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Short Communication |
From the Institute of Pathology,*
Charité,
Humboldt University Berlin, Berlin, Germany; Clontech Laboratories
Inc.,
Palo Alto, California; and the
Department of Obstetrics and Gynecology,
Baylor College of Medicine, Houston, Texas
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and mitogen-activated protein
kinase. The caveolin proteins (caveolin-1, -1ß, 2, and 3) are the
major integral protein components of membrane caveolae.6
Caveolin-1 has been shown to bind to the HRAS protein, the
EGF-receptor, SRC family tyrosine kinases, and protein kinase
C.7-9
These observations have led to the hypothesis, that
Caveolins act as docking proteins that concentrate signaling molecules
at distinct membrane domains in normal cells.6
In
addition, a critical role for caveolin-1 to act also as a signaling
regulator has been suggested by the observation that targeted
down-regulation of caveolin-1 in NIH3T3 cells is sufficient
to activate mitogen-activated protein kinase and stimulate
anchorage-independent growth.10
Loss of caveolae formation
on transformation by oncogenes has been described
earlier11
and the caveolin-1 protein was reported to be
phosphorylated or even lost in transformed cells. As shown recently,
caveolin-1 also inhibits c-Neu-dependent signaling in mice and loss of
caveolin-1 expression from human mammary carcinoma cell lines suggested
a role for the protein in human breast cancer.12
Although
the potential of caveolin-1 to restrain tumor cell growth has been
demonstrated,13,14
only a few studies investigated the
expression of caveolin-1 in normal and malignant human epithelial and
mesenchymal cells in situ.15-17 Our microarray-based approach to identify genes differentially expressed in human ovarian carcinoma as compared to normal ovary revealed down-regulation of the caveolin-1 gene (CAV1) in ovarian carcinomas. In addition, we used a second, tumor tissue-specific array to investigate caveolin-1 expression in 68 different matched cDNA pools. By immunohistochemistry, we further confirmed expression of the caveolin-1 protein in the epithelial cells of the normal ovary but not in the ovarian carcinoma cells and investigated the mechanism of down-regulation of the CAV1 gene.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human ovarian tissue specimens used for RNA preparation were snap-frozen in liquid nitrogen. Immunohistochemical analysis was conducted on formalin-fixed, paraffin-embedded specimens of normal ovaries, benign ovarian tumors, and ovarian carcinomas selected from the archives of the Institute of Pathology, University Hospital Charité, Berlin. Histopathological diagnosis of the tumors was performed according to the World Health Organization classification. The tissues included 6 normal ovaries, 19 serous cysts or serous adenomas, 7 mucinous adenomas, 5 serous ovarian tumors of borderline malignancy, 29 serous carcinomas (3 grade 1, 10 grade 2, 16 grade 3), 2 grade 1 mucinous carcinomas, and 3 grade 2 endometrioid carcinomas.
RNA Preparation
Frozen tissue sample were homogenized in liquid nitrogen and dissolved in lysis buffer. RNA was prepared using the Atlas pure RNA system according to the protocol supplied by the manufacturer (Clontech, Palo Alto, CA) and controlled for DNA contamination. RNA from the cell lines was prepared according to the method of Chomzcynski and Sacchi.18
Expression Analysis Using the Tumor Tissue Array
The matched tumor/normal expression array consists of 68 cDNAs, synthesized from human tumorigenic and corresponding normal tissue (http://www.clontech.com/techinfo/manuals/pdf/pt3424–1.pdf). Each pair was independently normalized based on the expression of three housekeeping genes and immobilized in separate dots.19 A CAV1-specific cDNA fragment was radiolabeled using a DECA-primeII labeling kit (Ambion, Austin, TX), hybridized overnight at 68°C using ExpressHyb Hybridization Solution (Clontech), washed, and exposed to Biomax MS X-ray film with an intensifying screen (Eastman Kodak Co., Rochester, NY). Signal intensities were calculated for individual spots using a STORM-860 phosphoimager (Molecular Dynamics, Eugene, OR).
Immunohistochemistry
Two-µm sections cut on silane-coated slides were deparaffinized and boiled for 5 minutes in 10 mmol/L sodium citrate buffer, pH 6.0. The mouse monoclonal anti-caveolin-1 antibody (clone 2297; Transduction Laboratories) was applied for 1 hour at a dilution of 1:500. To ensure consistent staining intensities, normal mesenchymal tissue at the periphery of each tumor specimen and the capillary endothelial cells within the tumors were examined as positive controls. In negative controls, the primary antibody was omitted or replaced by an antibody with irrelevant specificity (mouse IgG1, X0931; DAKO). Immunostaining was accomplished using a Vectastain ABC-AP kit (Vector Laboratories, Burlingame, CA) as recommended by the manufacturer. The sections were counterstained with hematoxylin and mounted in Permount. Digital images were acquired using an Olympus DP-10 charge-coupled device camera. Adjustments in image contrast were performed identically on the images. The caveolin-1 immunostainings were evaluated using a semiquantitative estimation. A composite score was obtained by multiplying the values of the mean staining intensity and the percentage of caveolin-1-positive cells. The intensity was graded as 1 (weakly positive), 2 (moderately positive), or 3 (strongly positive, equivalent to the normal mesenchymal cells of the surrounding stroma).
Cell Culture
The human ovarian carcinoma cell lines SKOV3, ES-2, OAW42, CAOV-3, MDAH 2774, and OVCAR3 were maintained in Dulbecco’s modified Eagles Medium (DMEM) (BioWhittaker, Walkersville, MD) supplemented with 10% fetal calf serum and 2 mmol/L glutamine. Human ovarian surface epithelial cells were cultivated in a 1:1 mixture of medium 199 (Sigma Chemical Co., St. Louis, MO) and MCDB105 (Life Technologies, Inc., Grand Island, NY) supplemented with 10% fetal calf serum and 2 mmol/L glutamine. Trichostatin A (TSA) (Sigma) was applied at 25 ng/ml, 5-aza-2'deoxycytidine (Sigma) at 5 µmol/L, the MEK1 inhibitor PD98059 (Alexis, San Diego, CA) at 50 µmol/L, the PI-3 kinase inhibitor LY294002 (Alexis) at 10 µmol/L. Methyl sulfoxide was used as a solvent control for PD98059, Ethanol was used as a solvent control for LY294002 and TSA. Cells were incubated for 3 days before preparation of cell extracts or RNA.
Expression Constructs
The pLNHX vector (Clontech) and pLNHX-caveolin-1 expression vector was described recently.15 In the pc-CAV-V5 plasmid (Genestorm; Invitrogen, Groningen, Netherlands), expression of caveolin-1 is controlled by the cytomegalovirus immediate early promoter and fused to a V5 epitope Tag.
Colony Formation Assays
In stable transfections, 2 x 105 OVCAR-3 cells per 6 well plate were transfected with 1.5 µg of pLNHX-caveolin or the empty vector using Fugene (Roche, Mannheim, Germany) according to the protocol of the manufacturer. Seventy-two hours after transfection, G418-resistant clones were selected by the addition of G418 at 0.5 mg/ml to the culture medium for 10 days. Several individual clones were further expanded and analyzed. Stable transfections using the pc-CAV-V5 plasmid or the empty vector pcV5 were performed in a similar way but selection was performed using 30 µg/ml Zeocin (Invitrogen) for 10 to 14 days.
Terminal dUTP Nick-End Labeling (TUNEL) Assays
For the detection of apoptosis, 1 x 106 OVCAR-3 cells per 10-cm2 dish were transiently transfected with 3 µg pc-CAV-V5 or the empty vector pcV5 using Fugene (Roche). Forty-eight hours after transfection cells were fixed in 4% formaldehyde and processed for a TUNEL assay using the ApoAlert DNA fragmentation kit (Clontech) as described by the manufacturer.
Northern Blot Analysis
For Northern blot preparation, 10 µg of total RNA were separated by electrophoresis through a 1.2% agarose gel and blotted onto Hybond N nylon membrane (Amersham, Arlington Heights, IL). A CAV1-specific cDNA fragment was hybridized at 58°C for 2 hours using ExpressHyb Hybridization Solution (Clontech), washed, and exposed to Biomax MS X-ray film with an intensifying screen (Eastman Kodak Co) for 2 days.
Western Blot Analysis
Protein extracts were prepared by incubation of 2 x 106 cells in 500 µl of RIPA buffer (150 mmol/L NaCl, 1% Nonidet P-40, 0.5% deoxycholate, 0.1% sodium dodecyl sulfate, 50 mmol/L Tris-HCl, pH 8.0, 100 µmol/L sodium orthovanadate, 2 mmol/L aprotinin) for 30 minutes on ice. Tissue samples were homogenized in the same buffer. Sample buffer (2x) was added to the cell extract (120 mmol/L Tris-HCl, pH 6.8, 200 mmol/L dithiothreitol, 4% sodium dodecyl sulfate, 20% glycerol, 0.002% bromphenol blue), samples were boiled for 10 minutes, centrifuged, and aliquots were stored at -20°C. Ten µg of each extract were used and processed as described previously.15 The caveolin-1 and the phospho-caveolin-1-specific antibodies (clone 2297 and P-Tyr14, Transduction Laboratories) were diluted 1:1000 and 1:2500 in TBST, respectively. To ensure equal loading, blots were stripped in 200 mmol/L glycine, 1% Tween-20, 0.1% sodium dodecyl sulfate for 2 hours at room temperature, incubated with an actin-specific monoclonal antibody (clone C4, Roche) diluted at 1:5000 and developed.
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Results |
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To search for novel markers differentially expressed in human ovarian cancer as compared to normal tissue, we used the Atlas Select human tumor cDNA array representing 437 genes selected as being up- or down-regulated in various human cancer tissues (Clontech; www.clontech.com/archive/oct99upd/atlasselect.html). We hybridized the arrays with total RNA obtained from two normal human ovaries and two grade 3 serous ovarian carcinomas. This analysis revealed 16 genes overexpressed and 41 genes down-regulated by a factor of 2 or more in both tumor samples (data not shown). Among the down-regulated genes, we observed a strong suppression of the CAV1 gene with relative expression levels in the carcinoma samples as compared to the normal samples of 0 and 0.09, respectively.
A CAV1-specific probe was then hybridized onto an
array containing 68 cDNA pair samples derived from multiple human
tumors and corresponding normal tissue from individual
patients19
(matched tumor/normal array;
http://www.clontech.com/archive/jan00upd/pdf/matchedarray.pdf).
As shown in Figure 1
, CAV1 is
strongly suppressed in three of three tumors derived from ovary, but
also in breast (nine of nine) and colon (eight of eleven). In contrast,
a significant up-regulation of CAV1 is observed in eleven of
fifteen tumor samples derived from kidney, in prostate (two of three),
and in stomach (six of eight) when compared to the corresponding normal
cDNA.
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Using Western blot analysis, high levels of caveolin-1 were
detected in immortalized human ovarian surface epithelial cells, in
SKOV-3 and ES-2 ovarian cancer cell lines and in protein extracts
prepared from two benign serous adenomas (Figure 2a
). However, no caveolin-1
expression was present in the MDAH 2774, CaOV-3, OVCAR-3, and in OAW42
carcinoma cells.
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) revealed a strong, fine-granular
expression pattern of caveolin-1 concentrated at the basal and lateral
membranes of the normal ovarian surface epithelium. In addition,
caveolin-1 expression was present in the cortical stroma underlying the
surface epithelium (Figure 2c
). In benign serous cysts and
adenomas a similar basolateral membrane-associated expression was
detectable (Figure 2d
), whereas in the epithelium of seven
mucinous adenomas analyzed, caveolin-1 was completely absent (data not
shown). Grade 1 carcinomas and serous tumors of borderline malignancy,
expressed reduced levels of caveolin-1. In these tumors, the
membrane-bound caveolin-1 expression present in the normal epithelium
was altered and the protein seemed evenly distributed through the whole
cytoplasm (Figure 2e
). Most interestingly, caveolin-1 staining was
significantly reduced in 29 grade 2 and 3 serous and endometrioid
ovarian carcinomas (Figure 2f
; Table 1
).
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Caveolin-1 was detected as a tyrosine-phosphorylated protein in
v-src-transformed cells20
and recently Lee and
colleagues21
showed that caveolin-1 undergoes
phosphorylation at tyrosine 14 in response to growth factor signaling.
To assess whether such a modification also occurs in ovarian carcinoma
cells, we performed Western blot analysis with extracts derived from
normal ovarian epithelial cells and from SKOV-3 and ES-2 carcinoma
cells using a phospho-caveolin-1-specific antibody. As shown in Figure 2b
, the 22-kd isoform of caveolin-1 is phosphorylated at tyrosine
14 in both carcinoma cell lines, however, not in the immortalized
epithelial cells.
Down-Regulation of Caveolin-1 Involves Hypermethylation
The CAV1 gene is located on chromosome 7q31.1.22 Loss of heterozygosity has been described within this region however, currently there is no evidence for deletions of the CAV1 gene in human tumors.17 To investigate the mechanism responsible for down-regulation of CAV1 in ovarian carcinoma cells, we used inhibitors of DNA methylation (5-aza-2'deoxycytidine) and histone deacetylation (TSA). In addition, we also analyzed the influence of RAS-dependent signaling pathways on CAV1 expression by interfering with MEK1/2 (MAP/ERK kinase) and PI-3 kinase (phosphatidylinositol-3 kinase) using the PD98059 and LY294002 inhibitors, respectively.
A strong up-regulation of caveolin-1 was observed both after
5-aza-2'deoxycytidine and TSA treatment in OVCAR-3 and OAW42 cells
(Figure 3, a
and b). Inhibition
of DNA methylation by 5-aza-2'deoxycytidine resulted in re-expression
of both CAV1 isoforms, whereas inhibition of histone deacetylation by
TSA had a weaker effect that seemed to be isoform-dependent. In OAW42
cells, a slight up-regulation of the smaller 22-kd caveolin-1 protein
was also detectable after inhibition of MEK1/2 by PD98059. This
inhibitor did not alter caveolin-1 expression in OVCAR-3 cells and no
effect of PI-3 kinase repression by LY294002 was observed.
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, inhibition of DNA methylation resulted in
up-regulation of the CAV1 mRNA in OVCAR-3 and OAW42 cells
(Figure 3c
, compare lanes 1 to 3 and lane 5 to 7, respectively).
Only in OAW42 cells, a stimulation of mRNA expression after inhibition
of histone deacetylation by TSA was observed, but not in OVCAR-3 cells
(Figure 3c
, compare lanes 1 to 4 and lane 5 to 8, respectively).
In both cell lines, the differences in expression levels observed at
the protein level were not fully reflected at the mRNA level. Forced Expression of CAV1 Reduces Survival of OVCAR-3 Ovarian Carcinoma Cells
To examine a functional involvement of CAV1 in growth
regulation of ovarian cancer cells, we introduced the gene into OVCAR-3
cells. In a colony formation assay, growth of G418-resistant clones
harboring the CAV1 (pLNHX-cav) expression construct or the
control vector (pLNHX) was measured. CAV1 expression
resulted in a reduction of colony formation of OVCAR-3 cells of 
70%
(Figure 4A)
. Analysis of G418-resistant
clones obtained after transfection with the pLNHX-cav plasmid revealed
that none of these clones expressed detectable levels of caveolin-1
protein (data not shown). Therefore, we used a different CAV-1
construct (pc-CAV-V5) in which a cytomegalovirus promoter induces high
levels of caveolin-1 expression after transient transfection (Figure 4B)
. Selection of stable clones harboring the pc-CAV-V5 construct
revealed >90% suppression of colony formation indicating that high
levels of caveolin-1 expression are incompatible with survival in
OVCAR-3 cells (Figure 4C)
. In these experiments we had noticed
increased amounts of detached cells 48 hours after transfection. When
we performed a TUNEL assay in OVCAR-3 cells transiently transfected
with either the pc-CAV-V5 construct or the empty vector pc-V5, the
number of apoptotic cells was significantly increased in the
CAV-1-transfected cells as compared to the control transfectants
(Figure 4D)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to CAV1 down-regulation in ovarian carcinomas, we observed a decreased expression of CAV1 in tumors derived from breast, colon, lung, and stomach using the matched tumor/normal array. These observations confirm data published by others,14,26 however care has to be taken in the interpretation of array-derived data because of the high expression of caveolin-1 mRNA and protein in normal mesenchymal and endothelial cells detected in situ.15 Using immunohistochemistry we confirmed loss of caveolin-1 expression from the ovarian epithelium on tumor progression. In other tissues such as breast and lung, expression of the caveolin-1 protein in the epithelial cells in situ has not yet been demonstrated. In normal resting breast tissue caveolin-1 expression rather seems to be restricted to the myoepithelial cells, whereas the secretory epithelial cells are negative17 (Wiechen and Sers, unpublished observations). In addition, the mRNA expression might not always reflect protein expression within a distinct cell type. Therefore, a combination of array hybridization, immunohistochemical, and functional analysis is crucial to define a role for caveolin-1 in the growth regulation of distinct human tumors.
CAV1 was found up-regulated in tumor-derived cDNAs prepared
from kidney, and prostate, suggesting an entirely different function of
the gene in these tissues. Involvement of caveolin-1 in prostate
carcinoma progression has been described by Yang and
colleagues,16
who suggested that the caveolin-1 protein
plays a role in prostate cancer progression and protects prostate
cancer cells from Myc-induced apoptosis.16,27
Thus,
depending on the cellular context, caveolin-1 seems to have opposing
functions that result either in growth inhibition or growth promotion.
Such alternative activities are also known for other gene products, eg,
the RAS protein that, by using similar signaling pathways, can induce
either differentiation or transformation in distinct cell
types.28
Whereas the majority of ovarian carcinoma cell
lines and tumors display down-regulation of caveolin-1, SKOV-3 and ES-2
cells express high levels of caveolin-1 despite their unlimited growth
capacity. One explanation for this seemingly contradictory finding is
the phosphorylation of the -isoform of caveolin-1 on tyrosine 14 in
these cells. Growth factor-dependent phosphorylation of caveolin-1
stimulates its capacity to bind the Grb7 adapter protein and thereby
enhances anchorage-independent growth in a cell type-specific
manner.21
The observation that SKOV-3 and ES-2 ovarian
carcinoma cell lines display high levels of phosphorylated caveolin-1
allows two potential interpretations: either the cells have developed
mechanisms to circumvent caveolin-1-mediated growth suppression,
or the specific phosphorylation of caveolin-1 as a consequence of
growth factor receptor overexpression results in an augmentation of
signaling in these cells.
In contrast, in OVCAR-3 cells that have the CAV1 gene suppressed, caveolin-1 overexpression resulted in increased apoptosis. Direct induction of programmed cell death by caveolin-1 has not been described and whether this is a cell type-specific effect remains to be investigated. A potential involvement of CAV1 in the regulation of apoptosis was demonstrated recently in fibroblasts and T24 human bladder carcinoma cells. Anti-sense-mediated suppression of CAV1 abrogated the sensitivity of these cells toward apoptotic stimuli.29,30 Inhibition of the PI-3 kinase pathway by LY294002, restored this sensitivity and overexpression of caveolin-1 repressed the activity of PI-3 kinase. OVCAR-3 cells harbor increased levels of PI-3 kinase activity31 and the simultaneous expression of high levels of caveolin-1 could initiate conflicting signals that result in cell death. Activation of the PI-3 kinase pathway and amplification of AKT2 have been shown in a significant proportion of ovarian carcinomas.31,32 The potential role of caveolin-1 in apoptosis sensitization or even induction by interfering with PI-3 kinase activity points toward a specific role of caveolin-1 in the suppression of ovarian carcinoma development.
The gene encoding caveolin-1 is located on human chromosome 7q31.1.22 Loss of heterozygosity on 7q31.1 has been detected in carcinomas of ovary,33 prostate,34 stomach,35 and kidney,36 suggesting loss of CAV1 in human ovarian cancer. However, deletions or mutations within the CAV1 gene were not detected.17 Methylation of CpG islands in the CAV1 promoter region was observed only in human breast cancer cell lines37 but not in ovarian cancer samples.17 This suggests, that CAV1 might act as a class II tumor suppressor gene. Class II tumor suppressor genes are characterized by a block in their expression rather than by mutations or deletions.38
Our data obtained after treatment of the ovarian carcinoma cell lines with 5-aza-2'deoxycytidine suggested that methylation of regulatory regions of the CAV1 gene is one mechanism to suppress CAV1. Persistent tumor suppressor gene silencing is accomplished by the concerted action of CpG methylation and histone deacetylation.39 Therefore the observation that caveolin-1 protein expression can be effectively induced using either 5-aza-2'deoxycytidine or the histone deacetylase inhibitor TSA was expected. However, investigation of the CAV1 mRNA expression in response to 5-aza-2'deoxycytidine and TSA revealed that mainly de-methylation of the DNA-stimulated expression of the CAV1 gene in OVCAR-3 and OAW42 cells. In OAW42 cells, inhibition of histone deacetylation could also activate CAV1 mRNA expression to some extent, not in OVCAR-3 cells. A complex regulation of the CAV1 gene was also described by Li and colleagues40 who investigated the mechanisms mediating up-regulation of caveolin-1 in prostate carcinoma cells by testosterone. Whereas the caveolin-1 protein was significantly up-regulated by testosterone, the response of the CAV1 promoter to this stimulation was rather low. These data and our own observations suggest, that in addition to promoter methylation and histone deacetylation, expression of the caveolin-1 gene and protein might be further regulated at a posttranscriptional level.
In summary, by using a combination of two different cDNA arrays hybridized with material prepared from human tissues, immunohistochemical analysis, and functional investigation we have identified CAV1 as a strong candidate tumor suppressor in human ovarian carcinoma.
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Acknowledgements |
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Footnotes |
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Supported by the Deutsche Krebshilfe (grants 10-332-Scha1 and 10-1485-Wi2) and the Deutsche Forschungsgemeinschaft (grant Scha396/1-1).
Accepted for publication August 10, 2001.
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H. Lee, D. S. Park, B. Razani, R. G. Russell, R. G. Pestell, and M. P. Lisanti Caveolin-1 Mutations (P132L and Null) and the Pathogenesis of Breast Cancer : Caveolin-1 (P132L) Behaves in a Dominant-Negative Manner and Caveolin-1 (-/-) Null Mice Show Mammary Epithelial Cell Hyperplasia Am. J. Pathol., October 1, 2002; 161(4): 1357 - 1369. [Abstract] [Full Text] [PDF]
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