REPORT |
A Ligand of Peroxisome Proliferator-Activated Receptor
, Retinoids, and Prevention of Preneoplastic Mammary Lesions
Rajendra G. Mehta,
Elizabeth Williamson,
Minu K. Patel,
H. Phillip Koeffler
Affiliations of authors: R. G. Mehta, M. K. Patel, Department of Surgical Oncology,
College of Medicine, University of
Illinois, Chicago; E. Williamson, H. P. Koeffler, Hematology/Oncology
Division, Cedars-Sinai Medical Center/University of California at Los
Angeles School of Medicine.
Correspondence to: Rajendra G. Mehta, Ph.D., Department of Surgical Oncology,
University of Illinois at Chicago, College of Medicine, 840 S. Wood St. (M/C 820), Chicago, IL
60612 (e-mail: raju{at}uic.edu).
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ABSTRACT
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BACKGROUND: Chemoprevention of breast cancer is an active area of investigation.
Recent in vivo and in vitro studies have shown that thiazolidinediones (e.g.,
troglitazone) and retinoids are able to inhibit the growth of breast cancer cells. Troglitazone
mediates its action via peroxisome proliferator-activated receptor
(PPAR
). We evaluated the ability of troglitazone, alone or in combination with retinoids, to prevent
the induction of preneoplastic lesions by 7,12-dimethylbenz[a]anthracene
(DMBA) in a mouse mammary gland organ culture model. METHODS: Mammary glands
of BALB/c mice were treated with DMBA (2 µg/mL) to induce preneoplastic lesions in
organ culture. Effects of troglitazone, all-trans-retinoic acid (retinoic acid; ligand for
retinoic acid receptor [RAR]
), and LG10068 (ligand for retinoid X
receptors [RXRs]), singly or in combination, on the development of lesions were
evaluated. Expression of retinoid receptors (RAR
and RXR
) and
PPAR
was determined by western blot analysis. Statistical significance was
determined by generalized chi-squared analysis using the GENCAT software program and
Bonferroni correction. All P values are two-sided. RESULTS: Troglitazone (at 10-5 M) or retinoic acid (at 10-6 M) markedly
inhibited the development of mammary lesions (both P values <.05); however,
together they did not enhance the effectiveness of the other. In contrast, LG10068 (at 10-7 M or 10-8 M) alone had very little ability to inhibit
development of these lesions, but a combination of LG10068 (at 10-8 M)
and troglitazone (at 10-5 M or 10-6 M) almost
completely inhibited (by 85% and 100%, respectively; both P values
<.05) the development of mammary lesions. The expression of PPAR
and RXR
remained unchanged with the various treatments, whereas the expression of RAR
was substantially reduced after treatment with the combination of retinoic acid and
troglitazone. CONCLUSIONS: To our knowledge, this is the first report showing the
possibility of a PPAR
ligand having chemopreventive activity. Furthermore, an
RXR-selective retinoid, LG10068, appears to enhance this activity.
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INTRODUCTION
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Breast cancer is one of the leading causes of
cancer-related deaths. Clearly, the prevention of breast cancer is the
best approach to this disease. For example, blockers of estrogen
receptors (ERs), including tamoxifen and raloxifene, appear to diminish
the frequency of breast cancer by about 50% in postmenopausal women
(1). We and other investigators (2,3) have shown
that
activation of the peroxisome proliferator-activated receptor
(PPAR
), a member of the nuclear hormone receptor
superfamily, by thiazolidinediones including the synthetic ligand
troglitazone inhibited proliferation of cultured breast cancer cells.
Furthermore, all-trans-retinoic acid (hereafter referred to as
retinoic acid), a ligand for another nuclear hormone receptor, i.e.,
retinoic acid receptor (RAR), enhanced the inhibition of proliferation
of breast cancer cells. The combination of troglitazone and retinoic
acid caused marked apoptotic cell death of tumors induced by MCF-7
breast cancer cells in immunodeficient mice without causing toxic
effects in these animals (3).
The PPAR
is a member assigned to the subfamily of nuclear hormone receptors that
includes receptors for retinoic acid and thyroid hormone (4). The
PPAR
heterodimerizes with retinoid X receptor (RXR) and binds to DNA by recognizing
target sequences that have a direct repeat of core recognition motifs (AGGTCA) spaced by one
nucleotide. Activation of PPAR
results in expression of genes associated with many
different aspects of differentiation, cellular development, and general physiology, including
differentiation of adipocytes, lipid metabolism, and glucose homeostasis (5,6). The natural PPAR
ligand appears to be 15-deoxy-
-12,14
prostaglandin J2, but a variety of polyunsaturated fatty acids including linoleic acid can also
activate PPAR
(7-9). Furthermore, nonsteroidal anti-inflammatory
agents, such as indomethacin, can bind and activate PPAR
(10). A
series of thiazolidinediones, including troglitazone and plioglitazone, are useful for the treatment
of type II adult-onset diabetes. Troglitazone has been used for the treatment of nearly one million
individuals with diabetes. The mechanism by which this class of agents lowers blood glucose is
unclear, although these agents may enhance differentiation of adipocytes associated with
increased function of their glucose pumps.
Retinoids mediate their activity through the RAR and RXRs, both of which are expressed in
breast cancer cells, although RARß may not be expressed in all breast cancers (11). The RAR and RXRs bind to specific retinoic acid-response elements and
regulate the transcription of a variety of target genes in a ligand-dependent manner (12,13). The all-trans-retinoic acid, an RAR-specific ligand, selectively
inhibits the growth of human ER-positive breast cancer cells (14-16).
These cells appear to express higher levels of RAR
than ER-negative cell lines (16,17). Inhibition of growth of ER-positive human breast cancer cells by retinoids
requires transactivation of retinoid-responsive genes (18). Often the
inhibition of growth of breast cancer cells by retinoids is reversible with the removal of the
ligand (19). These compounds also are effective in preventing mammary
carcinogenesis in rodents (20).
The murine mammary gland organ culture model system has been effectively used to
evaluate the ability of potential chemopreventive agents to prevent the
development of preneoplastic lesions (21-24). Mammary glands of
BALB/c mice are placed in organ cultures containing a variety of growth-promoting hormones
and are treated with the carcinogen 7,12-dimethylbenz[a]anthracene
(DMBA) to induce preneoplastic lesions (24,25). The mammary
epithelial cells isolated from these lesions, when placed into syngeneic hosts, develop into
adenocarcinoma (26). With the use of this technique, more than 150
potential chemopreventive agents have been tested (27). Effective
chemopreventive agents, such as retinoids, selenium, oltipraz, limonene, and vitamin D3 analogues, are able to inhibit the formation of these lesions. The assay is highly
reproducible and provides a good association with the efficacy of an effective chemopreventive
agent in the two-stage skin carcinogenesis in vivo assay and in prevention of chemically
induced mammary tumors in vivo (21,23,28). In this report, we
have analyzed the efficacy of troglitazone, with or without a retinoid, in preventing the formation
of DMBA-induced mammary lesions in a murine mammary gland organ culture model.
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MATERIALS AND METHODS
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Reagents. Troglitazone was dissolved in a solution containing 50% dimethyl
sulfoxide (DMSO) and 50% ethanol. The all-trans-retinoic acid (Sigma Chemical
Co., St. Louis, MO) and LG10068 (Ligand Pharmaceuticals, Inc., San Diego, CA) were
dissolved in 100% ethanol and added to organ cultures at a concentration of less than
0.1%. (Exact concentrations used are shown with the appropriate experiments.)
Protein extraction and western blot analysis. Murine mammary glands were
homogenized in Triton X-100 containing lysis buffer. (The lysis buffer mixture contained 20 mM Tris buffer [pH 8.0], 137 mM NaCl, 10% glycerol,
1% Triton X-100, 2 mM EDTA, and protease inhibitors and was obtained from
Boehringer Mannheim Biochemicals, Indianapolis, IN.) Protein lysate was separated on a
10%-20% gradient polyacrylamide Ready gel (BioRad Laboratories, Hercules,
CA), and western blotting was performed on polyvinylidene fluoride membranes (Immobilon;
Millipore Corp., Bedford, MA). The western blots were probed with an antibody raised against
PPAR
-amino acids 2-20 (N-20; Santa Cruz Biotechnology Inc., Santa Cruz, CA) used at a
1 : 2000 dilution and subsequently with an antibody against mouse actin (Oncogene Research
Products, San Diego, CA) used at a 1 : 1000 dilution. The membranes were stripped and probed
sequentially with RAR
, RXR
, RXRß, or RXR
(Santa Cruz Biotechnology
Inc.; 1 : 200 dilution). Results were visualized after reaction with horseradish
peroxidase-conjugated secondary antibodies and enhanced chemiluminescence (Amersham Life
Science Inc., Arlington Heights, IL).
Induction of preneoplastic lesions in mammary glands and their prevention by ligands of
nuclear hormone receptors. Young, virgin BALB/c female mice, 3-4 weeks of age, were
obtained from Charles River Laboratories, Wilmington, MA. All of the animal studies were
approved by the University of Illinois Animal Review Board and were performed in accordance
with institutional guidelines. The entire culture procedure has been described in detail previously
(21-25). Briefly, the mice were pretreated for 9 days with
17ß-estradiol (1 µg in 0.1 mL of saline/animal) and progesterone (1 mg in 0.1 mL of
saline/animal). They were then killed by cervical dislocation, and the thoracic pair of mammary
glands was removed, placed on silk rafts, and incubated for 10 days in serum-free Waymouth
MB752 medium (Life Technologies, Inc. [GIBCO BRL], Gaithersburg, MD)
containing the following growth-promoting hormones: insulin (5 µg/mL), prolactin (5
µg/mL), aldosterone (1 µg/mL), and hydrocortisone (1 µg/mL). The carcinogen
DMBA at a dose of 2 µg/mL in DMSO was added to the medium on day 3 for a duration of
24 hours to induce mammary lesions. The DMBA-containing medium was removed, and the
mammary glands were incubated for an additional 14 days with medium containing only insulin.
This procedure allowed the normal glands to undergo structural regression in which all the
normal alveolar structures were disintegrated. However, the alveolar lesions in the
carcinogen-treated glands behave differently. They acquired altered hormone responsiveness and
continued to grow. The nuclear hormone receptor ligand analogues were included in the medium
during the first 10 days of the in vitro culture to determine if they lowered the incidence
of formation of mammary lesions. Throughout the culture period, the glands were maintained at
37 °C in an environment of 95% O2 and 5% CO2. At
the end of the culture period, the glands were fixed in formalin, stained in alum-carmine solution,
and evaluated for the presence or absence of mammary lesions. All hormones and chemicals
were purchased from Sigma Chemical Co.
Statistical analysis. The statistical significance was determined with the use of the
GENCAT computer software program specifically written for the generalized chi-squared
analysis of categorical data using weighted least squares (29). The P values were further subjected to Bonferroni correction. All P values are two-sided.
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RESULTS
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To examine the efficacy of troglitazone and/or a retinoid in
preventing mammary lesions, we incubated 10-20 mammary glands per
group (239 glands in total) from BALB/c mice with appropriate growth
hormones and exposed them for 24 hours to DMBA on day 3 of culture.
Fig. 1, A, shows the presence of mammary alveolar
lesions in DMBA-treated glands. Mammary glands were cultured for 10
days with troglitazone with or without a retinoid. The incidence of
mammary lesions was calculated for each group and was reported as a
ratio of the number of mammary glands showing lesions compared with the
total number of mammary glands at risk. The percent inhibition of
formation of lesions for each treatment group was calculated by the
comparison of the incidence of lesions between the control and the
treatment groups. A dose-related decrease in the number of glands
exhibiting lesions occurred in both the troglitazone-treated group and
the retinoic acid-treated group (Table 1).
Troglitazone at 10-6 M and 10-5
M inhibited mammary alveolar lesions by 31% and 60%,
respectively. Glands treated with troglitazone (10-5
M) contained very few alveolar lesions, and no extensive
dilation of ducts was evident. Toxicity in organ cultures is
characterized by extensive dilation of mammary ducts, which results in
disintegration of the gland structure (24). Thus,
troglitazone was not toxic at these concentrations.

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Fig. 1. Effects of nuclear hormone receptor ligands on the
development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced
mammary lesions. Mammary glands were incubated with insulin, prolactin,
aldosterone, and hydrocortisone for 10 days either alone or with
troglitazone and/or a retinoid. The glands were treated with DMBA on
day 3, for 24 hours, during the initial 10 days of culture. The glands
were further cultured for an additional 14 days with insulin alone. At
that time, the glands were fixed in formalin and processed for
morphologic evaluation. Panel A: mammary gland cultured with
DMBA (24 hours) in the absence of chemopreventive agents.
Representative mammary lesions (MAL) are shown. Panel B:
representative photograph of the nearly normal ducts in a gland after
culture with DMBA (24 hours) on day 3 of the culture plus troglitazone
(10-5 M) and an RXR ligand (LG10068,
10-8 M) added to the culture from days 1 through
10 of culture (original magnification x40).
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Table 1. Effects of troglitazone and/or all-trans-retinoic acid on development of 7,12-dimethylbenz[a]anthracene
(DMBA)-induced lesions in mouse mammary glands*
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The retinoic acid at 10-8 M, 10-7 M, and 10-6 M inhibited formation of lesions by 43%,
54%, and 77% (all P values <.05), respectively (Table 1). To evaluate
the effects of the combination of troglitazone and retinoic acid, we used various concentrations of
troglitazone (10-6 M to 10-5 M) and
retinoic acid (10-8 M to 10-6 M).
Inhibition of lesions with both ligands was similar to that with retinoic acid alone, with the
exception of the combination of 10-5 M troglitazone and
10-7 M retinoic acid, which resulted in 100% inhibition of the lesions as
compared with 66% by 10-5 M troglitazone or 54%
inhibition mediated by 10-7 M retinoic acid. Since both
troglitazone and retinoic acid were independently very active, the combined effect did not appear
to be synergistic. There was no dilation of ducts or no noticeable toxicity observed with retinoic
acid or with the combination of retinoic acid and troglitazone.
The PPAR
heterodimerizes with RXR, and each can simultaneously bind to its ligand,
resulting in enhanced activity of this activated receptor complex. Thus, we examined the effect of
troglitazone combined with an RXR ligand (LG10068). The RXR ligand (10-7 M to 10-8 M) was unable to inhibit
DMBA-induced mammary lesions, and troglitazone (10-6 M) in
this series of experiments inhibited mammary lesions by approximately 14% (Table 2). However, when the two were combined, the percent inhibition of
development of alveolar lesions in mammary gland cultures was 85% or more
(100%) showing that the two ligands together were clearly more effective than either
alone (Table 2). The effect of the combination appears to be much
enhanced compared with that of the individual compounds and may be synergistic. As shown in
Fig. 1, A, DMBA induced mammary alveolar lesions in the absence of chemopreventive agents.
However, the presence of the combination of troglitazone and LG10068, an RXR ligand,
inhibited the development of DMBA-induced mammary lesions (Fig. 1,
B).
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Table 2. Effects of troglitazone and/or the retinoid X receptor
ligand LG10068 on development of 7,12-dimethylbenz[a]anthracene
(DMBA)-induced lesions in mouse mammary glands*
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In the same experiment, the effects of troglitazone on the initiation and promotion of lesions
were investigated. When troglitazone (10-5 M) was present in the
culture for only the first 4 days, we observed 71% inhibition of DMBA-induced mammary
lesions. During the first 4 days of culture, DMBA was present for 24 hours on day 3 in the
culture medium. Likewise, troglitazone, when present from days 4 through 10 of culture, was
similarly able to inhibit development of mammary lesions (71% inhibition). During that
period, DMBA was no longer present. Taken together, the results showed that troglitazone could
inhibit both initiation and promotion of lesions of the mammary gland.
Expressions of RAR
, RXR
, and PPAR
were examined in the control and
experimental glands (Fig. 2). Results showed that RXR
and
PPAR
were expressed in all glands; when normalized for the expression of actin, little
change occurred in levels of RXR
or PPAR
with the various treatments. Mammary
glands following the organ culture did not express RXRß or RXR
(data not shown).
However, RAR
was expressed in all glands. Results showed that there was a
25%-30% reduction in the RAR
expression in the glands treated with retinoic
acid (10-6 M) or troglitazone (10-6 M). The expression of RAR
was further reduced by 60% when the glands were
treated with a combination of troglitazone (10-6 M) and retinoic
acid (10-6 M).
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DISCUSSION
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Chemoprevention of cancer is clearly of great benefit to the
individual and is less costly to society than is the treatment of
established cancer. This one approach of cancer prevention is known as
chemoprevention (30). Compounds that can arrest either
initiation or progression of breast carcinogenesis include ER
antagonists, retinoids, monoterpenes, isoflavonoids, thiols, inhibitors
of polyamine synthesis as well as prostaglandins, and vitamin
D3 analogues (31-34). The synthetic ligand of
PPAR
, troglitazone, has been shown to be effective against the
proliferation of breast cancer cells; however, it has not been
evaluated for its possible activity as a chemopreventive agent. In this
study, troglitazone was able to inhibit the development of DMBA-induced
mammary lesions, and this activity was potentiated by an RXR ligand,
although by itself this ligand had no chemopreventive effects. On the
other hand, unlike the RXR ligand, retinoic acid inhibited the
development of mammary alveolar lesions in culture. The combination of
retinoic acid and troglitazone resulted in additive chemopreventive
activity. These experiments represent one of the initial steps toward
the long-range goal of identifying effective chemopreventive agents for
breast cancer. The lack of toxicity for most individuals receiving
troglitazone for adult-onset diabetes, as well as the lack of adverse
effects of several RXR ligands, including 9-cis-retinoic acid,
makes the combination of troglitazone and an RXR analogue attractive
for in vivo chemopreventive trials. Furthermore, several new
thiazolidinediones are now available, and these compounds do not appear
to have the idiosyncratic liver toxicity that occurs rarely with the
administration of troglitazone.
How troglitazone, the synthetic ligand of PPAR
, inhibits transformation of mammary
tissue is unclear. PPAR
is an important regulator of metabolism and storage of lipid (35,36). This study and previous studies (2,36,37)
showed that breast tissue expressed PPAR
. The amount of PPAR
expressed in
normal breast epithelium appears to be less than that expressed in breast cancer (3). Furthermore, the level of expression of PPAR
varies in normal mammary
ducts, depending on whether the breasts are examined during the lactogenic period or the
nonlactogenic period. We previously showed that, after culture with troglitazone and other
natural and synthetic ligands of PPAR
, the MCF-7 breast cancer cells had an increased
accumulation of fat and an increased expression of CD36 protein that was associated with active
metabolism and storage of lipid (3). However, these cancer epithelial
cells did not cross-differentiate to adipocytes, as shown by their lack of expression of a number
of key markers, such as aP2, lipoprotein lipase, and adipsin (2,3). Our
present data also showed that troglitazone had no marked effect on the level of expression of
PPAR
, as shown by western blot analysis (Fig. 2). In addition,
examination of these mammary cells by light microscopy revealed no increase in the level of
apoptotic cell death, with the cells appearing perfectly normal. Studies have shown that
PPAR
ligands can induce cell cycle arrest; the mechanism for this effect is unclear, but it
may be a result of the receptor's reported involvement in inhibiting the activity of the
E2F/DP family of transcriptional factors implicated in the initiation of the S phase of the cell
cycle (38) and/or to antagonize the activity of the secondary signal
proteins AP-1, STAT, and NF-
B (39,40).
Thiazolidinediones can inhibit proliferation of a variety of cancer cells (6,41,42). Activation of PPAR
promotes the differentiation and cessation of
proliferation of human liposarcoma cells (6). PPAR
ligands also
induce differentiation and reverse the malignant phenotype of colon cancer cells (41). Furthermore, PPAR
ligands can inhibit the proliferation of prostate cancer
cells in vitro and in laboratory animals (42). Clinical studies in
which troglitazone is given to individuals after radical prostatectomy for prostate cancer but who
are still having a detectable serum prostate-specific antigen are now ongoing both in Los
Angeles, CA, and Boston, MA. PPAR
ligands have also been shown to induce
differentiation of myeloid leukemia cells (43).
Previous studies by others and us (32,33) have shown that, after
activation of the PPAR
receptor for several days, troglitazone could be removed and the
breast cancer cell still had a markedly reduced capacity for clonogenic growth. Similarly, we
showed here that exposure to troglitazone during either the first 4 days, i.e., initiation phase, or
the final 6 days of the growth-promoting phase of culture suppressed transformation of the cells
by DMBA (Table 2). In this experiment, the cells were pulse-exposed to the carcinogen only on
day 3 of culture; therefore, the troglitazone appeared capable of inhibiting both the initiation and
the promotion of cellular transformation.
The retinoic acid (RAR-specific ligand) also inhibited the carcinogen-induced development
of mammary lesions. Previous studies have shown that the AP-1 transcriptional factor can be
inhibited by retinoic acid (44) and may be responsible for the
antitumor-promoting activity of retinoic acid (45). Therapy with retinoic
acid is strikingly successful for acute promyelocytic leukemia by inducing terminal
differentiation of these leukemic cells (46,47). Moreover, clinical trials
have shown that N-4-hydroxyphenyl retinamide, a retinoid, may provide an effective
therapy for some breast cancer patients (32,33).
In this study, we found that combining a PPAR
ligand with a ligand specific for RXR
(LG10068) enhanced the suppression of development of mammary lesions. A previous study (48) has shown that simultaneous activation of both receptors can result in
synergistic activity in several assays of cultured cells as well as in augmented in vivo
antidiabetic activity. Furthermore, we have previously shown that a PPAR
ligand and an
RXR ligand can have enhanced antiproliferative effects against breast and prostate cancer cells (3,42). Another study (49) has also shown that an
RXR-specific agonist (LG10069) had chemopreventive activity against chemically induced rat
mammary tumors; however, such activity for LG10068 has not been reported. Further studies are
required to determine the target genes associated with this anticancer activity.
As far as we know, this is the first report showing the possibility of troglitazone, a
PPAR
ligand, having chemopreventive activity. Troglitazone is a relatively nontoxic
compound at a wide range of concentrations, but it is a potent inhibitor of the development of
preneoplastic lesions of the mammary gland in organ culture. Also, an RXR- or an
RAR-selective retinoid appears to enhance this chemopreventive activity; thus, the combination
of a thiazolidedione and a retinoid, such as either retinoic acid or LG10068, may be a good
candidate for an in vivo breast cancer chemoprevention study. Because of advances in
the knowledge of genetics and epidemiology of breast cancer, individuals at high risk for
developing breast cancer can be identified; these are the individuals who may receive the benefit
from a chemoprevention regimen containing a PPAR
ligand combined with an appropriate
RXR-selective retinoid.
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NOTES
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Supported by Public Health Service grant CA26038-20 from the National Cancer
Institute, National Institutes of Health, Department of Health and Human Services; by U.S. Army
grant PC970577; by the California Breast Cancer Research Program; by the Parker Hughes
Trust; and by the C. and H. Koeffler Fund.
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Manuscript received June 6, 1999;
revised December 10, 1999;
accepted December 27, 1999.
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