed that Qp, in
contrast to Cp, is hypomethylated in virtually all eBL samples and in
the Rael cell line. Recently, the methylation status of a 5 Kb region, including Fp and Qp, has also been reported in three type-I BL cell
lines by genomic Southern hybridization and shown that Qp and Fp are
located within a hypomethylated region.58 Our analysis of
the methylation of the Qp region showed that although Qp is hypomethylated, Fp, which is only 200bp away from Qp, is actually variably methylated. This provides further evidence that Qp and Fp are
distinct promoters30,32 and probably are regulated by different mechanisms. Qp has many features of a housekeeping promoter and the absence of methylation is consistent with this
function.30,59
With regard to EBV strain, the nearly equal mix of type-A and type-B
virus contrasts with studies of HD, NPC, and PTLD in America, Europe,
and Asia, where type-A virus predominates and type-B is less frequently
detected.60-62 However, this strain mix is in agreement
with a previous report on eBL tumors,63 and similar to that
detected in BL-derived cell lines from patients in equatorial
Africa.60,64,65 It is also similar to the strain association of AIDS-associated EBV lymphomas, the latter having led to
the suggestion that type-B EBV is more commonly seen in immunocompromised patients.63,66 Whether the virus type (A or B) detected in tumor tissue simply reflects the frequency of infection in the affected population or there is a specific virus-type tumor association in some instances remains to be determined. In one
tumor we detected dual infection with type A and B viruses. Dual
infections have been reported occasionally in other settings as
well.61,67
LMP1 is a transforming gene product which interacts with tumor necrosis
factor receptor (TNFR)-associated factors (TRAFs), and is involved in
NF- B activation.68 A 30-bp deletion at the carboxyl
terminus (amino acids 346-355) of LMP1 gene was first reported in a
Chinese NPC and has since been reported in a variety of EBV(+)
tumors.28,29,69,70 This 30-bp deletion has been shown to be
important to the transforming ability of LMP1 protein in Balb/3T3
cells. Its wild-type counterpart transformed Balb/3T3 cells only when
driven by a strong promoter. 71-73 In addition, the deleted
type LMP1 protein is reported to be non-immunogenic in a murine
system.74 However, the TRAF interacting domains are still
well conserved in the deleted LMP1,75 and the deleted LMP1
is as efficient as the wild type in activating NF-B .76
Although it has been suggested that this 30-bp deletion in the LMP1
gene is related to tumor pathogenesis or disease
progress,29,70 these conclusions are still controversial.
We detected this deletion in half of our eBL cases, but we have no
information about the frequency of this deleted variant in healthy
Ghanaians. Moreover, the LMP1 gene itself is not transcribed in BL
tumor tissue, thus the pathogenetic importance, if any, remains
uncertain. Overall, the deleted variant tends to be more frequently
detected in Chinese and Japanese, but is also present in approximately
half of Caucasians.60
In summary, the pattern of viral gene expression detected in primary
eBL tumor [EBNA1 (Qp)(+), LMP2A(+), BART(+)] differs from that of BL
cell lines in that the cell lines showed more lytic activation and more
promiscuous use of EBNA1 promoters. The viral expression pattern in eBL
tumor tissue is similar to what has been described in PBMCs isolated
from healthy individuals and reinforces the notion that aspects of
viral gene expression in BL may mirror viral gene regulation in
latently infected normal B cells in vivo. In contrast to
hypermethylation elsewhere in the EBV genome, the active Qp is
hypomethylated in eBL tumors and BL cell lines. Type-A and type-B EBV
are detected in eBL tumor tissue with approximately equal frequency and
a 30bp carboxyl terminal deletion in the LMP1 gene is also common.
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FOOTNOTES |
Submitted July 25, 1997;
accepted October 2, 1997.
Support was provided by National Institutes of Health Grant No. R01
CA63532 (to R.F.A.). R.F.A. is a Leukemia Society Scholar.
Address correspondence to Richard F. Ambinder, MD, PhD, Johns Hopkins
Oncology Center, 418 N. Bond St, Baltimore, MD 21231.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
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ACKNOWLEDGMENT |
We thank the clinical and laboratory staff of the Burkitt's Tumor
Project at the University of Ghana (Accra, Ghana) for collecting eBL
specimens, and Dr. I-H Chen at the MacKay Memorial Hospital (Taipei,
Taiwan) for providing the two NPC tumor specimens.
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[Abstract]
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I. K. Ruf, P. W. Rhyne, C. Yang, J. L. Cleveland, and J. T. Sample
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G. J. Inman and M. J. Allday
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Viral Disease in Hematology
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[Abstract]
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K. M. Izumi, E. C. McFarland, E. A. Riley, D. Rizzo, Y. Chen, and E. Kieff
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E. J. Paulson and S. H. Speck
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Q. Tao, L. J. Swinnen, J. Yang, G. Srivastava, K. D. Robertson, and R. F. Ambinder
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D.H. Wright
What Is Burkitt's Lymphoma and When Is It Endemic?
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Q. Tao, K. D. Robertson, A. Manns, A. Hildesheim, and R. F. Ambinder
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Abstract
Introduction
Abstract