LINUS
PAULINGINSTITUTE
OREGON STATE UNIVERSITYRESEARCH NEWSLETTERSPRING–SUMMER 2018

Research Update on ALS Clinical Trials with Copper ATSM. LOOK INSIDEEMBRACING BOTANICALDIETARY SUPPLEMENTS

IN THIS ISSUE
Embracing Botanical
Dietary Supplements.......... 1

BOTANICAL SUPPLEMENT USE IS ON THE RISE, BUT SAFETY ISSUES REMAIN
By Richard B. van Breemen and Ruth Muchiri, Ph.D.

In addition to nutrients, plants synthesize
a vast array of metabolites that we call
phytochemicals. Since many phyochemicals
have pharmacological activities, plants are theoriginal source of medicines for treating diseaseor maintaining human health.
Today, many of the synthetic (or semisynthetic)
drugs that we use regularly still find their origins
in plants. Although pharmaceuticals now replace
many plant-based traditional medicines,
botanical supplements (see sidebar on page5) are a primary source of health products fora large part of the global population. In several
cases, they remain a viable alternative to drugs.
And it is safe to say that the demand forbotanical products is increasing. The worldwide

market for botanical dietary supplements
exceeded $33 billion in 2010 and is projected tosurpass $140 billion by 2024.
Despite their prevalence and popularity, there
is much to learn about the beneficial propertiesof botanical products, as well as the potential
drawbacks of their use. This is the focus of thevan Breemen laboratory.
Our laboratory has decades of experiencestudying a variety of natural products. Beginningin the 1990’s, we were part of an internationalteam of scientists and nutritionists conducting
human studies of the bioavailability andbioconversion of provitamin A carotenoids
like beta-carotene. These molecules, naturally
produced by plants, can be converted by the bodyContinued on page 4

From the Director................ 2
Giving Aging Cells a
Needed Boost....................... 6
Vitamin D-Infused
Bandages .............................. 8
Micronutrients forBone Health........................10
An Update on
Copper-ATSM Clinical
Trials......................................12
LPI Students........................14
Outreach..............................15
Developments....................15

FROM THE DIRECTOR

Richard van Breemen, Ph.D.
The new director of theLinus Pauling InstituteAt the end of 2017, after packing mylaboratory and household in Chicago
onto several moving vans during a snowy
Illinois winter, my wife Denise Hynes andI boarded a flight headed west. We wereready for our new adventures in Oregon
and at Oregon State University. Ever since,
we have been enjoying the much milder
climate of the Willamette Valley and thebeautiful OSU campus.
Leading the Linus Pauling Institute is anincredible opportunity, and I am humbled
to have been selected for this great honor.
Having met Dr. Pauling after he gave aseminar during my first year as an assistantprofessor of chemistry at North Carolina
State, I think of how amazed I would havebeen to glimpse into the future. I now leadthe Institute that he founded.
I had followed Dr. Pauling’s researchconcerning dietary supplements for years
before I met him, sharing in the belief thatvitamins and other dietary supplements
can enhance health and prevent disease.
We also shared a passion for promoting
peace. In our brief conversation, Dr. Paulingand I talked about the process of writing
scientific manuscripts and approaches toteaching undergraduate chemistry. It wasover 30 years ago now, but I wish we had
more time in our conversation to discuss
his beloved Institute.

Is there something you
would like to see in thenext LPI newsletter?
Let us know!
Email lpi@oregonstate.edu
or call 541-737-5075

Although dedicated to research, theLinus Pauling Institute has always provided
an exceptional environment for educating
the next generation of experts on
micronutrients and dietary supplements asthey relate to maintaining human healthand preventing disease. All of our principal
investigators are professors or associate
professors at Oregon State University
and maintain active research programs.
Undergraduates, graduate students,
postdoctoral fellows, and visiting scholars
are found in every program. The LPI is
the perfect environment to promote theeducation of brilliant young minds.
Many of my own graduate students
completed their Ph.D. disserations before
leaving the University of Illinois, but fiveremain in my laboratory at the LPI: Emily
Rue, Luying Chen, Jialin Liu, Alan Wong,2and Danial Nosal. I would like to thank
Kerry McPhail and Theresa Filtz for helping
my students transfer to the Department ofPharmaceutical Sciences in OSU’s Collegeof Pharmacy and to resume course work
immediately.
To enhance support for graduate
education in natural products research,my first grant application since arriving
at OSU was a predoctoral training
grant to the NIH National Center for
Complementary and Integrative Health.
I would like to thank my co-principal
investigator, Taifo Mahmud in the Collegeof Pharmacy, for all his help making thispossible. If successful, this will provide
funding for additional students at OSU tocomplete their Ph.D. programs in the LPI.
Ruth Muchiri, a postdoctoral trainee who
worked with me in Chicago, has now joined
the ranks of the LPI. Ruth is now part of
the research staff, helping to manage ourresearch laboratory.
Our group complements others
within the LPI, not just by adding newexpertise, but because of our history ofa collaborative approach. We have been
an integral part of NIH-funded research
centers for over three decades, including
centers dedicated to the discovery ofmechanisms of cancer chemoprevention
by natural products and the discovery ofnatural products with pharmacologicalactivities.
Currently, we are working with the Center
for Botanical Dietary Supplements that I
co-founded while working in Chicago withthe late Norman Farnsworth. This center
is focused on the study of the safety andefficacy of botanical dietary supplements
for women’s health. This experience will
guide the development of collaborative
research teams within the LPI and otherexperts at Oregon State University,
supported by new external center grants.
All the members of my research teamare pioneers in the development andapplication of mass spectrometry-based
methods for natural product drug discovery(see cover article). We are also experts inhuman metabolism and bioavailability ofmany compounds from natural products.

Dr. van Breemen strongly supports
increased training opportunities for all
students in the LPI’s research laboratories.
Pictured with Dr. van Breemen is Danial
Nosal, a graduate student in his laboratory.

Continuing to rely heavily on biomedical
mass spectrometry, I will work toward
developing strong relationships with
manufacturers of instrumentation for
scientific research and establishing newcenters of excellence that will benefit not
only the LPI but also researchers acrossthe Oregon State University campus.

The building is also home to Ava’s Cafeon the first floor (named after Ava HelenPauling, wife to Linus; she also attended
OSU). The art enriching the Linus Pauling
Science Center includes colorful light
sculptures by Steven Knapp, paintings
based on the crystal structure of vitamin
C by Bill Shumway, amazing lenticular art
by Chris Dean, and recently, due to thegenerosity of Joahn H. Facey, a collectionof paintings by Gershon Benjamin.

My thanks go to the generosity of themany friends of Linus Pauling and the LPI,
alumni of OSU, the support of University
President Ed Ray, and the tireless effort of
All told, I certainly enjoy the privilege of
the OSU Foundation. Because of you, theworking at the LPI.
Institute is located in the beautiful andstate-of-the-art research building, the Linus I would like a moment to thank Dr. Fred
Stevens for his phenomenal effort as interim
Pauling Science Center (LPSC).
director of the Linus Pauling Institute.
The facilities of the LPSC are designed
As you know, following the retirement of
to support translational research.
director Balz Frei, Fred volunteered his
This includes high-end chemistry
services. During the 18 months that
instrumentation like mass spectrometry
followed, Fred reorganized the coreand nuclear magnetic resonancelaboratories of the LPI to improve efficiency,
spectroscopy, research animal facilities,
replaced retiring administrative staff,
and core laboratories dedicated to theencouraged the LPI faculty to submit grant
implementation and successful execution applications, and succeeded in expandingof human clinical trials.
external support for the LPI from the3

National Institutes of Health.
Fred also helped recruit a new LPI
principal investigator, Melissa Haendel,
who joined OSU this spring (more about
Melissa and her research program comingin the next newsletter). Therefore, all mygratitude goes to Fred for continuing the
LPI on the path to success.
I look forward to working with Fred,
Melissa, and all of the faculty, students, andstaff at the LPI as we continue and expand
our research into understanding how
micronutrients and natural products canhelp all of us live healthier and longer lives.
Sincerely,

Richard B. van Breemen, Ph.D.
Linus Pauling Endowed Chair and Director
Linus Pauling InstituteContinued from cover — Embracing Botanicals

to vitamin A when needed. Until recently,
there was very little information on how
efficiently people process the carotenoids
from fruit and vegetable sources.

Consistent with the mission of the LPI,
our laboratory seeks to promote optimal
health by understanding uses of botanicalproducts. By determining the mechanismsof action for these dietary supplements,
their roles in maintaining health andpreventing disease can have a strong
scientific foundation.

One of these approaches is called Pulsed
UltraFiltration (or PUF) mass spectrometry.
Compounds binding to cellular protein
receptors are separated from unboundcompounds using filtration techniques.
Thus, only the compounds that interact
with cell proteins are saved for further
analysis.

This process includes identifying
active constituents, such as a compoundor a group of compounds that has adesired effect. After doing so, it allows
standardization of supplements bothchemically and biologically. Although many
approaches are available for the chemical
standardization of a botanical dietary
supplement, we typically rely on mass
spectrometry-based (MS) assays.

A similar approach, called MagMASS(Magnetic Microbead Affinity Selection
Screening), tethers cell receptors to
microscopic magnetic particles. Thisfacilitates the separation of the boundcomponents of a natural product simply
by applying a magnetic field. These
separated constituents are identified by
MS to precisely define which compounds
have biological activity.

Indeed, our laboratory has pioneered
the use of mass spectrometry for theidentification of active compounds inbotanical dietary supplements and othercomplex mixtures of natural products, suchas microbial and fungal extracts.

Once active botanical compounds are
identified, the next step for our laboratory
has always been to apply well-establishedtechniques typically employed in drug
development to determine how wellcompounds are absorbed and metabolized
by the body.

“Invented over a century
ago to prove the existence
The need for this approach may not beof isotopes of the elements,
immediately apparent. Throughout
biomedical mass spectrometry
history, issues have plagued botanicalsupplements. A frequent problem washas become the fastest andcontamination, either by heavy metals,
most sensitive analytical
microbes, or pesticides. Misidentification ofplant species was also common, producing tool for determining bothsupplements that contained little to none identities and amounts ofof the compounds intended to provide
compounds.”

Some of these assays utilize a humancolon cell line as a mimic of the intestinal
wall. These cells can be used to estimate
intestinal permeability and transport,
predicting how much of the compound
could reach the blood stream.

With highly specific tracer studies, werevealed that the body has an inherent
inefficiency in the conversion of plant
carotenoids to vitamin A. These findings
resulted in changes to how many
regulatory agencies throughout the world
now calculate the amount of bioavailable
vitamin A from plant sources.
More recently, we co-founded the first
NIH-funded center for botanical dietary
supplements research. At that point,
the focus of our laboratory shifted toinvestigating the safety and efficacy
of botanical supplements, with thephilosophy that consumers everywhereshould have access to botanical dietary
supplements backed by quality scientificevidence.
Thus, we support a stepwise approachto achieving this goal: mandate quality
assurance, determine a mechanism ofaction, enact standardization, and conductclinical studies.

health benefits.

For too long, regulations on botanicalsupplements have been lax. Because ofthis, we have adovcated that botanicaldietary supplements should be produced
using best practices and evidence-backed
techniques. In 2007, the US Food andDrug Administration (FDA) implemented
a regulation requiring current Good
Manufacturing Practice to be used in the
production of all dietary supplements
marketed in the United States. Although
this has made a significant contribution
to the safety of botanical supplements,
issues remain.

–Richard van Breemen, Ph.D.

Key to our success is advancing the stateof-the-art quantitative analysis of natural
products.
The screening assays that we employ
start with an extraction of the active
compound from the mixture. This often
involves a chemical binding reaction of
the molecule to a protein or other target
macromolecules. Once extracted, thecompound of interest can be analyzed
by employing mass spectrometriccharacterization.
4

Other assays address metabolic stability
and conversion to active, inactive, or toxic
compounds by enzymes. If compounds
are modified by drug metabolizing
enzymes found in the liver, for example,
the information can be used to predictpossible interactions that may occur withconventional prescription drugs.
To ensure that these laboratory
studies are as relevant to human healthas possible, it is important to conduct
these experiments not only with theactive compounds we have isolated but
also with mixtures of compounds that
represent what is found in a given dietary
supplement.
However, these assays are all performed
in a laboratory. Ultimately, addressing
issues of safety and efficacy in botanicaldietary supplements requires properly
designed trials with human volunteers.
Such studies begin with Phase I clinical
trials specifically designed to explore
issues of safety. They also provide valuable
information regarding the bioavailability
and pharmacokinetics of the active
constituents as well as possible drugbotanical interactions.
Phase II clinical trials are the next stepin the process. These studies are generally
longer and use more participants. While
Phase II trials provide additional safety
data, the primary purpose is to measureoutcomes on health or the progress toward
treatment of a disease. Thus, these are thefirst studies to address efficacy, whether or
not the supplement can work as intended.
Our laboratory has carried out five Phase
I clinical trials and three Phase II clinical
trials of botanical dietary supplements.
This includes trials on black cohosh (Actea
racemosa), red clover (Trifolium pratense),
hops (Humulus lupulus), and lycopene(commonly found in tomato).
These studies were all made possible
by utilizing the speed, senstitivity, andaccuracy of MS-based methods on the
cutting edge of scientific discovery.
Consumers of botanical dietary
supplements expect that the products
they use today are safe and effective.
Our laboratory is setting the standard for
rigorous preclinical and clinical scientificstudy to achieve these goals. Studies
of botanical dietary supplements andeducating young investigators about
natural product research will continue tobe the focus of the van Breemen lab at the
Linus Pauling Institute.
References
van Breemen, RB et al., Chem Res Toxicol. 20(2007) doi: 10.1021/tx7000493
van Breemen, RB, J Med Chem. 58 (2015) doi:
10.1021/acs.jmedchem.5b00417
Rush, MD et al. J Am Soc Mass Spectrom. 28(2017) doi: 10.1007/s13361-016-1564-0

What is a botanical supplement?
A botanical is a plant or, more often, a part of a plant that is valued for its
therapeutic properties. Botanical products are usually prepared in some sortof easy-to-use form, but people use botanical products for many different
reasons and in different ways. Today, we can find botanical extracts in things
we eat, put on our skin, or use to clean our clothes.

Botanical dietary supplements are botanical products intended for
consumption along with your everyday diet. A large variety of forms areavailable: Teas, tinctures, extracts, powders, and tablets are the mostcommon.
Because many plants can be included in botanical supplements, it should
be stressed that the nutrients and chemical metabolites (referred to as
phytochemicals) inside them can be equally varied. Indeed, plants used for
producing botanicals can contain different compounds depending on thevarieties used or how they are grown.
This also means that some botanical products can contain compounds
that are considered beneficial alongside others that are not. This presents
challenges in determining how well they perform their intended purpose(efficacy) or how much harm they can cause (safety). These are now important
areas of research at the LPI.
Although the analysis of a whole botanical supplement is important, it canhave many overlapping effects. Often, researchers test a class of compounds,
or one specific molecule, isolated from plants to determine its function.
Recent examples of this type of work from the LPI include the research
conducted by Dr. Fred Stevens on xanthohumol (a chalcone isolated from thehops plant) and by Dr. Emily Ho on sulforaphane (an isothiocyanate typicallyfound in cruciferous vegetables).

5

GIVING AGING CELLS A NEEDED BOOST

WHEN CELLS PRODUCE THEIR OWN ANTIOXIDANTS, IT HELPS THEM RESIST STRESS.

Despite the outward steps we take every day to live longer and feel better as we age, biochemical changes occurring‘behind the scenes’ can undermine those efforts. Researchers from the Linus Pauling Institute – especially those in the
Healthy Aging Program – are investigating new ways to help keep us as healthy as possible as we get older.
In advanced age, our bodies have moretrouble dealing with the stresses ofeveryday life. This is not in reference
to anxiety-provoking events that occur
throughout your day but to stresses on acellular level. Cells encounter potentially
dangerous molecules all of the timeand are constantly at risk of developing
permanent damage.
What are the sources of these harmful
compounds? Unfortunately, you don’t needto look further than your medicine cabinet.
Pharmaceutical drugs and over the counter
medicines that are designed to keep us
healthy can also do us harm, especiallywhen mixed together in a number ofdifferent ways. Although cells naturally
have protective mechanisms, these start tofall apart with time, leaving us vulnerable
to injury as we get older.
Tory Hagen, Ph.D., the Helen P. Rumbel
Professor for Healthy Aging Research andDirector of the Healthy Aging Programat the Linus Pauling Institute, is leadinga team of researchers to investigate
ways to help older cells resist stress. For
decades, Dr. Hagen has studied a specificdetoxification compound produced by cells
called glutathione, which helps them resist
a variety of toxic stresses. The problem isthat glutathione levels decline with age,setting the stage for a wide range of
age-related health problems.
Studies by Dr. Hagen’s group have shownthat there may be new strategies to help
older cells boost their glutathione levels.
Before going into details of their findings,
including their paper published in 2016(see References), it may be helpful to givea short primer on glutathione: what it isand how it acts in the body.
Glutathione is produced by cells fromthree amino acids: cysteine, glycine, andglutamate. The cysteine in the molecule
is particularly important because it makes
glutathione a very reactive molecule.

One role of glutathione is to bind toreactive oxygen species, preventing themfrom reacting with cell proteins or DNA.
This makes glutathione one of the cell’smost important antioxidant defenses.
Cells also use glutathione to bind totoxins and other foreign compounds theymight encounter. This immediately limits
the toxin’s potency and hastens its removalfrom the body.

“...glutathione is such avital antioxidant that its
existence appears to dateback as far as life on thisplanet began to utilize
oxygen...”–Tory Hagen, Ph.D.

“We’ve known for some time of theimportance of glutathione. It is a strong
antioxidant and detoxicant,” explains
Dr. Hagen, “In fact, glutathione is sucha vital antioxidant that its existenceappears to date back as far as life on thisplanet began to utilize oxygen – about 1.5
billion years. It’s a principal compoundto detoxify air pollutants, heavy metals,
pharmaceuticals, and many other toxic
insults.”
Dr. Hagen was one of the first in theworld to characterize that glutathione– and the associated detoxification it
provides – declines with age. This loss of
glutathione presents a particular issue forolder adults, especially those who takemultiple pharmaceutical drugs. If thesecompounds aren’t removed from thebody fast enough, they can cause lastingdamage.
Failures in these detoxification pathways
have links to cardiovascular disease, type 2
diabetes, and cancer.
6This brings us back to the most recent
work by Nicholas Thomas, Ph.D., a
postdoctoral researcher working with Dr.
Hagen. To explore the roles of glutathione
in the body, Dr. Thomas compared theresistance of animals of varying ages to theeffects of a molecule called menadione.
Drs. Hagen and Thomas use menadione
as a model toxin, probing not one but
a variety of cellular dextoxification
pathways. Watching the response of liver
cells to menadione provides them with amodel of how the liver would respond toencountering any toxin. In this case, cells
use glutathione to defend themselves fromthe harmful effects of menadione, ideallypreventing any damage from occurring.
Their results show that cells isolated
from young animals can meet a menadione
challenge. Although it initially dropped,
the cells maintained their glutathione
concentrations at about 40% of theirinitial levels.
However, liver cells isolated fromold animals quickly demonstrated theextent to which age affected them: After
menadione was added, glutathionelevels dropped rapidly from alreadylow concentrations. After 5 minutes of
exposure to the toxin, only about 10% of
the glutathione remained in these cells.
“Our work shows how cells from younger
animals are far more resistant to stressthan those from older animals,” says
Hagen, “When placed under the samestress, older cells were quickly depleted ofglutathione and died.”
In their more recent studies, the Hagenlab took this work a step further andinvestigated the impact of glutathione
depletion on mitochondria. Mitochondria
are cellular organelles involved in energy
production and other roles critical tooverall cell function. Mitochondria are also
seen as a critical linchpin for changes inMitochondria are not only the major
source of energy production in ourcells, but they can also determine
many aspects of how well we age.
However, maintaining glutathionelevels in the mitochondria is vitally
important in all stages of life.

cells that are observed with age.
Although most (~75%) of a cell’s
glutathione is found in the cytosol – thefluid that fills the cell – mitochondria
contain much of the rest, more than any
other cellular organelle. Glutathione
synthesis occurs only in the cytosol, but
the mitochondria can accumulate andmaintain its own shareof this antioxidant.
Therefore, it is possible that you candeplete the glutathione present in the
mitochondria without markedly affecting
the rest of the cell, and vice versa. So if
cells are losing glutathione in response to
menadione, does it affect mitochondria to
the same degree?
This was the focus of the next set ofstudies by Dr. Thomas. He found that
exposing the whole cell to menadionealso depleted glutathione levels in
mitochondria. Like the rest of the cell,
mitochondria isolated from older animals
had dramatically lower glutathione levels
after the menadione was added.
Although these data are in preliminary
stages, it seems that there are otherconsequences to this loss in glutathione.
There are indications that mitochondria

from older animals exposed to menadione
show a decline in energy production, aphenomenon not observed in cells fromyoung animals.
Overall, the core problem is that whencells or mitochondria have low levels of
glutathione, they aren’t able to adequately
protect themselves. To address this, Dr.
Thomas administered a compound called
N-acetyl-cysteine (or NAC) to cells to help
maintain glutathione levels.
It is known that the cysteine provided
by NAC can be funneled into the cell’s
glutathione synthesis machinery, butthey wanted to know if NAC provided
before a challenge would be an effective
prophylactic against exposure to a toxin.
The results of their studies are clear:pre-treatment with NAC increased
glutathione levels in the older cells
and largely helped offset the degree ofcell death. It is not yet clear what NAC
supplementation does to glutathionelevels in the mitochondria.
NAC is currently in use in hospitals: In
emergency medicine, it is given to patientsin a toxic crisis, such as ingestion of heavy
metals. The results so far show NAC to7

be a safe compound, even at extremely
high levels, at least in the short-term.
Dr. Hagen is optimistic: “Using NAC
might improve the metabolic resiliencethat we’re naturally losing with age.”
Dr. Hagen believes that low levels of
a NAC supplement as a prophylactic,
instead of an intervention may allow
glutathione levels to be maintained fordetoxification in older adults. The uses of
NAC are not just limited to the elderly:
The detoxification potential offered byglutathione could apply to prescription
drugs, cancer chemotherapies, andtreatment of other health issues.
However, these applications will require
additional research in human subjects. For
now, the Hagen lab is working on otherways of bolstering the stress response ofolder adults, at least on a celluar level.
References
Hagen, TM, Antioxid Redox Signal. 5 (2003); doi:
10.1089/152308603770310149
Suh, JH et al., Arch Biochem Biophys. 423(2004); doi: 10.1016/j.abb.2003.12.020
Thomas, NO et al., Redox Biol. 10 (2016); doi:
10.1016/j.redox.2016.09.010

Dr. Adrian Gombart focuses his
research on understanding the roleof vitamin D in the immune system.
Pictured with Dr. Gombart is his
graduate student, Yang Zhang.

VITAMIN D-INFUSED BANDAGES:PROVIDING VITAMIN D INSIDE A WOUND IS A NOVEL APPROACH TO FIGHTING
POST-SURGICAL INFECTION
With the help of new technology, researchers at the Linus Pauling Institute are developing nanofiber “vitamin D bandages”
that may cut the risk of post-surgical infections.
Working with collaborators at the
University of Nebraska Medical Center,
Dr. Adrian Gombart, a principal
investigator at the LPI, is investigating
the use of nanofiber wound dressings.
These are no ordinary bandages. Createdby a process called electrospinning, thedressings are made of very thin fibers that
can incorporate molecules like vitamins or
drugs. In Dr. Gombart’s case, the fibers are
impregnated with vitamin D.
Vitamin D is useful in a number of ways
when it comes to wound healing. It can
reduce the amount of inflammation causedby an overactive immune system toimprove the healing process (seesidebar). Vitamin D can also help fightagainst microbial infections, primarily bystimulating immune cells to produce theanti-microbial peptide called cathelicidin.
In theory, the nanofibers would provide
vitamin D to immune cells gathering ata surgical site or a wound, allowing theimmune system to destroy the invading
bacteria before infection can take hold.
Since these dressings are dissolvable,
there is no need for a repeat surgery to
remove them.
“The materials we are developing will
hopefully be used in surgical patients to
reduce the possible risk of a variety of
infections from drug-resistant bacteria,”
Gombart said. “Vitamin D is safe, and the
bandages simply harness the host’s own
immune response to fight infection directly,
in a manner that antibiotic-resistantpathogens are less likely to defend against.”
8

Surgical site infections are not only
common but also very costly to treat,
especially when antibiotic-resistantbacteria like MRSA are involved. Unlike
antibiotics, which target specific enzymes
found in bacterial cells in order to weaken
them, anti-microbial peptides work by amechanical action on bacterial cell
membranes. They either burrow into thebacterial membrane to make a pore (orhole) or they cover the membrane todisrupt it. Either action makes it easier forother aspects of the immune system tokill the offending microbe.
“Antibiotic compounds typically represent
a single point of attack on bacterial
pathogens,” says Gombart, “One reason
we’re pursuing this strategy of vitamin D
release is that an activated immune systemprovides multiple points of attack.”

testing the dressings in animals.”

Two recent studies by the Gombart lab,
Dr. Arup Indra (adjunct faculty memberof the LPI), and their collaborators from
Nebraska Medical Center have explored
how these vitamin D dressings will workin patients.

Moving into animal models presents a
unique challenge. One of the problems ofusing laboratory mice in a vitamin D study
is that their immune cells do not make antimicrobial peptide in response to vitamin D.
In fact, this is an adaptation found only inhumans and other primates.

The first study, published in late 2017,
focuses on the use of nanofibers containing
25-hydroxyvitamin D3 – the form ofvitamin D found circulating in the blood.
This molecule is formed in the liver,following vitamin D consumption (fromfoods or supplements) or synthesized in
the skin after exposure to UV light fromthe sun.
Through exposing isolated skin cells
or immune cells to the sutures containing
25-hydroxyvitamin D nanofibers, Dr.
Gombart’s team observed a continuous
release of the molecule. As they expected,
this was followed by the production ofanti-microbial peptides.
When immune cells are activated, moreof these peptides are produced, suggestingthat a vitamin D conversion process wasnecessary for full activation. This produces
1,25-dihydroxyvitamin D, a form of thevitamin so potent that the body only
converts it from 25-hydroxyvitamin D
when needed.

One of the problems ofusing laboratory mice in avitamin D study is that theirimmune cells do not makeanti-microbial peptide in
response to vitamin D.
In their recently published study,
the team decided to work with dressingsthat contain only the active 1,25-dihydroxyform of the vitamin. In cell models, itworked just as well as the fibers usedin the previous study containing the
25-hydroxy form.
In addition, they took one step closer
to getting it into human patients byemploying an animal model. “The workin our first paper was completely in cell
culture,” Gombart explained, “Cells don’t
always act the same way in isolation as
they do in the body. So the next step was

Therefore, Dr. Gombart routinely uses a
genetically modified mouse model where
specific portions of the human cathelicidin
gene are inserted into the mouse genome.
This allows vitamin D to control the
production of the anti-microbial peptide,as it does in humans.
To make use of this animal model, theygave the animals a surgical wound intheir skin under controlled conditions
to minimize the animal’s discomfort.
After wounding, a sterile nanofiber disccontaining 1,25-dihydroxyvitamin D wasplaced inside the wound. As expected,
cathelicidin production increased near
the wound site but not in skin that had
no wound or in the wound without
1,25-dihydroxyvitamin D.
Their colleagues in Nebraska repeatedthe experiments in human skin samples
obtained from people undergoing plastic
surgery, finding similar results.
Together, this shows a great advancein the application of vitamin D. While
their latest studies did not look at riskof infection or measure rate of woundhealing, this is planned for the future.
While they clearly saw benefits of the
bandages in their animal trials at the siteof a wound, it is unclear how a sustained
release of 1,25-dihydroxyvitamin D might
affect other tissues.
Gombart and his collaborators currently
have funding from the National Institutesof Health to continue their animal trials,
looking at different aspects of the vitamin
D dressings in order to bring them safely
into human trials.
References
Chen, S et al., Nanomedicine. (2018) – Currently
In Press
Chen, S et al., Nanomedicine. 12 (2017) doi:
10.2217/nnm-2017-0161
Chen, S et al., Nanomedicine. 12 (2017) doi:
10.2217/nnm-2017-0017

9

Vitamin D and
Immunity
The active form of vitamin D regulates
the expression of many genes and is
now recognized to be a potent
modulator of the immune system.
The vitamin D receptor is expressed inseveral types of immune cells. Human
macrophages (one type of immunecell) can convert vitamin D to its active
form where the cells become activated,targeting the immune response.
Vitamin D regulates adaptive immunity,
which involves antibody reactions andcertain inflammatory responses. For
instance, vitamin D inhibits a classof T helper cells (called Th1 cells) andtherefore may limit inflammatory
responses that might damage healthy
tissue. On the other hand, vitamin D
stimulates regulatory T cells, which may
have a role in preventing autoimmune
disease or complications due to organtransplants.
Despite the relationship between low
vitamin D status and autoimmune
disease, few randomized controlled
trials have been conducted. Vitamin
D is currently under investigation by
a number of laboratories across theworld; evidence from clinical trials isforthcoming.
For more information on vitamin D orother micronutrients in immunity, see
the Micronutrient Information Center:
lpi.oregonstate.edu/mic/healthdisease/immunity

MICRONUTRIENTS FOR BONE HEALTH
FROM THE MICRONUTRIENT INFORMATION CENTER

By Victoria J. Drake, Ph.D. and Barbara Delage, Ph.D.

INTRODUCTIONCALCIUM

VITAMIN D

The skeleton serves as a mineral
storehouse for the body, primarily areserve for calcium and phosphorus.
While it may seem like an inert structure,
the skeleton is made of tissues and cells
that are continually active throughout
a lifetime. Bones grow in size and shapeduring childhood, adolescence, and early
adulthood, but replacement of old bone
tissue by new bone tissue – a process called‘remodeling’ – occurs throughout life. The
remodeling phase consists of a constantprocess of bone resorption (breakdown)
and formation, replacing old bone that isbrittle or damaged with new bone. This
also can release calcium and phosphorus
into the circulation when they are neededby the body.

Calcium is a major structural element inbones and teeth; in fact, 99% of calcium inthe body is found here in the form ofhydroxyapatite, a molecule made of calcium
and phosphate. Calcium is also found inblood and soft tissues where it is criticalto body functions like muscle contraction,
nerve impulse conduction, or constriction
and relaxation of blood vessels.

An important function of vitamin D is tocontrol blood concentrations of calcium andphosphorus in order to preserve normal
physiological function. Very severe vitamin
D deficiency causes rickets in children andosteomalacia in adults.

Beginning around age 34, the rateof bone resorption exceeds that offormation, leading to an inevitable lossof bone mass with age. If bone mass falls
to a critically low level, bone softening(osteomalacia), pre-osteoporosis(osteopenia), osteoporosis, and bone
fracture can occur.
Nutrition and physical activity haveimportant roles in building bone mass
during childhood and young adulthoodand slowing bone mineral loss laterin life. Calcium and vitamin D play a
prominent role in bone health throughout
life, but other micronutrients, including
magnesium, fluoride, and vitamins A, B,
C, and K, are also important for producing
and maintaining healthy bone.

The body tightly regulates blood calcium
concentrations. When intake of calcium islow, calcium is leeched from bone tomaintain normal calcium concentrations
in blood; therefore, adequate dietarycalcium is critical to limit bone resorption(demineralization) and preserve skeletal
integrity and health.
Chronically low calcium intake inchildhood and early adulthood prevents
bone from reaching optimal mineral mass
and will increase the risks for osteoporosis
and bone fracture in older age. Low calcium
intake in the adult years can accelerate thedecline in bone mineral density.
There are many food sources of calcium,including dairy and fortified food. Calcium
intake from food is preferred oversupplements, since the safety of longterm calcium supplement use has notbeen adequately evaluated. Total intake ofcalcium should not exceed 2,500 mg/day
in adults 19-50 years, and 2,000 mg/day inadults over 50 years.
There is currently no consensus regarding
the use of calcium supplements to prevent
fractures in older adults.

Vitamin D is found naturally only in a few
foods. Exposure to sunlight is the primarysource of vitamin D; however, the use ofsunscreen effectively blocks vitamin D
production in the skin. Additionally,geographical location, season, and timespent outdoors affect vitamin D synthesisin the skin. For example, sunny days in thewinter at northern latitudes produce novitamin D in the skin, even when goingoutside at midday when UV light is at its
strongest.
Supplementation may be needed inchildren and adults to reach recommended
levels – the American Academy of
Pediatrics recommends 400 IU/day of
supplemental vitamin D for all infants,
children, and adolescents. The Linus Pauling
Institute recommends that all adults take
2,000 IU/day of vitamin D. Physicians canperform blood tests to determine if yourvitamin D status is low.
Intervention studies in older adults
have found little-to-no effect of vitamin D
supplementation alone on fracture risk, butsome studies have found that combined
vitamin D and calcium supplementation
reduces fall or fracture risk.

PHOSPHORUS
Along with calcium, phosphorus is amajor structural component of bone
in hydroxyapatite crystals. Althoughphosphorus deficiency can lead to rickets
and bone softening, it is uncommon in
healthy people.

Two types of bone cells are involved inmaintaining mineral balance in bone.
Osteoclasts dissolve bone, liberating minerals
into the blood stream. Osteoblasts build
the bone matrix, depositing minerals onto
collagen proteins. If mineral levels in the
body are lacking, the resulting bone will be
low in mineral density.

High phosphorus intakes – which arequite common in the US – have not been
associated with an increased risk ofosteoporosis. However, low calcium intakes
10combined with high phosphorus intakes
represent a serious risk to bone health.

MAGNESIUM
About 60% of the body’s magnesium
is found in bone, where it influences thesize and strength of the hydroxyapatite
crystals. The effect of magnesium
inadequacy on bone health in humans ispoorly understood. Higher magnesium
intakes may be linked to a lower risk ofpoor vitamin D status, but the evidence
is currently too limited to suggest thatmagnesium supplementation could
reduce risk of osteoporosis or fracture.

CALCIUM
There are varied food sources of calcium, though the highest amounts areoften found in dairy products. Plants provide dietary calcium, but it is lessbioavailable in plants with high levels of oxalate or phytate. Calcium intakesof 1,000 mg/day (total from diet and supplements) should cover the needs ofmost adults. The RDA is higher for adolescents (1,300 mg/day), older women(>50 years, 1,200 mg/day), and older men (>70 years, 1,200 mg/day).

OTHER MICRONUTRIENTS
Many other micronutrients haveessential roles in bone health, including
fluoride, vitamin A, some B vitamins,
vitamin C, and vitamin K. However,there is little evidence to suggest that
supplementation with these micronutrients above current recommendations
provides further benefit.
Striving to reduce phosphorus andsodium intakes while increasing intakes ofpotassium (e.g., by eliminating processedfood and increasing intake of fruit andvegetables) is likely to indirectly benefit
bone health through improving overall
health. In addition, physical activity ishighly beneficial to bone health during
development and throughout life. Anyamount of physical activity, even in frail
elderly people, is better than none andwill bring some benefits to bone health.

VITAMIN D
Food is a poor source of vitamin D. Vitamin D production by sun exposure
can vary by season, latitude, and skin type. Therefore, supplements
are often recommended. The Linus Pauling Institute recommends
that generally healthy adults take 2,000 IU (50 µg) of vitamin D fromsupplements daily. LPI also recommends daily intakes (total from dietand supplements) of 400 to 1,000 IU for infants and 600 to 1,000 IU forchildren and adolescents.

References:
lpi.oregonstate.edu/mic/health-disease/bonehealthHeaney, RP. Bone biology in health and disease.
Modern Nutrition in Health and Disease. 11th ed:
Lippincott Williams & Wilkins (2014) ISBN-10:
1605474614
Weaver, CM et al., Osteoporos Int. 27 (2016) doi:
10.1007/s00198-015-3440-3

11

AN UPDATE ON
COPPER-ATSM
CLINICAL TRIALSSuperoxide dismutase (SOD) is a
protein that transforms a reactive
form of oxygen called superoxide into
relatively harmless hydrogen peroxide.
In the development of Amyotrophic
Lateral Sclerosis (ALS), this might allchange. With a genetic mutation or withthe loss of an important mineral in theprotein, SOD can start to harm motor
neurons.
Dr. Joseph Beckman’s work at the
Linus Pauling Institute has focused aroundunderstanding the role of SOD in thedevelopment of ALS. Because ALS is adisease that results in progressive loss of
motor neurons in the spinal cord, it isdifficult to target and treat. However, a
breakthrough came in 2016.
With Dr. Blaine Roberts (Beckman’sformer graduate student) and theircollaborators from Australia, Dr.
Beckman’s group published his results witha molecule called copper-ATSM. Later thatyear, we introduced their findings in thisnewsletter: copper-ATSM increases thelifespan of mice genetically engineered tocontract ALS.
It was far from a cure for the disease,
but it was a start. In a field where progress
is very difficult to achieve, their results
seemed miraculous. Yet, a lot of questions

remained. Primarily, since the studies had
been completed in mice, would copperATSM work in people with ALS?
Despite these limitations, the response
from the ALS community has beenenthusiastic. Needless to say, many people
who are currently living with the disease
are desperate for treatment, because
diagnosis is usually considered a death
sentence.
Since the work on copper-ATSM is
progressing, we thought it would be a goodtime to provide you with a short update by
way of answering a few frequently asked
questions on this topic.

CAN COPPER REALLY HELP ALS?
Linus Pauling advocated the importanceof the right micronutrient at the right timeand in the right place to promote healthand prevent disease. In animal models of
ALS, one of the problems was that the SOD
protein was missing a mineral – it could
either be zinc or copper, as they both were
important to enzyme function. Yet SOD
deficient in just one of these metals wasvery toxic to motor neurons.

Recently, Dr. Beckman and his colleagues
began to focus on restoring copper
to SOD, hoping to make the proteinfunctional again. Although copper was
important, giving animals more of themineral alone did not help restore theprotein. This is because their approach was
untargeted: copper went to every part ofthe body. Eventually the large amounts ofcopper became harmful to the animals.
12

The special chemical carrier called
ATSM was key to their success. The ATSM
backbone provided a shield around thecopper atom, one that would only come off
in specific tissues of the body. Effectively,
ATSM delivered copper to the spinal
cord and prevented other tissues fromexperiencing the negative effects ofexcess copper.

WHAT IS THE STATE OF CU-ATSM
CLINICAL TRIALS?

WHAT ABOUT OTHER ALSDRUGS?

WHAT ABOUT THE FUTURE OF ALSRESEARCH AT LPI?

Copper-ATSM is already used in people
for the imaging of hypoxic tissues. Before
Dr. Beckman and his collaborators finishedtheir trial in animals, it was not considereda treatment of ALS. Because of it was not
approved for this use, clinical trials must
be conducted to test it for that purpose.

Copper-ATSM has a long way to go
before general approval by the FDA.
However, two other drugs are muchcloser to approval for the treatment of
ALS.

Dr. Beckman’s group and his collaborators
continue to work on understanding theunderlying causes of ALS. Their research
has identified multiple targets for therapy –pointing the way to the next generation oftherapies for the treatment of ALS.

Masitinib is a tyrosine kinase inhibitorthat is designed to reduce some of the
To develop this compound as a treatment effects of chronic inflammation in cells.
for disease, special clinical trials are
Much of the preclinical work for Masitinib
needed to evaluate safety and efficacy.
was done here at the LPI in collaboration
Although the trials on safety are nearlywith the Pasteur Institute of Montevideo
concluded and the results are promising,Director, Dr. Luis Barbeito. Masitinib is
the truth is that many ALS drugs do not get currently being used with other drugs inpast this critical step.
Phase III clinical trials to find its efficacy
in ALS.
Phase I clinical trials are the first stepin the process of new drug development.
Edaravone (also called Radicava) is a
These studies test for safety, starting withsynthetic free radical scavenger
small doses of the drug to determine(antioxidant) that reduces protein
any side effects that would indicate
nitration, a particular problem in the
toxicity. As the trial progresses, subjects
progression of ALS. Edaravone wastake increasing doses of copper-ATSM
recently approved for use in the United
to determine how much poses a risk toStates since it appears to slow thehealth.
progression of the disease. Edavarone isOnce the Phase I trial is complete,researchers can begin testing for efficacy.
This comes in the form of Phase II and
III clinical trials that are designed todetermine if a particular dose of the drug
can slow or stop the progression of ALS.
Procypra is a company that is taking
the lead in developing copper-ATSM
for treatment of Parkinson’s disease
and ALS. Their Phase I clinical trial isnearly complete, and it can be found on
ClinicalTrials.gov under the identifier,
NCT02870634. The first results from thisclinical trial show that copper-ATSM
appears to be safe even at the projected
therapeutic doses. However, many hurdles
lie ahead before it can be available to many
ALS patients.
ALS families question the need for suchtrials. Time is very valuable, especiallyfor those with the diagnosis of a terminal
disease. The risks in taking an unproventreatment are very serious. The wrong
amount, timing, or route of administrationof the drug, combined with issues of drug
purity, metabolism, and interactions, havethe potential of killing someone within amatter of days.

currently only available as an intravenous
infusion.
More drugs are also in development.
Progress towards the treatment of ALS
has been accelerating. Although drugs likecopper-ATSM are going to clinical trials
faster than ever before, it is still a slow
process. Now that there has been somesuccess in treating this awful disease,more substantive successes are justaround the corner.

NH

We know that many people around theworld are watching these studies carefully,
and we will bring you more updates fromDr. Beckman’s lab as soon as they become
available.
For more information on copper-ATSM,
clinical trials, or the current state of ALS
research at the Institute, we encourage you
to email us at lpi@oregonstate.edu
The copper-ATSM molecule (shown below)
has one atom of copper protected by a ringof carbon, sulfur, and nitrogen. Originallydeveloped to image tumors, it can alsodeliver copper to hypoxic tissues like thespinal cord.

N

N
Cu
S

N

For example, they are testing different
compounds based on the structure ofcopper-ATSM that may work on multiple
forms of ALS and other neurodegenerative
diseases. Novel compounds are being
tested in ALS models to see if they, too, canprevent or delay the onset of disease. Also,
the Beckman group continues working on
ways to improve the efficacy of existing
drugs like Edaravone and copper-ATSM.

SCuATSM molecule

13

N
N
H

LPI STUDENTS

Isabelle Logan

Brian HeadAmanda Kelley

Ph.D. Student, Department ofBiochemistry and Biophysics

Ph.D. Student, Department of
Molecular and Cell Biology

Ph.D. Student, Department ofBiochemistry and Biophysics

Born and raised in Belgium, Isabelle
became the first person in her family tomake the leap to the United States, where
she made her new home in Oregon. Firstin her family to earn a degree in higher
education, she graduated summa cum
laude from Portland State University witha bachelor’s degree in Chemistry. Upon
graduation, she took the opportunity tocome to OSU to continue her educationin science.

Originally from southern California,
Brian came to OSU with an interest in
animal medicine. He obtained a bachelor’s
degree in Zoology here in 2014. As anundergraduate, Brian had many
experiences in laboratories across
campus, which kindled an interest in
research. This led him to complete an M.S.
in Animal Science, also from OSU.

Growing up only a mile away fromYellowstone National Park, Amanda foundherself wanting to know more about thediversity of organisms living in such harshconditions. Her curiosity about life at themolecular level led her to Montana State
University where she received a bachelor’s
degree in Chemistry. Positive research andteaching experiences, along with a desire toknow more about human health, brought
her to explore more of the scientific worldin graduate school.

During her first year as a graduate
student, Isabelle not only found a passion
for teaching but also found her place atthe bench. She joined the lab of Dr. Adrian
Gombart, principal investigator at the LPI.
In conjunction with Dr. Stevens’ laboratory,
Isabelle studies xanthohumol and its
derivatives as potential anticancer agents.
She is also working to establish animalmodels to test the effects of xanthohumolon gut health.
Isabelle’s goal after she completes her
dissertation is a postdoctoral positionat the Fred Hutchinson Cancer ResearchCenter in Seattle. She is passionate about
stimulating young students’ interests inentering STEM fields. Isabelle was selected
as the 2017-18 Christopher and Catherine
Mathews Graduate Fellow in the
Department of Biochemistry andBiophysics and has received the Franz
Stenzel M.D. and Kathryn Stenzel II
Scholarship for two years running.

After his master’s work, Brian spentsome time working at the LPI with Dr.
Maret Traber on projects related tovitamin E. Not long after, Brian started
the Ph.D. program under the guidance ofDr. Traber. His current project focuses on
the genetic regulatory networks involvedin vitamin E deficiency in zebrafish,
especially how lower vitamin E levels
may alter embryonic development.
Brian is also interested in the effectsof vitamin E in the aging brain anddetermining if vitamin E can play arole in preventing neurodegenerative
disorders like Alzheimer’s disease. Beyond
graduate school, Brian plans to advanceknowledge of nutritional adequacy
during development and aging in his
own laboratory, incorporating moleculartechniques with bioinformatics. He iscurrently supported by the Provost’s
Distinguished Graduate Fellowship,and he was recently awarded the Mark
Sponenburgh Endowed Graduate
Fellowship through the LPI.

14

Because of interests in mitochondrial
function and healthy aging, she is now
working with the LPI’s resident expert on
aging, Dr. Tory Hagen. She is examining thechanges that occur in the mitochondria ofa mouse model of Alzheimer’s disease.
Shortly after coming to LPI, Amanda
entered the IGERT (Integrative Graduate
Education and Research Traineeship)program in Aging Sciences, with funding
from the National Science Foundation.
The training program’s focus oninterdisciplinary projects allowed her
to learn about the relationship between
systolic blood pressure and dog ownershipin older adults. Amanda was the previous
recipient of the Mark Sponenburgh
Endowed Graduate Fellowship at the
LPI and also received a travel award toattend the American Aging Association
conference, giving her much appreciatedsupport for her work.

OUTREACH
As part of the LPI’s public outreachmission, the Healthy Youth Program(HYP) empowers youth and families toachieve optimal health through hands-on
education. The HYP is currently cultivating
partnerships with a local hospital andmedical school to execute the Culinary
Health Education and Fitness (C.H.E.F.)
Project, which aims to build a cultureof health in local Oregon counties. This
includes annual training of medical
students to help implement dozens ofyouth and family cooking classes in ruralcommunities.
In Corvallis, the HYP summer work
and internship program for high school
students is gearing up for their fourth year
in the school gardens. This year, weekly‘Farm Stand’ events feature distributionof fresh fruit and vegetables for physicianreferred families through a partnershipwith the Benton County Health
Department. This program is supportedby the OHSU Knight Cancer InstituteCommunity Partnership Program.
Since its debut in 2000, the LPI’s
Micronutrient Information Center(MIC) has provided evidence-based,
expert-reviewed information on the rolesof vitamins, minerals, and other dietaryfactors in health and disease. This freewebsite (lpi.oregonstate.edu/mic) has a
global audience of more than one million
people. Some articles are available in
Spanish, and Japanese translations areunderway.
New content is available on the topics
of bone health, osteoporosis, andmicronutrient inadequacies; recent updates
include articles on fruit and vegetables; theB-vitamin, niacin; and coenzyme Q10.
We would like to thank ChromaDex for
their support and Pfizer for awarding us
two grants. Many thanks to our readers
who have generously supported the MIC!

DEVELOPMENTS
Things have been quite busy at LPI!
The arrival of Dr. van Breemen has
brought with it lots of new faces, activity,and equipment to LPI labs. With thearrival of his team comes many brilliant
young scientists, hard at work advancing
the Institute’s research. They remind us
all of the impact that a public research
institution can have on the developmentof a young person’s career.
We have also been very fortunate torecruit Dr. Melissa Haendel as our new
Director of Translational Data Science.
She brings tremendous expertise inbiomedical data analytics that can beapplied to both basic science research andtranslational clinical work. Her expertise
will allow our researchers to access,interpret, and incorporate large data sets
across multiple disciplines in incredibly
powerful ways.

Nothing excites researchers more than“multidisciplinary collaborations,” and thewhole Institute is buzzing with new waysthat our strengths can be leveraged toadvance the work of the Institute. This istruly an exciting time to be at LPI – newleadership, researchers, and technologies
have set the stage for a new era ofbreakthroughs at the LPI.
All of us at LPI want to thank the many
loyal supporters who have kept the windin our sails throughout the years. You
have been integral partners in our success.
We hope that you will stay engaged with
our work as we continue to advance Dr.
Pauling’s legacy of research and discovery.
Sincerely,

Amanto Marcotulli, J.D.
OSU Foundation
OSUFoundation@osufoundation.org
15

A group from the Healthy Youth
Program’s C.H.E.F. Project cooking
class practice their knife skills as
they prepare a recipe together.

GIVE TO THE LPI
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support the research and education
missions of the LPI - Contact the
OSU Foundation today!
(800) 354-7281 or
osufoundation.org/GiveToLPI

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LINUS PAULING INSTITUTE

Alexander Michels, Newsletter Editor
Victoria Drake, Associate Editor

Oregon State University
307 Linus Pauling Science Center
Corvallis, Oregon 97331
phone: 541-737-5075
fax: 541-737-5077
email: lpi@oregonstate.edu
website: lpi.oregonstate.edu

Dr. Richard van Breemen, Director of
the Linus Pauling Institute, describes
his work on botanicals. LOOK INSIDELPI’S FUTURE
STARTS NOW
Under new leadership, the Linus Pauling
Institute is moving forward in new andexciting ways. We want you to be a partof it all. Support the LPI by calling the
OSU Foundation at (800) 354-7281 or visit
osufoundation.org/GiveToLPI