The Effect of Flaxseed in Breast Cancer: A Literature Review

Abstract

Breast cancer is one of the most common cancers and the second most responsible for cancer mortality worldwide. In 2014, in Portugal approximately 27,200 people died of cancer, of which 1,791 were women with breast cancer. Flaxseed has been one of the most studied foods, regarding possible relations to breast cancer, though mainly in experimental studies in animals, yet in few clinical trials. It is rich in omega-3 fatty acids, α-linolenic acid, lignan, and fibers. One of the main components of flaxseed is the lignans, of which 95% are made of the predominant secoisolariciresinol diglucoside (SDG). SDG is converted into enterolactone and enterodiol, both with antiestrogen activity and structurally similar to estrogen; they can bind to cell receptors, decreasing cell growth. Some studies have shown that the intake of omega-3 fatty acids is related to the reduction of breast cancer risk. In animal studies, α-linolenic acids have been shown to be able to suppress growth, size, and proliferation of cancer cells and also to promote breast cancer cell death. Other animal studies found that the intake of flaxseed combined with tamoxifen can reduce tumor size to a greater extent than taking tamoxifen alone. Additionally, some clinical trials showed that flaxseed can have an important role in decreasing breast cancer risk, mainly in postmenopausal women. Further studies are needed, specifically clinical trials that may demonstrate the potential benefits of flaxseed in breast cancer.

Full text

February 2018 | Volume 5 | Article 41
REVIEW
published: 07 February 2018
doi: 10.3389/fnut.2018.00004
Frontiers in Nutrition | www.frontiersin.org
Edited by:
Marc Poirot,
Institut National de la Santé et de la
Recherche Médicale, France
Reviewed by:
Alessandro Laviano,
Sapienza Università di Roma, Italy
Omer Kucuk,
Emory University, United States
*Correspondence:
Ana Calado
anacalado1990@gmail.com
Specialty section:
This article was submitted
to Clinical Nutrition,
a section of the journal
Frontiers in Nutrition
Received: 15July2017
Accepted: 16January2018
Published: 07February2018
Citation:
CaladoA, NevesPM, SantosT and
RavascoP (2018) The Effect of
Flaxseed in Breast Cancer: A
Literature Review.
Front. Nutr. 5:4.
doi: 10.3389/fnut.2018.00004
The Effect of Flaxseed in Breast
Cancer: A Literature Review
Ana Calado1*, Pedro Miguel Neves2, Teresa Santos3,4,5 and Paula Ravasco2
1 Instituto de Ciências da Saúde, Universidade Católica Portuguesa, Lisbon, Portugal, 2 Faculdade de Medicina da
Universidade de Lisboa, Hospital Universitário de Santa Maria and Centro de Investigação Interdisciplinar em Saúde da
Universidade Católica Portuguesa, Lisbon, Portugal, 3 Faculdade de Motricidade Humana (FMH) (Projecto Aventura
Social-Social Adventure Team), Universidade de Lisboa, Lisbon, Portugal, 4 Instituto de Saúde Ambiental (ISAMB),
Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal, 5 William James Center for Research, ISPA––Instituto
Universitário, Lisbon, Portugal
Breast cancer is one of the most common cancers and the second most responsible
for cancer mortality worldwide. In 2014, in Portugal approximately 27,200 people died
of cancer, of which 1,791 were women with breast cancer. Flaxseed has been one of
the most studied foods, regarding possible relations to breast cancer, though mainly
in experimental studies in animals, yet in few clinical trials. It is rich in omega-3 fatty
acids, α-linolenic acid, lignan, and bers. One of the main components of axseed is
the lignans, of which 95% are made of the predominant secoisolariciresinol diglucoside
(SDG). SDG is converted into enterolactone and enterodiol, both with antiestrogen
activity and structurally similar to estrogen; they can bind to cell receptors, decreasing
cell growth. Some studies have shown that the intake of omega-3 fatty acids is related
to the reduction of breast cancer risk. In animal studies, α-linolenic acids have been
shown to be able to suppress growth, size, and proliferation of cancer cells and also to
promote breast cancer cell death. Other animal studies found that the intake of axseed
combined with tamoxifen can reduce tumor size to a greater extent than taking tamoxifen
alone. Additionally, some clinical trials showed that axseed can have an important role
in decreasing breast cancer risk, mainly in postmenopausal women. Further studies are
needed, specically clinical trials that may demonstrate the potential benets of axseed
in breast cancer.
Keywords: breast cancer, axseed, lignan, nutrition, omega-3
INTRODUCTION
Cancer is one of the most serious health problems in Public Health given its high and increasing
prevalence worldwide, being one of the main causes of morbidity and mortality and also responsible
for a signicant decrease in life quality. According to the World Health Organization (WHO), in
2012, 14 million new cases of cancer were diagnosed, which were responsible for 8.2 million deaths
worldwide, with 521,000 of them being attributed to breast cancer (1–3).
In 2012, it was estimated that approximately 32.5 million people were cancer survivors, 5 years
aer being diagnosed with the disease. In 2030, it is expected that approximately 23.6 million new
cases of cancer will be diagnosed each year (4).
In 2014, in Portugal approximately 27,200 people died of cancer, of which 16,600 were men and
10,600 were women (2).
According to the WHO, approximately one-third of the deaths caused by cancer are due to bad
eating habits and lack of physical activity. By improving eating habits and increasing physical activity,

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more than 30% of the cancers diagnosed could be avoided. us,
with the increased risk, a proper nutrition intervention is neces-
sary (1–3).
Nutrition plays a fundamental role in cancer, as it can reduce
complications that happen during treatment and can contribute
to the patient’s well-being (3, 5).
Many people with cancer choose to make some changes in
their eating habits while subjected to conventional, like chemo-
therapy. e patients do this in the hopes of decreasing the treat-
ment’s severe side eects such as anxiety, depression, insomnia,
headaches, nausea, and vomiting (among others) (6–9).
ese less-conventional treatments may include diets with
food that has proper nutritional characteristics to help ght the
disease. Flaxseed has been one of the most studied foods regarding
the possible relation to breast cancer. Some experimental studies
in animals have been done but few progressed to clinical trials.
MATERIALS AND METHODS
To review the eect axseed may have in breast cancer, we
conducted a bibliography research using sources from PubMed,
and websites of institutions like Cancer Research UK and the
WHO. e keywords used in the research were as follows: cancer,
axseed, lignan, breast cancer, and nutrition.
RESULTS
Breast Cancer
Breast cancer is considered as one of the most common cancers
with the highest number of deaths worldwide. According to the
WHO, it was estimated that in 2012, more than 1.68 million of
women were diagnosed with breast cancer worldwide. Of these,
approximately 521,000 died and in Europe, during the same year,
more than 464,000 new cases were diagnosed and approximately
131,000 women died (1, 10, 11).
In 2014, in the United Kingdom, there were approximately
55,200 new cases of breast cancer (390 men and about 54,800
women), of which approximately 150 were diagnosed daily with
approximately 11,400 deaths due to this kind of cancer. It is con-
sidered that one in eight women will be diagnosed with breast
cancer during their lifetime (11).
In 2014, in Portugal, approximately 27,200 people died of
cancer, with 1,791 of the victims being women with breast can-
cer. Also, approximately 6,088 new cases of breast cancer were
diagnosed in women (2).
ere are several factors that can be associated with breast
cancer, such as gender, bad eating habits and respective lifestyles,
family history, alcohol or tobacco consumption, lack of breast
feeding, hormone treatments, overweight, and obesity, among
others (10, 11).
Aer being diagnosed, many patients with breast cancer decide
to change their eating habits and respective lifestyles (12, 13).
Flaxseed and the Lignans
Flax (Linum usitatissimum), also known as linseed, belongs to
the Linaceae family which originates from Europe, Asia, and the
Mediterranean region. Flaxseed can be divided in two species:
brown and golden. Golden ax develops in very cold climates,
while brown ax develops in warmer and more humid climates.
e latter must be ground to be better digested and absorbed by
the body, thus increasing the bioavailability of the nutrients. It
is considered a functional food that has nutrients with specic
properties (antioxidant and/or antitumorigenic functions), such
as omega-3 fatty acids, α-linolenic acid (LA), lignan, or bers
that are benecial to one’s health, preventing some diseases, such
as cancer and cardiovascular diseases, among others (14–16).
Flaxseeds are rich in ber and are suggested for situations of
constipation, as they help to improve the intestinal function. ey
have omega-3 fatty acids that promote the reduction of cholesterol
levels, thus preventing cardiovascular diseases. Additionally, they
are still a good source of magnesium, phosphorus, manganese,
vitamin B1, selenium, and zinc.
Although they are dened as one of the richest plant sources
in omega-3 fatty acids, these seeds are also characterized by
their lignan content. Although lignans are found in a variety of
vegetable sources, such as whole grains, sesame seeds, vegetables,
and fruits, axseeds have approximately 100 times more lignans
than other foods (9, 17, 18).
Lignans are phytoestrogens that relieve the symptoms of
menopause and can balance the eects of estrogen in the body by
connecting to their receptors, as they have a very similar chemical
structure as to an estrogen molecule (19).
e predominant lignan in axseeds is secoisolariciresinol
diglucoside (SDG), making up around 95% of the seed’s lignan
content. e remaining 5% consist of lariciresinol, pinoresinol,
and matairesinol. Aer SDG lignan ingestion, bacteria in the
colon act by converting the lignan into mammalian lignans,
enterolactone, and enterodiol. ese are structurally similar to
estrogen, and have antioxidant activity and a weak estrogenic
action (Figure1). It also works as an antiestrogenic because its
structure is very similar to the main form of estrogen, which
allows its binding to the cell’s receptors, thus inhibiting the
growth of cancer cells (9, 20–23).
Breast tumors that contain estrogen receptors are called
estrogen receptor positive (ER+) and tumors that lack estrogen
receptors are estrogen receptor negative (ER−). Women who have
ER+tumors are more likely to respond to hormonal treatments
than women with ER− tumors (24).
In our body, the biological active form of estrogen is estra-
diol, which is oxidized mainly in the liver to estrone. Estrone
can be converted to two metabolites with dierent biological
eects: 2-hydroxyestrone (2OHE1) and 16α-hydroxyestrone
(16OHE1). While the rst one has a small biological activity,
the latter will increase the estrogen’s activity, promoting cell
proliferation (growth of cancer cells) (Figure2) (25, 26). Women
who produce more 16OHE1 are likely to have an increased risk
of breast cancer (27).
Two clinical trials concluded that 28 postmenopausal women,
who followed a diet including 10 or 25g of ground axseed for 7
or 16weeks, witnessed an increased level of excretion of 2OHE1
in their urine, without an increase in the excretion of 16OHE1.
ese studies imply that axseed can have some protective
eects in postmenopausal women (28).

FIGURE 2 | Inuence of estrogen metabolism in cancer cells.
FIGURE 1 | Metabolism of lignans in axseeds.
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Omega-3 Fatty Acids and Breast Cancer
Polyunsaturated fatty acids (PUFAs) can be composed of omega-3
and omega-6. Linolenic acid and arachidonic acid (AA) are the
main components of omega-6. e α-linolenic acid (ALA) is the
precursor of the PUFA omega-3 family which forms eicosapen-
taenoic acid (EPA) and docosahexaenoic acid (DHA) (29, 30).
Omega-3 and ALA are also constituents of axseed. Flaxseed
is considered as the best plant source of the essential omega-3
fatty acid. Studies suggest that the omega-3 fatty acid may have
anticancer properties while omega-6 fatty acid can contribute
to the development of cancer. Currently, in a regular diet, there
is a higher amount of omega-3, than omega-6 (29, 30). Studies
have revealed that PUFA omega-3 ingestion is associated with
the reduction of risk of breast cancer (31). In animal studies, the
ALAs have been shown to be able to suppress the growth, size,
and proliferation of cancer cells. An increase in the death of these
cells has also been observed (32, 33).
Tamoxifen and Breast Cancer
Tamoxifen is a drug used in the treatment of breast cancer, mainly
in women with ER+. It can be used as an adjuvant therapy for
breast cancer or metastatic breast cancer. It is a type of hormone
therapy that is done during 5–10years with several side eects
(34–37).
is drug works as an antiestrogen since, as it is an ER+ type
of cancer, the tamoxifen acts throughout the whole body, block-
ing the action of estrogen on tumor cells, thus preventing their
growth (34, 35).
According to experimental studies, axseed does not have any
type of interaction with drugs used in breast cancer treatments
and can provide an additional protective eect when consumed
along with the treatment. In animal studies, it was also veried
that axseed, ax oil, or lignan SDG ingestion, in combination
with tamoxifen, reduced the tumor’s size to a greater extent than
tamoxifen treatment alone. Until now, there are no clinical trials
that can prove the benets that axseed ingestion can have in
women with breast cancer during tamoxifen therapy (38).
A study undertaken at the University of Toronto evaluated the
eect of axseed and tamoxifen, alone and in combination, on
the growth of ER+human breast tumor cells in mice. ese mice
were injected with MCF-7 tumors and fed with dierent diets.
e diets had 20–25g of ground axseed, a tamoxifen pill (5mg)
or both. Tumor growth was monitored weekly. As a result, the

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axseed diet fed to the mice was the one that inhibited the growth
of the ER+human breast tumor cells. At low 17 beta-estradiol
levels, ax inhibited tumor size approximately 74%, while at
high 17 beta-estradiol levels it inhibited approximately to 22%.
Furthermore, the combination of ax and tamoxifen inhibited
tumor size more than 53%, as compared with tamoxifen action
alone (39).
Other experimental studies conducted in mice injected with
ER+human breast tumor cells reveal that both at low- and high-
estrogen levels (pre- and postmenopausal breast cancer), axseed
either increased or kept tamoxifen’s eectiveness in decreasing
tumor growth, cell proliferation, and increased apoptosis (38–42).
ere are currently no known results from clinical trials
regarding axseed ingestion during tamoxifen therapy (38).
Animal Studies
In animal studies with mice injected with breast tumor cells,
feeding them with axseed caused a decrease in tumor incidence,
number, and size. ese results were also revealed to be inde-
pendent of the tumor’s stage (23).
A research group from the University of Toronto has also dem-
onstrated that ground axseed has an eective anticancer activity.
eir experimental study was conducted in mice to which tumors
were administered, along with the introduction in their diet of a
mixture of lignan. e result was a decrease in the tumor load
due to the presence of axseed and lignan SDG in the mice diet
(43–45).
Recently, the same research group injected another mice group
with human breast tumor cells. While the cancer was progress-
ing, the mice were on a regular diet for 8weeks aer cancer cells’
injection. One group was fed with 10% of axseed, while the other
group kept the same kind of diet. e rate of the tumor growth
was reduced by 45% due to axseeds (43–45).
In several other experimental studies, diets including 5 or 10%
of axseed (approximately 25–30g of axseed daily, in humans)
inhibited the growth of the ER+ in human breast cancer cells
injected in mice (39–42, 46, 47). e same happened with the
growth of the ER− (44, 48, 49). Flaxseed also reduced metastasis
of ER− breast tumor (44, 48, 50).
Clinical Trials
Observational studies indicate that axseed consumption (appro-
ximately 32g/daily) can reduce breast cancer risk (38, 51, 52).
Lignans also contribute to the decrease of breast cancer risk.
Vegetarians have a higher level of lignan ingestion, meaning that
their breast cancer risk is lower than that of omnivores (53).
A study revealed that 70% of newly diagnosed patients with
breast cancer consume food rich in lignans, 52% consume ax
bread, and 30% consume axseed at least once a week (13).
A pilot study including 24 postmenopausal women with
ER+breast cancer was conducted to show the eects of axseed
and the aromatase inhibitor, anastrozole (drug used in the treat-
ment of breast cancer), and possible interactions between them in
selected breast tumor characteristics and serum steroid hormone.
ese women were then divided randomly into four groups:
Group 1 with 25g/daily of ground axseed and 1 placebo pill daily;
Group 2 with 1mg/daily of anastrozole; Group 3 with 25g/daily
of ground axseed and 1 mg/daily of anastrozole; and Group
4 with 1 placebo pill daily. is study did not show any eects
regarding axseed on the aromatase inhibitor activity in selected
breast tumor characteristics and serum steroid hormone levels
(9). Further studies are needed to support a possible interaction
between axseed intake and the aromatase inhibitor––anastrozole.
Ingestion of axseed or bread containing this ingredient is
associated with a 20% reduction in the risk of breast cancer, in
accordance with the protective eect observed in lignans from
other vegetables. is risk decrease may be related to a reduction
in inammation, since the presence of large amounts of lignans
can lead to a decrease in several inammatory markers (52, 54).
In two meta-analysis studies, it was found that a higher intake
of lignans from dietary sources was associated with a signicant
reduction in postmenopausal breast cancer risk (54, 55). In a case-
control study, the highest lignan consumption was associated
with signicantly lower postmenopausal breast cancer mortality
but that association did not happen relatively to premenopausal
breast cancer mortality (56).
A case-control study using the Ontario cancer registry data-
base consisted of a random sample of women diagnosed with
breast cancer, with the aim of analyzing the phytoestrogen
intake (isoavones and lignans) and their association with breast
cancer risk. A food-frequency questionnaire was used, which
also included foods rich in phytoestrogens. Lignan intake was
associated with a reduction in the risk of breast cancer for all
women, although this was only statistically signicant in over-
weight women (BMI>25). In premenopausal women, the total
phytoestrogen intake was associated with a signicant reduction
in the risk of breast cancer, but only in overweight women. ere
was no association between breast cancer risk and the intake of
phytoestrogen in postmenopausal women (51).
Another case-control study also using the Ontario cancer
registry database conducted a food-frequency questionnaire
with the aim of establishing if phytoestrogen intake during ado-
lescence could protect against breast cancer in adulthood. e
results of this study revealed that a higher phytoestrogen intake
(isoavones and lignans) during adolescence can be associated
with a reduced breast cancer risk (57).
To explore the association between axseed ingestion and
breast cancer risk, a case-control study was conducted by apply-
ing a food-frequency questionnaire to women who joined the
Ontario Women’s Diet and Health Study in Canada (2002–2003).
Both the monthly and weekly/daily consumption of axseed
(approximately 32.5g) and ax bread (1 unit, roughly 2.5 − 5g of
axseed) were associated with a signicant reduction from 18 to
24% in the risk of breast cancer in all women. It was also showed
that axseed only reduced breast cancer risk in postmenopausal
women, while ax bread reduced breast cancer risk in both
postmenopausal and premenopausal women (52).
A prospective cohort study, including 58,049 postmenopausal
French women, found that those with the highest lignan inges-
tion (>1,395μg/day) had a signicantly decreased risk of breast
cancer. e benecial eects of lignans in this study were limited
to ER+breast cancer and progesterone receptor positive (58).
On the other hand, researchers conducted a double-blind,
randomized clinical trial, with a placebo control in patients with

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breast cancer. e investigators tracked postmenopausal women
that had been recently diagnosed with breast cancer and with a
scheduled surgery. ese women were then divided, randomly,
into two groups: Group 1, which included 19 women, ate a muf-
n daily with approximately 25g of powdered axseed, while
Group 2, which included 13 women, ate a similar looking mun,
without axseed. Biopsies were performed in both groups, at
the beginning of the trial, which were later compared with the
pathology of the tumor removed during surgery, approximately
5 weeks aer the study began. Women who ate the mun
containing axseed presented, on average, a decrease in the
tumor cell proliferation, a reduction in the expression of c-erB2
levels (also known as HER2––an oncogene associated with the
development and progression of breast cancer) and an increase
in cell apoptosis. Researchers concluded that axseed has the
potential of reducing tumor growth in patients with this type of
cancer (38, 59).
In another clinical trial, researchers selected about 45 pre-
menopausal women with a high risk of developing breast cancer
(either with suspicious breast biopsies or former breast cancer
survivors) and they gave them 50mg of SDG lignan daily, or the
equivalent of two spoons of powdered axseed. e research-
ers conducted needle biopsies on the breast tissue, both before
and aer the study, which lasted a year. Results showed that,
on average, women had less breast precancerous changes aer
a 1 year period of taking daily axseed lignans, than they had
before they started being studied and also that 80% (36 out of 45)
had a decrease in the Ki-67 levels––a biomarker that signals the
increase of cell proliferation. According to this clinical trial, SDG
lignan can reduce the risk of breast cancer (60).
Some studies showed no association between risk of breast
cancer and serum enterolactone levels (54, 55, 61, 62). ere is
a study that indicates a decreased breast cancer mortality with
higher serum enterolactone levels (63). In a meta-analysis study,
it was found that enterolactone biomarkers were associated with a
statistically signicant reduction of 28% in risk of postmenopau-
sal breast cancer (64). A study including 1,140 postmenopausal
patients with breast cancer showed that serum enterolactone con-
centrations in the highest quartile were associated with a reduc-
tion of approximately 40% in mortality (65). Also, a case-control
study concluded that a greater amount of serum enterolactone
levels can be associated with a decreased breast cancer risk (66).
It is necessary to conduct more studies to be able to conrm if
there is an association between serum enterolactone levels and
breast cancer risk.
Five studies published between 2010 and 2011, which included
patients diagnosed with breast cancer who were observed for a
period of 6–10years, with the aim of nding out if lignans could
prolong the survival of patients with breast cancer. rough the
measurement of food records or of serum lignan levels, research-
ers concluded that there was an increased exposure to lignans,
which led to a signicant reduction of approximately 40–53% in
mortality and a 33–70% reduction in mortality by breast cancer.
is increased exposure to lignans was mostly observed in
postmenopausal women. ere is a possibility that lignans could
prolong the lifespan of patients with breast cancer, but further
studies are needed to conrm this (15, 56).
Breast cancer survivors who have higher levels of lignans in
their bloodstream and on their diet seem to survive for a signi-
cantly longer period of time (56, 65).
DISCUSSION
Since breast cancer has been considered one of the most common
cancers with the highest mortality rate worldwide, it is important
to include nutrition as part of this disease treatment. With the
improvement in eating habits and the practice of physical activity,
more than 30% of the cancers diagnosed could be avoided. It has
been shown that an individualized nutritional intervention can
reduce treatment complications and can improve the patients’ life
quality. Flaxseed has been a vastly studied food due to the relation
that it may have with breast cancer. Some experimental studies
have been conducted in animals, but only a few clinical trials have
been done in humans with the aim of discovering the eects of
axseed on tumors and on the risk of this type of cancer.
Some studies revealed that the ingestion of omega-3 fatty acids
is associated with the reduction of breast cancer. Animal studies
showed that ALA can decrease the growth, size, and cell prolifera-
tion and can increase the death of breast tumor cells.
e majority of experimental studies conducted showed that
axseed increases or maintains tamoxifen’s ecacy on the decrease
of tumor growth on cell proliferation and on the increase of apopto-
sis. It is however necessary to conduct more clinical trials to conrm
the association and respective ecacy of axseed with tamoxifen.
In several experimental studies, diets including 5 or 10% of
axseed (approximately 25–30 g of axseed daily, in humans)
inhibited the growth of the ER+ in human breast cancer cells
injected in mice. e same happened with the growth of the ER−.
Flaxseed also reduced the metastasis of ER− breast tumor.
During clinical trials, researchers have concluded that axseed
has the potential to reduce the growth of tumors in patients with
breast cancer, mainly postmenopausal women, and decrease the
risk of this type of cancer.
Although many of the studies reported in this paper concluded
that axseed intake may be related to the decreased risk of breast
cancer and also to the reduction of the tumor’s growth and size,
some studies including premenopausal and postmenopausal
women did not show the same results.
However, more studies are still necessary, especially clinical
trials, to verify the benets of axseed on the treatment of breast
cancer.
ETHICAL STATEMENT
None sought.
AUTHOR CONTRIBUTIONS
AC conceived the study, participated in its design and coordina-
tion, and draed and authored the manuscript. PR participated
in the study design, interpretation of the data, and helped to dra
manuscript revisions. TS and PN were responsible for scientic
writing and manuscript editing. All authors have read and
approved the nal manuscript.

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ACKNOWLEDGMENTS
e authors thank the support extended by the Portuguese
Catholic University in Lisbon. A word of thanks also goes to Paula
Ravasco, who provided insight and expertise that greatly assisted
during the course of this research and for the chance given to
perform it and Teresa Santos, who shared her wisdom regarding
her experience performing review articles.
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