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Explor i ng r esearc h at th e
U n iversity of N ebraska M edical C enter
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an d beyon d...
targeted
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bones
FA L L 20 08
discover
UNMC
exploring research at the
success
against
the odds
University of Nebraska Medical Center
and beyond...
UNMC Discover is published twice a year by the Vice
Chancellor for Research and the Department of Public
Affairs at the University of Nebraska Medical Center. The
magazine is supported by UNeMed Corporation, the
technology transfer organization for UNMC.
Issues of the magazine can be found at www.
unmc.edu, News link. Permission is granted to
reprint any written materials herein, provided proper
credit is given. Direct all requests to ekumru@unmc.
edu. Subscriptions to UNMC Discover are free. To
subscribe, go to unmc.edu/discover.
UNMC’s mission is to improve the health of
Nebraska through premier educational programs,
innovative research, the highest quality patient care
and outreach to underserved populations.
UNMC is accredited by The Higher Learning
Commission of the North Central Association of Colleges
and Schools (HLC-NCA) and enjoys full accreditation of
all its professional academic programs.
UNMC does not discriminate in its academic,
employment or admissions programs, and abides by
all federal regulations pertaining to same.
Director of Public Affairs: Renee Fry, J.D.
Senior Associate Director: Tom O’Connor
Managing Editor: Karen Burbach
Publications Editor: Elizabeth Kumru
Design: Daake Design
Photography:
Scott Dobry
Elizabeth Kumru
Andrew Nelson
Dewayne Gimeson, Chadron State College
Research Advisory Board:
Thomas Rosenquist, Ph.D. • Kenneth Cowan, M.D., Ph.D.
Courtney Fletcher, Pharm.D. • John Gollan, M.D.
The research enterprise at the University of Nebraska Medical Center
continues to grow, against the odds. When the economy struggles, institutions
often view their research dollars as discretionary budget items that can be
reduced, rather than seeing basic discovery as the engine that ultimately
revives the economy. The National Institutes of Health (NIH) is an example of
this phenomenon.
The NIH is the most successful and most respected biomedical research
institution in the world. Its support of the basic sciences is unique. For 50 years
or more, the NIH has provided the basis for most of the major discoveries in
human biology. These discoveries have led to improved therapies, which have
prolonged and enriched lives. Nevertheless, over the past few years, the annual
funding increases for the NIH have failed to meet inflation and the availability
of NIH dollars has fallen by about 25 percent.
We are losing a myriad of opportunities to support wonderful, innovative
projects. We do not know which discoveries will most directly lead to
improved diagnosis, treatment or cure; but we do know no gains are made
without discovery. We hope and trust that our leaders in government and in
the private sector will see the grave error inherent in this strategy and change
directions, soon.
Nevertheless, the competitive environment is intense and for many
institutions, disheartening. But at UNMC, we have had continuous gains. The
first quarter for this fiscal year set a new record for total extramural research
funding of more than $32 million.
This remarkable achievement is the result, in part, of the determined
efforts of a reliable corps of deans, directors and department chairs who
understand well that the principal role of the academic health sciences center
is discovery. These men and women have worked hard and used great vision
to keep or recruit outstanding scientists and nurture them. Of course, the
fundamental strength of our research enterprise is in the scientists themselves,
whose creativity and performance under duress has been remarkable.
This issue of UNMC Discover focuses on a few of these admirable men
and women. It is impossible to read about their excellent, innovative work and
not see with greater clarity why UNMC is succeeding against the odds, and
why it is so important to expand the research enterprise globally.
Robert Lewis, Ph.D. • James Linder, M.D.
Keith Mueller, Ph.D. • Rubens Pamies, M.D.
Jeffrey Payne, D.D.S. • John Reinhardt, D.D.S.
Warren Sanger, Ph.D. • James Shull, Ph.D.
Joe Sisson, M.D. • Shelley Smith, Ph.D.
Virginia Tilden, D.N.Sc. • Paula Turpen, Ph.D.
Margaret Wheelock, Ph.D. • Irving Zucker, Ph.D.
Tom Rosenquist, Ph.D.
UNMC Vice Chancellor for Research
FA L L 20 08
contents
lotus leaf and fake
diamonds lead to better
orthopaedic implants
Nature inspires UNMC scientist
4
New coating makes implants more durable
apathy – why should you care?
Drug jolts people to care about their
chronic illness 7
growing our own
UNMC researchers mentor
junior investigators
10
i
targeted delivery
New system taxis drugs to ailing bones
14
the care connection
i
NursingINNOVATION
study examines new model
of care for chronic disease 20
determined to make earlier
diagnosis a reality
Pancreatic cancer eludes detection –
but not for long
22
under the microscope
Clinical researcher co-authors largest
study on HIV drugs
26
Lotus leaf and fake diamonds lead
to better orthopaedic implants
by Chuck Brown
Inspiration often comes from
unexpected places.
Just ask UNMC’s Fereydoon Namavar, Sc.D.
In the case of a coating he designed for orthopaedic implants,
the scientist – who worked on NASA’s Mars Rover, Star Wars
and optical communications projects before entering the world
of biomedical research 10 years ago – found inspiration in his
mother-in-law’s jewelry case and the leaves of the lotus flower.
One day a few years back, Dr. Namavar listened as his
mother-in-law shared how much she liked her cubic zirconia
jewelry – except for one thing that bothered her.
“When it would get wet, it would fog up,” said Dr. Namavar,
professor and director of the nano-biotechnology laboratory in the
UNMC Department of Orthopaedic Surgery.
fall 2008
While bad news for his mother-in-law, this was an epiphany
for Dr. Namavar.
A common issue with implants is wear and tear because
joint surfaces rub together. This can lead to repeat surgeries, as
well as send an unhealthy mix of wear particles into a person’s
blood stream.
The wear and tear happens, in part, because surfaces used on
orthopaedic implants are too soft and lack the ability to stay wet.
With orthopaedic implants, ideally, it is important that one
of the two contact surfaces be wettable, while the other is
hydrophobic or rejects water, Dr. Namavar said. He needed
opposites, a Yin and a Yang.
“If both were wet, the surfaces would stick together and
drastically increase friction,” Dr. Namavar said. “But, when
Atomic force microscopy image of cubic zirconia
showing pyramidal nanostructures with sizes
ranging from 130 to 210 nanometers.
you have these opposites together, you have lower friction and
smoother motion on the surface.”
Dr. Namavar’s ears immediately perked up when his motherin-law complained about how cubic zirconia fogs up when wet.
“I knew I had my substance,” he said. “I thought, ‘here is a
material that could be hard and also seems to be able to stay wet.’”
In other words, cubic zirconia might work just as well in a hip
joint as it does in a gold tennis bracelet.
As he designed his implant coating, Dr. Namavar wanted to
alter the properties of cubic zirconia to attain maximum wettability.
The cubic zirconia would provide the Yin (wet) to his existing
model, the lotus leaf, the Yang (dry).
The lotus leaf is considered a symbol of purity in many cultures
because of its self-cleaning properties.
“When a drop of water hits a lotus leaf, it rolls off the surface,
washing away dirt and dust,” Dr. Namavar said. “This is because
the lotus leaf is water resistant, or hydrophobic.”
Hydrophilic (wettable) and hydrophobic properties of
substances are actually flip sides of the same coin and thus
identical at a nanostructure level, he said.
As a result, Dr. Namavar decided to alter the physical
properties to mimic the hydrophobic lotus leaf to make his coating
super-hydrophilic or more wettable.
To alter the cubic zirconia, Dr. Namavar uses a technique
called ion-bombardment, during which he exposes a substance
to a large amount of ions – atoms that have gained an electrical
charge by losing an electron.
Dr. Namavar’s team uses a special ion beam assisted
deposition (IBAD) process to enhance the zirconia’s hardness and
ability to stay wet. They are one of the few research teams at an
academic institituion in the country that uses the IBAD process.
“Utilizing billions of energetic ions as an ionic hammer, we
have forged nano pyramidal structure films possessing combined
properties of super-hardness and complete wetting behavior,” Dr.
Namavar said.
With his coating made of altered pure cubic zirconia, Dr.
Namavar knew he had created a harder, wettable substance that
stands to improve the life of orthopaedic implants.
By altering the hydrophilic (wettability) properties of these
novel materials, Dr. Namavar also created a substance that bones
like to grow on.
Tests done in collaboration with John Jackson, Ph.D.,
associate professor, pathology and microbiology, and Graham
Sharp, Ph.D., professor, genetics, cell biology and anatomy, have
shown that bone stem cells actually attach to and grow on Dr.
Namavar’s coating.
“I knew I had my substance. I thought,
‘here is a material that could be hard and
also seems to be able to stay wet.’ ”
Fereydoon Namavar, Sc.D.
UNMC
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“We hope this leads to prolonged life
of orthopaedic implants and fewer
revision surgeries due to reduced
friction and wear of the implant, as
well as enhanced bone growth.”
Fereydoon Namavar, Sc.D.
Thomas Gustafson, intern, prepares the ion beams
assisted deposition (IBAD) system that produces the
nanocrystalline coating.
fall 2008
“It seems that our pyramidal nano-structures have a charge
distribution, which the cells find hospitable,” he said. “This was an
unexpected development and one we were thrilled to encounter.”
Dr. Namavar and his team plan to do tests on animal models.
“We hope this leads to prolonged life of orthopaedic
implants and fewer revision surgeries due to reduced friction
and wear of the implant, as well as enhanced bone growth,” Dr.
Namavar said.
Dr. Namavar said his work has been aided by strong
support from Kevin Garvin, M.D., chairman of the department
of orthopaedic surgery, and Hani Haider, Ph.D., an associate
professor of orthopaedic surgery.
Collaborations have been important to his work, Dr. Namavar
said. A grant from the Nebraska Research Initiative has allowed
him to work with Barry Li Cheung, Ph.D., of the chemistry
department at the University of Nebraska-Lincoln, and Renat
Sabirianov, Ph.D., and Wai-Ning Mei, Ph.D., of the physics
department of the University of Nebraska at Omaha.
Dr. Garvin said Dr. Namavar’s coating could prove particularly
important as the health care system faces a surge in the elderly
population, which will lead to more implant surgeries.
“By making implants last longer, this coating could make life
better for patients and physicians alike,” Dr. Garvin said.
“Patients, of course, may be able to avoid the discomfort and
inconvenience of multiple surgeries, which also would take stress
off a system that already is overburdened.”
ap-a-thy, n., 1. lack of emotion. 2. lack of interest;
listless condition; indifference.
apathy
Why Should You Care?
by Tom O’Connor
It’s easy to be apathetic. It’s something we all
experience. Some days we just wake up and have
no motivation. Nothing seems to matter.
However, in some chronic diseases apathy turns into a
clinical syndrome characterized by poor initiation, loss of
motivation, indifference and lack of persistence.
Apathy syndrome impairs self-management behaviors,
leads to functional decline, poor compliance with treatment
and generally poor outcomes in chronic diseases.
That’s why two UNMC physicians – Prasad Padala,
M.D., and Cyrus Desouza, M.D. – zeroed in on apathy as
one of the key culprits in patients with Alzheimer’s disease
and chronic conditions such as diabetes and obesity.
Dr. Padala, assistant professor, psychiatry, and Dr.
Desouza, associate professor, endocrinology, also hold
appointments at the Omaha Division - VA NebraskaWestern Iowa Health Care System. Dr. Padala has two grants
to study the connection between apathy and Alzheimer’s
UNMC
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Prasad Padala, M.D.
“Apathy is considered
an untapped behavioral
problem. If treated well, it can
have significant impact on
management of dementia
and diabetes.”
Prasad Padala, M.D.
disease. Dr. Desouza’s grants focus on the impact of apathy
treatment in people who are obese. They also have two
federal grants that are under review.
The two researchers are studying a well-known drug
– Ritalin – as a treatment for apathy. Yes, the same Ritalin
that is used to slow hyperactive children.
“Ritalin works differently in adults and children,” Dr.
Padala said. “With adults, it gives them more energy. Simply
put, it increases the dopamine in the brain.”
Dopamine is like the gas in your car. Low dopamine
levels in the front of the brain can lead to apathy.
“Apathy is one of the most profound and disabling
aspects of Alzheimer’s disease,” said William Burke, M.D.,
professor and vice chairman of the UNMC Department of
Psychiatry.
One study determined that apathetic persons are nearly
three times more likely than those without apathy to be
impaired in day-to-day activities such as dressing, bathing,
walking, eating and using the toilet.
In addition, apathy is linked to cognitive dysfunction
in dementia patients. With no interest or motivation,
it becomes difficult for these patients to use their
remaining cognitive function. Their memory, learning and
communication skills deteriorate.
“People are getting excited about apathy now because it
may be a behavioral marker for a more rapidly progressing
fall 2008
dementia,” Dr. Padala said. “Apathy is considered an untapped
behavioral problem. If treated well, it can have significant
impact on management of dementia and diabetes.”
Dr. Padala is conducting a VA-funded placebo-controlled
study for apathy treatment in 60 veterans with Alzheimer’s
dementia. He said that early study results have been
promising, as illustrated by the comments from the wife of
an Alzheimer’s patient who is taking Ritalin.
“After one month in the study, she came to me and said,
‘Thank you for giving my husband back to me. He’s doing
things that he hasn’t done in the last five years,” Dr. Padala said.
Diabetes is a major public health problem in the United
States. It is much more common among veterans than
in the general population. Self-management is a critical
component to treating diabetes.
“The key to living with diabetes is disease management,”
Dr. Desouza said. “You have to exercise, watch your diet
closely, keep your weight down and continually monitor
your blood sugars. It’s not easy. You have to be driven.
“Apathy can be devastating for patients with diabetes.
Once they lose interest and stop managing the disease, the
health ramifications can be dramatic,” he said.
Dr. Desouza knows how difficult it is to motivate
patients with diabetes. Despite all the innovations in
treatment and guidelines, only about 10 percent of patients
meet the benchmarks for diabetes control (blood sugar,
blood pressure and cholesterol).
The use of Ritalin is encouraging in the group of study
participants, he said.
“However, the brain is very complicated. We don’t know if
improvement is due to the neuro chemical reaction resulting
from taking Ritalin. More research needs to be done.”
Ritalin is not the optimal drug, Dr. DeSouza said.
Although it does increase dopamine, it also has several side
effects, such as sleep disturbances, decreased appetite and
increased blood pressure.
Cyrus Desouza, M.D.
Children who are hyperactive receive 80 mg of Ritalin as
their daily dose. Adults in the studies are given much lower
doses of Ritalin with Alzheimer’s patients receiving 10 mg
and obesity patients receiving 20 mg. The lower dose helps
lessen the side effects.
“We need to find a pharmaceutical agent that can impact
apathy,” Dr. Desouza said. “Ritalin is the best drug we have
right now, but we are hopeful that we can find a better agent.”
Dr. Desouza has funding to study the impact of treating
apathy on weight loss initiatives. Through the Omaha VA,
125 veterans were enrolled in the pharmacological and nonpharmacological treatments for apathy.
As part of the study, Drs. Padala and Desouza also are
investigating a group therapy, “Medical Crisis Counseling,”
for treatment of apathy.
“There seems to be a common thread linking
Alzheimer’s disease and diabetes, since people with diabetes
are three times more likely to develop Alzheimer’s disease
than non-diabetic individuals,” Dr. Padala said.
Apathy may be that thread. Dr. Padala recently received
funding from the Alzheimer’s Association to improve
functional status, quality of life and glycemic control in
patients with co-morbid dementia and diabetes.
“This is ground breaking work,” Dr. Burke said. “They
are trying to determine if treating apathy will not only
benefit the day-to-day life of people with Alzheimer’s but if
it might also have additional medical benefits in improving
glucose control and increasing activity levels. This is a
completely novel and exciting approach to a number of well
known, often intractable, problems.”
Are you apathetic?
CHANGE IN APATHY OVER 12 WEEKS
APATHY EVALUATION SCALE
59
54
49
If you answer ‘yes’ to any of these questions, you might
suffer from apathy syndrome and should seek more
detailed testing:
44
39
34
29
❚ Have you lost interest in the world around you?
24
BASELINE
4 WEEKS
8 WEEKS
12 WEEKS
Significant improvement in apathy scores was seen in the subjects
with a mean decrease of 20 points on the apathy scale (p<.0001).
Most improvement in apathy was noted at the fourth week visit,
although the improvement continued throughout the study period.
❚ Are you more difficult to engage in conversation
or in doing chores?
❚ Have you lost interest in doing things or in
starting new activities?
❚ Are you apathetic or indifferent? UNMC
discover
UNMC researchers mentor
junior investigators
Growing Our Own
by Lisa Spellman
Mentor: a trusted friend,
counselor, teacher, a more
experienced person.
Much like spreading fertilizer on
young seedlings, federal grants
awarded to two experienced
UNMC researchers – Peggy
Wheelock and Alexander
Kabanov – are helping young
investigators advance their
careers, enhance their education
and build their networks through
mentoring. Here are their stories.
10
fall 2008
Junior investigator Jenny Wang,
Ph.D., was about to submit her first R01
grant application to the National Institutes
of Health (NIH), and she wanted it to
be perfect.
Fortunately, so did Peggy Wheelock,
Ph.D., who suggested Dr. Wang wait to
submit the grant. Having sat on review
boards, Dr. Wheelock knows what it takes
to write a grant that will pass muster.
That was in June and for the next four
months Dr. Wheelock patiently helped
Dr. Wang re-write and refine her grant
proposal until it was nearly perfect.
“It was the nicest thing anyone could
have done for me,” Dr. Wang said. “Her
support was just the confidence boost I
needed.”
Right up until the last minute Dr.
Wheelock was still asking Dr. Wang if she
wanted her to read it, just one more time.
“I said no, she had already helped
me make it more understandable for the
reviewers,” Dr. Wang said. “Once we had a
draft that she felt was solid, I was completely
comfortable submitting it in October.”
It’s not unheard of for Dr. Wheelock,
professor of oral biology in the UNMC
College of Dentistry, to take time away
from her research to pour over the grant
proposal of a junior investigator. In fact, Dr.
Wheelock spent countless hours reading
and re-reading Dr. Wang’s grant proposal.
Dr. Wang, who came to UNMC last
year from the Roswell Park Cancer
Institute in Buffalo, N.Y., is one of five
junior investigators finding guidance under
Dr. Wheelock’s wing.
The mentoring program is part of
a $10.9 million Centers of Biomedical
Research Excellence (COBRE) grant that
was originally awarded to Dr. Wheelock
in 2003.
Dr. Wheelock also is the director of the
Nebraska Center for Cellular Signaling,
which was established in 2003 with the
Grow • Nurture • Support
Peggy Wheelock, Ph.D.
initial COBRE funding. The center focuses
on the study of cell signaling and involves
multidisciplinary collaboration between
researchers. Under the grant, Dr. Wheelock
mentors several junior investigators and
oversees the progress of others whom she
has paired with senior researchers.
Researchers from UNMC, the
University of Nebraska-Lincoln and
Creighton University Medical Center lead
five projects within the grant. Each project
involves the study of cellular signaling with
a focus on its role in producing tumors.
The five-year grant was recently
renewed by the National Center for
Research Resources (NCRR), a division of
the NIH, partly due to the success of seven
junior investigators at UNMC who, with the
help of this program, obtained their own
R01 grants from the NIH.
“The grant allows us to bring together
outstanding junior and senior faculty with
similar interests, which greatly enhances
the science knowledge and opportunities
for collaboration,” Dr. Wheelock said.
When they first met, Dr. Wang was
struck by Dr. Wheelock’s warmth and
friendly personality.
“Right away, she asked me how I
was doing and offered to help in any way
she could,” said Dr. Wang, an assistant
professor in the UNMC Eppley Institute.
Colleagues say Dr. Wheelock’s
willingness to help is what has made her
successful as a mentor.
“Dr. Wheelock is approachable. The
junior investigators working with her
know this and are comfortable going to
her,” said Rob Lewis, Ph.D., a professor
in the Eppley Institute. “She will do
everything she can to help her junior
investigators succeed.”
That includes pairing every junior
investigator with two mentors who can
help them navigate the complex world of
grant writing. It also may mean extending
a junior investigator’s funding from the
usual three years to four – to give them
more time to work on their research.
“Dr. Wheelock could buy a lot of fancy
equipment and fund core facilities, but
instead she invests in human capital and
the potential of young investigators,” Dr.
Lewis said.
The nurturing and feeding of seed
money has worked so well, Dr. Wheelock
has another five years to show more results.
“The COBRE grant we received in
2003 helped us strengthen the biomedical
research infrastructure in Nebraska. We’ve
established a multi-disciplinary thematic
center that enhances the research of
young investigators and now we have
seven success stories,” Dr. Wheelock said.
Dr. Wheelock said one objective of the
renewed funding will be to initiate pilot
projects that further encourage and support
collaborative, multi-disciplinary projects.
“Teaching one how to be a successful,
productive scientist is not a trivial task,”
said Paula Turpen, Ph.D., director of
research resources at UNMC.
“The fact that three of the COBRE
mentors (Drs. Wheelock and Lewis
and Keith Johnson, Ph.D.) have been
recognized as UNMC Distinguished
Scientists in the past two years only
confirms the quality of mentors in the
Center for Cell Signaling. There is no doubt
that the seven new NIH-funded junior
faculty will continue to benefit from the
guidance they received while participating
in the COBRE program.”
Steve Caplan, Ph.D., assistant professor,
biochemistry and molecular biology, is one
of the seven researchers who received a
boost from the COBRE grant.
Dr. Caplan joined the grant in 2004 when
Dr. Wheelock selected him for a pilot project.
He was later asked to become a project
leader and was paired with two mentors:
Richard MacDonald, Ph.D., biochemistry
and molecular biology, and Dr. Lewis.
“They taught me how to write better
grants and advised me on where to
submit my application,” Dr. Caplan said.
“Peggy also helped, reading through parts
of my grant proposals and manuscripts.
She sets the tone for the mentorship part
of the grant.”
Dr. Caplan’s area of study is in protein
trafficking – how proteins get from place
to place in the cell. While it is basic
research, he collaborates with other
researchers who study specific protein
receptors and want to better understand
how proteins move around.
Even though he no longer qualifies
as a COBRE project leader, Dr. Caplan
maintains a connection to Dr. Wheelock
and her work. He finds himself in the
nurturing role.
“I try to help out as much as I can with
the new investigators coming in, because
I believe in what Dr. Wheelock is doing,”
Dr. Caplan said.
“She is an incredible role model,
who dedicates a huge amount of time
to mentoring while maintaining her own
lab. She never stops worrying about what
everyone else who is involved with the
grant is doing. She is amazing.”
The Research Project Grant (R01) is the original
and historically oldest grant mechanism used
by the Natiional Institutes of Health. The R01
provides support for health-related research and
development based on the mission of the NIH.
UNMC
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11
Alexander Kabanov, Ph.D.
New COBRE grant to grow
nanomedicine program
Alexander Kabanov, Ph.D., just
received $10.6 million and he knows
exactly what he’s going to do with it.
The UNMC researcher hopes to save
as many lives as he can by finding better
ways to treat and cure hypertension,
Parkinson’s disease and cancer.
He plans to do this through
nanomedicine, an emerging area of
science that uses small polymeric
particles to deliver drugs safely to
disease sites.
He has formed a team of highly
talented junior investigators whose
own complimentary projects will
help Dr. Kabanov grow a world-class
program in nanomedicine. Each of the
junior investigators will be paired with
mentors, including Dr. Kabanov.
“The research projects funded
by this grant will one day provide
drug therapies to physicians that
12
fall 2008
target disease without harming the
surrounding healthy tissue, which will
result in better clinical outcomes for
patients,” Dr. Kabanov said.
He received a five-year COBRE
(Centers of Biomedical Research
Excellence) grant award in October
from the National Center for Research
Resources (NCRR), a part of the
National Institutes of Health (NIH).
As the director of the Nebraska
Center for Nanomedicine, a part of
the regent approved Center for Drug
Delivery and Nanomedicine, and the
Parke-Davis Chair in Pharmaceutics in
the College of Pharmacy at UNMC,
Dr. Kabanov tried for five years to get
the grant.
It was worth the wait.
“While working on the grant
proposal, I got to know UNMC and
its scientists and administrators much
better, giving me a deeper sense of
pride for the institution,” he said.
“Those years also gave me time to
develop myself into a leader and for
that I am very grateful.”
GROWING OUR OWN
There are other benefits to having
the COBRE grant.
“It allows us to attract the best and
brightest scientists to Nebraska and
develop novel technologies that could
contribute to the economy of the state
with the help of spin-off companies
that would bring the results of the
scientific research to public use,” Dr.
Kabanov said.
Not a bad combination, saving
lives – and helping the economy.
The COBRE is part of the
Institutional Development Awards
Grow • Nurture • Support
(IDeA) network created by the NIH/NCRR to more
equally distribute funding to states that have not
traditionally received as much funding. The awards
support multidisciplinary centers – each concentrating on
one general area of research – that strengthen institutional
biomedical research capability and enhance research
infrastructure.
“By bridging the research funding gap in IDeA states,
we are building innovative research teams, leveraging the
power of shared resources, and enhancing the science and
technology knowledge of the state’s workforce,” said NCRR
Director Barbara M. Alving, M.D.
“It allows us to attract the
best and brightest scientists
to Nebraska and develop
novel technologies that
could contribute to the
economy of the state.”
Alexander Kabanov, Ph.D.
Research seedlings
The four young investigators whose projects will be
supported through Dr. Kabanov’s COBRE grant are:
Project 1:
Principal investigator: Elena V. Batrakova, Ph.D., assistant professor of
pharmaceutical sciences.
Mentor: Howard Gendelman, M.D., chairman, department of pharmacology
and experimental neuroscience; director, Center for Neurovirology and
Neurodegenerative Disorders.
Dr. Batrakova’s project focuses on creating a drug delivery system to treat
Parkinson’s disease using nanozymes and immune cells in the brain as the
delivery agent. Nanozymes are tiny particles consisting of an enzyme in a
protective polymer coat.
Project 2:
Principal investigator: Matthew Zimmerman, Ph.D., assistant professor,
cellular and integrative physiology.
Mentor: Irving Zucker, Ph.D., professor and chairman of the cellular and
integrative physiology department.
Dr. Zimmerman’s research project focuses on using antioxidant therapy
and nanozymes to treat hypertension.
The COBRE grant will support the research projects of
four junior faculty members, all of whom have been paired
with an established faculty member, Dr. Kabanov said.
The grant promotes collaboration among researchers with
complementary backgrounds, skills and expertise.
“All four projects focus on how polymer nano
systems may be used to enhance the delivery of drugs,
inhibit tumor growth, and improve treatment of cancer,
neurodegenerative and central nervous system-associated
cardiovascular disorders,” Dr. Kabanov said.
The grant also will help establish core facilities
needed to carry out the objectives of the multidisciplinary
collaborative program. The first is a bioimaging
core lab that will allow noninvasive diagnostics of
neurodegenerative disease. The second will focus on
preparation of new nanomaterials and ensure that these
materials are safe for human use.
Dr. Kabanov has prepared the ground and planted the
seeds of research success. This grant provides the fertilizer
that he needs to help grow the program.
Ultimately, it is up to Dr. Kabanov and his team of
researchers to make it thrive.
Project 3:
Principal investigator: Huanyu Dou, Ph.D., assistant professor, pharmacology and
experimental neuroscience.
Mentor: Surinder Batra, Ph.D., professor, biochemistry and molecular biology.
Dr. Dou’s research project focuses on developing a cell-based
nanoformulated anti-tumor therapy that would improve biodistribution of
the drug to the tumor and reduce chemotherapy-induced neurotoxicity.
Project 4:
Principal investigator: Joseph Vetro, Ph.D., assistant professor, pharmaceutical
sciences, and Center for Drug Delivery and Nanomedicine.
Mentor: Alexander Kabanov, Ph.D., director, Center for Drug Delivery and Nanomedicine.
Dr. Vetro’s research focuses on inhibiting the growth of cancer tumors by
using specially developed nanocarrierse that disrupt the tumor’s ability to
recruit surrounding blood vessels.
UNMC
discover
13
i
Targeted
delivery
i
INNOVATION
by Elizabeth Kumru
New system taxis drugs
to ailing bones
14
fall 2008
What you are about to read may cause you to brush
your teeth after every meal. You may also want to rinse
your mouth each night with a special mouthwash
created by a UNMC researcher.
The mouthwash, formulated by Dong Wang, Ph.D.,
associate professor of pharmaceutical science in the
UNMC College of Pharmacy, will not only protect
your teeth from harmful plaque, but it also may help
prevent bone loss in the jaw.
UNMC
discover
15
Dr. Dong Wang in his laboratory
in UNMC’s College of Pharmacy.
Run your tongue over the back of your teeth. If it feels as if they
are coated with something, that’s biofilm.
Biofilm, or plaque, is a sticky film of bacteria that constantly
forms on the teeth. Food and drink that contain sugar or starch
are converted by the bacteria in plaque to produce acids that
attack tooth enamel. Over time, the enamel breaks down and
cavities form.
It’s difficult for mouthwash to break through plaque. While
brushing takes it away, plaque resumes its cycle of buildup after
brushing is completed.
A polymer chemist by training, Dr. Wang has taken a
commercially available polymer, or macromolecule, and
formulated it into a novel drug delivery system to carry
antimicrobial agents directly to teeth. The U.S. Food and Drug
Administration has approved the polymer as a pharmaceutical
excipient, or drug carrier.
For commercialization, Dr. Wang envisions a mouth rinse
formula that protects teeth from plaque. “The beauty of this
design is the simplicity. All you have to do every night before
bed is to brush your teeth and then rinse your mouth with our
special formula.
“We certainly will look at different flavors. I want something
that’s tasty,” he said.
The mouth is home to some of the most common diseases
known to humans. Besides tooth decay, known to at least one-half
of American children, unchecked plaque can lead to loss of bone
around the teeth (periodontitis). Other diseases that affect the
gums and lining of the mouth, include canker sores, oral herpes or
cold sores and gingivitis.
Although, collectively, it has declined among young children,
tooth decay still can be a problem for individual children, and even
teens and adults. If untreated, this type of decay can infect the
internal structure and ultimately cause loss of the tooth. Nearly 12
percent of the adult population – more than 35 million people in
the United States – lose bone support around their teeth.
At present, Dr. Wang is collaborating with Kenneth Bayles,
Ph.D., professor of pathology and microbiology, and his team to
evaluate the formula against bacteria found in the oral cavity. “This
synergistic effort with Ken’s group is our first test in the real world,”
Dr. Wang said.
Dr. Wang came to UNMC in January 2005 from the University
of Utah where he started his research in targeted drug delivery for
bones and joints.
After his arrival in Omaha, the Beijing native began a
collaboration with Richard Reinhardt, Ph.D., D.D.S., the B.J.
and Ann Moran Professor of Periodontology and co-director of
16
fall 2008
undergraduate periodontics at the UNMC College of Dentistry.
Together, they have designed several systems for oral applications.
One system developed by Drs. Wang and Reinhardt is a bonetargeting cyclodextrin conjugate that targets and selectively binds to
teeth and bones. The agent delivered can be released slowly over
time, which increases the therapeutic index, or effectiveness, and
overall performance of the agent.
“The major advantage of the invention over the traditional
formulation is that it offers a very simple mechanism of drug
retention in the target area,” Dr. Wang said. To their surprise, a
control study revealed that the carrier itself has some bone-building
effect. Now the team is exploring the possibility of using this
compound to treat osteoporosis.
“This will be a great addition to the tools dentists have to fight
bone loss and tooth decay,” Dr. Reinhardt said.
Dr. Wang’s other research interests include the development of
improved di­agnostic and therapeutic systems for diseases such as
rheumatoid arthritis, cancer bone metastasis and osteomyelitis.
For the treatment of rheumatoid arthritis, Dr. Wang says his
polymeric drug delivery system acts like a Mini Cooper in the way it
delivers medications precisely to the destination.
“The delivery system is small, agile and delivers drugs to an
exact address in the body,” he said.
Traditionally, a drug enters the body through a pill or injection
and travels around to fulfill its purpose. But it also goes places it
shouldn’t, which can cause harmful side effects to bones, organs
and tissues.
For people with rheumatoid arthritis (RA), the prescribed
medications can cause such side effects as osteoporosis, nausea,
easy bruising, mouth sores and possible kidney and liver damage.
Dr. Wang’s drug delivery method uses a more efficient approach
with a polymeric structure that could differentiate the healthy and
arthritic joint. By preferentially delivering drugs to the arthritic joint,
the “Mini Cooper” drug carrier would enhance therapeutic efficacy
and potentially reduce side effects.
Dr. Wang’s joint-targeting delivery system for arthritis
treatment is supported by a three-year, $660,000 R01 grant
from the National Institutes of Arthritis and Musculoskeletal and
Diseases. He is collaborating with one of the world’s foremost
RA experts, James O’Dell, M.D., the Larson Professor and vice
chairman of internal medicine, and chief of UNMC’s section of
rheumatology/immunology.
“The delivery system is small, agile and delivers drugs
to an exact address in the body.”
Dong Wang, Ph.D.
UNMC
discover
17
The MRI pictures
demonstrate the
targeting of the
macromolecular
dexamethasone prodrug
to the ankle joints of
the arthritic rats (upper
panel). The prodrug Does
not stay in the healthy
animal and is quickly
cleared via urination
(lower panel).
“The strength of Dr. Wang’s approach
is that he pursues scientific
understanding, while keeping an eye
on the clinical problems that require
a solution.”
On the left is a micro-computed tomography image of
an arthritic rat treated with the macromolecular
dexamethasone prodrug that Dr. Wang invented. The image
shows preservation of the bones in the ankle joint. The image
on the right shows severe deterioration of the bone in an
arthritic rat that was not treated.
Dr. O’Dell’s seminal contributions to improvements in RA
therapy include his research on combination disease-modifying
anti-rheumatic drugs (DMARD) and the use of tetracyclines as
therapy for RA. Perhaps his best known work is his study of triple
combination DMARD therapy in the treatment of refractory RA
published in the New England Journal of Medicine in 1995.
“Dr. Wang is doing exciting and cutting-edge research that will
help us deliver medicine to sites of inflammation in the body,” Dr.
O’Dell said. “With his system, we also have the ability to image those
sites more clearly. This will allow us to better diagnose and treat
patients with inflammatory arthritis such as RA.”
With RA, people initially are offered glucocorticoid therapy for
their disease. “But, one side effect of those drugs is osteoporosis,”
Dr. Wang said. “With our polymer carrier, the drugs will be delivered
directly to the arthritic joint and provide long-lasting relief – up to
three weeks in animal studies. Potentially, we may use this as a safer
bridging therapy to allow the effects of DMARD therapy to kick in.”
18
fall 2008
James Linder, M.D.
UNeMed Corporation, the marketing and licensing arm for
UNMC, has negotiated with the University of Utah to combine
technology Dr. Wang developed there with his new RA inventions
developed at UNMC. Human trials may begin in two years.
As a creative thinker, Dr. Wang also wants to know how his
drug delivery systems can be used in the treatment of breast and
prostate cancer that has escaped chemotherapy and taken refuge
in the bone.
“With our bone-targeting polymeric delivery system, it is
possible that we can stop bone damage from cancer metastasis
and kill cancer cells in the bone. The bone often provides a safe
hiding place and a launching pad for the spread of cancer to other
organs,” he said.
If it seems that Dr. Wang is everywhere, it’s because he is
eager to explore how his delivery systems can be applied to
other diseases.
James Linder, M.D., president and CEO of UNeMed, said that’s
characteristic of successful researchers.
“The strength of Dr. Wang’s approach is that he pursues
scientific understanding, while keeping an eye on the clinical
problems that require a solution. This is a key attribute of anyone
who does translational research,” Dr. Linder said.
Dr. Wang also credits his success to the strong support he has
received from his college and department.
Dr. Wang’s drug delivery research is a perfect example of
translational research that bridges the gap between basic science
and the patient, said Courtney Fletcher, Pharm.D., dean of UNMC’s
College of Pharmacy.
“His projects illustrate to the public how their investment in
research at UNMC and the College of Pharmacy can directly
improve human health,” Dr. Fletcher said.
Research that translates into practical use requires a
curious clinician.
“Clinicians know the science and ask questions and asking the
right question is part of the success,” Dr. Wang said. “Physicians
sometimes use different language, so we as researchers need
patience to learn their language. It’s a very humbling experience.
The same also applies to our collaborations with biologists.
“Pharmaceutical research goes nowhere if we don’t have a
clinical problem. The participation of physicians is essential.”
Web
Extra
More on Dr. Wang’s research
www.unmc.edu/discover
Ankle joints of rats demonstrate the effectiveness of
Dr. Wang’s drug delivery system. Image (A) shows the joint
treated with an arthritis drug using Dr. Wang’s system is
well-preserved, which is similar to the bone in a healthy rat
(B). When an arthritic rat was treated without the system,
the rat’s ankle joint experienced significant bone loss (C),
which is similar to an arthritic rat that did not receive any
treatment (D).
Xin-ming Liu, Ph.D., research associate, works with Dr.
Wang on chemical synthesis for the drug delivery system.
Dr. Wang recognized
On Oct. 23, Dr. Wang was honored as the recipient of UNeMed’s first
Emerging Inventor Award and received a $25,000 innovation grant for
unrestricted research from UNeMed during the 2008 Innovation Awards.
The Emerging Inventor demonstrates exceptional skill and appreciation
for scientific achievements.
Dr. Wang was among dozens of UNMC inventors who were
recognized for their new inventions, patents and licensed technologies.
UNeMed Corporation, the marketing and licensing arm for UNMC,
sponsored the awards.
“Dr. Wang’s research is a promising step in the search for treatment
for the joint damage and pain experienced by people who have
rheumatoid arthritis. In addition, his other research efforts focus on
osteoporosis and are equally as promising as therapeutics,” said Sara
Conrad, licensing associate for UNeMed.
Dr. Wang filed eight New Invention Notifications that have resulted
in the filing of seven provisional patents and one international patent
application covering several variations of the conjugates and their
synthesis, Conrad said.
Michael Dixon, Ph.D., vice president and chief operating officer of
UNeMed, said Dr. Wang is one of UNMC’s most prolific inventors.
“His inventions have drawn significant interest from both the
clinicians and the pharmaceutical industry. His osteoporosis and
arthritis technology have great potential to reach the clinic and improve
health care,” he said.
Dennis Robinson, Ph.D. chairman of pharmaceutical sciences, UNMC
College of Pharmacy, said Dr. Wang is a worthy recipient of UNeMed’s
first Emerging Inventor Award.
“Since joining us in 2005, Dr. Wang’s enthusiasm and commitment
has enabled him to rapidly establish a research program of outstanding
quality and creativity,” he said.
“He continues to build a growing national and international
reputation for his research in drug delivery strategies that target bone
and joints. Dr. Wang is an excellent scientist with a truly exciting future.”
UNMC
discover
19
The care
connection
by Elizabeth Kumru
Diabetes is a difficult disease to manage.
It affects the entire body. Management of blood sugar levels
through healthy diet and physical activity is critical. Effective
management helps patients lower the risks of developing
such health problems as kidney disease, heart and blood
vessel disease, blindness and neuropathy.
But for millions of uninsured adults, help with
management skills and preventive care seem like a luxury.
A team of UNMC College of Nursing researchers want
to change that paradigm for patients with Type 2 diabetes
mellitus (T2DM) and health care providers across Nebraska.
They are studying how the chronic care model can help
patients take small incremental steps toward effectively
managing their diabetes and other diseases.
“This project will help us determine the effectiveness
of our interventions. We know in theory that prevention
is good, self-management works and nursing clinics are
valuable. Now we’re putting all these elements together into
one comprehensive care plan,” said Susan Beidler, Ph.D.,
associate professor, community based health, and director
of the Morehead Center for Nursing Practice.
The UNMC team is led by project director Teresa Barry,
Ph.D., assistant professor, families and health systems,
and Dr. Beidler, assistant project director. They are in the
second year of a five-year, $1.6 million Health Resources and
Services Administration (HRSA) grant.
“We want to help empower people with diabetes to
manage their disease better through small, achievable steps
in lifestyle changes,” Dr. Barry said. “We find a higher degree
20
fall 2008
Nursing study examines
new model of care for
chronic disease
of success if goals are set by the patient rather than the health
care provider.”
T2DM is the most common form of diabetes, affecting
95 percent of the 21 million people with diabetes. T2DM
also is more prevalent in minorities and the uninsured. Lack
of insurance leads to significant disparities in access and
quality of care received, Dr. Barry said.
In the United States, there are 47 million uninsured
people. The diabetes rate among uninsured blacks is twice
as high as Caucasians and three times as high among
Hispanics, according to the Census Bureau report: Income,
Poverty, and Health Insurance Coverage in the United
States, 2007.
“For individuals who have limited access to health care
and other resources, trying to manage a chronic condition
such as T2DM creates stress and can lead to depression and
feeling powerless to improve their health,” Dr. Barry said.
Untreated, the disease can lead to severe complications
and increased cost to the health care system and patient.
“We’re trying to change these outcomes,” Dr. Beidler said.
The research project tests the effectiveness of a
“three pronged” approach to care. It involves enhancing
undergraduate and graduate student learning opportunities
in caring for patients with chronic conditions, incorporating
the latest evidence-based practice guidelines in provider
practice, and promoting patients’ ability to manage their
diabetes better.
“If we prove this strategy of care is successful, it can be
used in every clinic and applied to other chronic diseases,”
Dr. Beidler said.
Patients who are eligible to be in the study have limited
financial resources and find it difficult to get medication
and follow through with their appointments, Dr. Barry said.
Often, preventive efforts are not valued because patients
don’t feel sick and the long-term implications of the disease
are not understood.
The research project uses the UNMC Mobile Nursing
Center as one way that patients with limited access to a
Jan Herzog, project nurse coordinator, and Lucy Zavala, a
bilingual medical assistant, inspect the diabetes foot models
they use for patient education.
Drs. Susan Beidler and Teresa Barry are studying how a chronic care
model can help patients with diabetes manage their disease.
regular health care provider can get referrals for care and
free health screening for diabetes and other conditions.
This site also gives students an opportunity to work with
underserved patients.
Study participants in Omaha who need follow-up care
can get health care services from the UNMC Community
Health Center or other local health clinics. Participants
outside of Omaha are referred to a local health care
provider for care.
To date, the study has enrolled 42 low-income patients
through the UNMC Family Health Care Center, which is
part of the Community Health Center at 5155 S. 36th St.
People enrolled in the study are mostly Hispanic who
have little or no insurance. They are offered education
support in English or Spanish, group sessions at the clinic,
and home visits.
The key component of the study involves the patient
using a diabetes action plan. This action plan helps the
patient pick a goal they feel they can meet, such as walking
two blocks three days a week. The patient and health care
provider can talk about the patient’s progress toward their
self-management goals, as well as possible barriers or
changes to the goals. Goal setting, using the action plan, is
an ongoing process and successes are acknowledged
and celebrated.
So far, 13 people have participated in the home visit
program that is conducted through the Ambulatory Care
Community Health Nursing Project.
This project pairs undergraduate public/community
health nursing students with a patient or family for
education and self-management support in their home
environment where day-to-day management issues can
be dealt with realistically. When needed, Lucy Zavala, a
bilingual medical assistant at the health center, provides
interpretative services for the home visits.
The research has shown that home visits have helped
gain the trust of patients.
Jan Herzog, the project nurse coordinator at the health
center, said that behavior changes can be difficult, but home
visits reinforce two messages for the patient.
“It says ‘we care about you and your challenges’ and ‘we
take your disease seriously,’ ” she said.
Research shows that home visits also motivate patients
to stick to their self-management plan, Zavala said.
“They know we are coming to visit and they want
to show improvement. The patients feel comfortable
being taken care of in their own home and it has made a
difference in their plan of care. They feel a sense of trust and
comfort having someone in their home who can speak their
language and understand their culture,” she said.
Resources available to assist patients with developing
a self-management plan include food models to show
correct portion sizes, illustrated booklets on nutrition and
cooking and handouts on exercise. Plastic foot models are
used to demonstrate proper foot care and identify possible
complications that may occur.
The team plans to expand the study with other
community partners in other College of Nursing sites
in Lincoln, Scottsbluff and Kearney. In addition, Drs.
Barry and Beidler are exploring opportunities for
interprofessional education and practice with other health
care team members.
Ultimately, they hope this model of care will be
implemented in health care practices across the state to help
patients deal with chronic diseases beyond diabetes.
“Then we will truly have established a care connection,”
Herzog said.
UNMC
discover
21
determined
to make
earlier
diagnosis
a reality
by Karen Burbach
Pancreatic
cancer eludes
detection – but
not for long
George Watson knows the grim statistics for pancreatic cancer.
One in 76 people will develop pancreatic cancer, according to
the American Cancer Society. Once diagnosed, a person has less
than a 5 percent chance of living more than five years.
Even so, the Chadron (Neb.) State College professor and
private practice attorney is determined to beat the odds.
“When you first get the diagnosis, you think it’s terminal,”
Watson said. “But there is a percentage who overcome it.”
Watson increased his odds for survival by being eligible for the
Whipple procedure (see sidebar).
But, researchers at UNMC’s Eppley Cancer Center, led by Tony
Hollingsworth, Ph.D., want to increase every patient’s odds by
identifying diagnostic markers that detect pancreatic cancer before
symptoms appear and when surgical removal is still possible.
“I’ve dedicated my career to making earlier diagnosis of
pancreatic cancer a reality,” Dr. Hollingsworth said.
Tissue donated by Watson helps Dr. Hollingsworth and the
UNMC team, one of the largest pancreatic cancer research
groups in the country. “Anything I can do that helps in the
diagnosis and treatment is important for the future,” Watson said.
The National Cancer Institute (NCI) funds three pancreatic
cancer programs of excellence – one is at UNMC.
The $5.3 million, five-year Specialized Program of Research
Excellence (SPORE) grant in pancreatic cancer – sought after
22
fall 2008
by the country’s most prestigious research and medical facilities
– funds translational research.
“The SPORE grant earned by Dr. Hollingsworth and his
colleagues is an outstanding achievement and important milestone
for scientific research at UNMC and the UNMC Eppley Cancer
Center,” said Ken Cowan, M.D., Ph.D., director of the cancer
center. “The National Cancer Institute continues to recognize the
important work being done at the Eppley Cancer Center.”
For Dr. Hollingsworth and his team, there is an unrelenting
drive to learn more about the basic biology of pancreatic cancer
and study new biomarkers that enable them to diagnose
the disease earlier. They also want to better understand the
progression of the disease and develop new therapies that extend
a patient’s life.
“We’re at the cutting-edge of making a difference in people’s
lives,” Dr. Hollingsworth said.
A 6-inch long, spongy organ, the pancreas resembles a pear
on its side and helps the body digest food and regular body sugar
levels. Cancer occurs when cells in the pancreas develop genetic
mutations, which cause cells to grow uncontrollably. Tumors form
as these cells accumulate.
“If we could shut down that process, we could significantly
extend the patient’s life span,” Dr. Hollingsworth said.
Early detection of the disease, however, is a major hurdle.
Tony Hollingsworth, Ph.D.
“We’re at the
cutting-edge
of making a
difference in
people’s lives.”
Tony Hollingsworth, Ph.D.
The location of the pancreas, deep in the abdomen, hinders
early discovery of the disease and, unlike mammography, which
provides early detection of breast cancer, there are no screening
tools for pancreatic cancer. By the time tumors are found they
often measure 1 centimeter or more and have metastasized
or spread.
“The disease has to be managed differently,” said UNMC
researcher Surinder Batra, Ph.D. “We need a more systematic
approach with pancreatic cancer because there’s so little time.”
Watson went to the doctor in February for a nagging ache in
his upper stomach. At first, he was treated for acid reflux and
indigestion, but nothing changed.
When he became jaundiced, doctors ordered a flurry of tests.
The ultrasound and CAT scan showed a tumor on the pancreas.
“I didn’t know much about pancreatic cancer, but knew it was
a bad one to get,” Watson said.
Fortunately, the cancer had not spread beyond the pancreas.
Dr. Batra says a simple blood test – one that detects a
protein produced by pancreatic cancer – would help alert
patients to the disease.
An internationally patented biomarker – first identified by
UNMC researchers in 2001 and featured on the April 2007 cover
of the Molecular Cancer Research Journal – shows promise in
the early detection of the disease. Mucin 4, a human gene also
known as MUC4, is associated with the disease progression and
can be found in blood and tissue.
A high level of the biomarker, detected through a costeffective blood test, may mean that cancer is in the body.
“MUC4 expression is strongly associated with the lifespan
of patients and could be a new early and specific marker for the
diagnosis and prognosis of pancreatic cancer,” Dr. Batra said.
“About 80 to 90 percent of pancreatic cancer patients have high
levels of MUC4 in tumors, fine needle aspiration biopsies and
blood, which that makes it easy for us to diagnose cancer.”
Preliminary studies of the blood test show promise and a
validation trial, funded by the NIH RO1 and SPORE grants, is
underway. “The results of our trial could help us better manage
the disease, determine who should go to surgery, how we should
treat the patient and how we might stop or decrease expression,”
Dr. Batra said.
MUC4 may not be the only marker, though.
Several of Dr. Hollingsworth’s projects focus on the study of
MUC1, a glycoprotein that scientists believe plays an important
role in the normal function of the pancreas. MUC1, they have
found, interacts with and alters the function of p53, a tumor
suppressor gene.
“We want to study the big questions and understand how the
tumors invade and metastasize so we can understand why the
UNMC
discover
23
“Patients should have
hope and take comfort
in the fact that there are
researchers who care.”
Tony Hollingsworth, Ph.D.
SPORE grant spawns
many projects
The UNMC Eppley Cancer Center’s pancreatic program receives
nearly $15.5 million in external funds, most of which comes from the
National Cancer Institute (NCI).
Of that, $5.3 million is part of a competitive five-year Specialized
Program of Research Excellence (SPORE) grant in pancreatic cancer.
The SPORE grant compliments the cancer center’s work with the
NCI’s Early Detection Research Network (EDRN) and the UNMC-based
Pancreatic Cancer Collaborative Registry. It also supports translational
research projects, creates a new core in biostatistical support and
provides partial support for UNMC’s tissue bank and unique rapid
autopsy program.
The EDRN brings together dozens of institutions to evaluate new
ways to test for cancer risk and accelerate the translation of biomarker
information into clinical use.
The registry, meanwhile, unites at least 12 centers, including Johns
Hopkins University, the University of Pittsburgh, Evanston Northwestern
Healthcare and the University of Genoa (Italy), with expertise in
pancreatic cancer research. The one-of-a-kind, Web-based registry
has collected critical information and biological samples from 1,600
patients to develop prevention and treatment strategies.
UNMC’s tissue bank, directed by Julia Bridge, M.D., and its unique
rapid autopsy program, which allows cancer patients to donate entire
organs, help researchers to study the disease.
“The rapid autopsy program allows us to acquire a large volume
of rarely obtained tissues,” said Tony Hollingsworth, Ph.D., who directs
the program and the volunteer efforts of more than 30 technicians,
students, nurses, residents and faculty members. “The program enables
us to undertake many studies that are not otherwise possible.”
24
fall 2008
disease is so deadly,” Dr. Hollingsworth said. “Patients should have
hope and take comfort in the fact that there are researchers who care.”
Dr. Hollingsworth’s team helped discover MUC1 years ago. Since
then, they have learned that it protects the cell surface and sends
information about the cell surface to the nucleus. That information
will be used to design tumor vaccines and make better diagnostic
tests for pancreatic cancer. Plans already are underway on a clinical
trial of an immunotherapy protocol that induces the patient’s immune
system to recognize or attack the pancreatic cancer tumor – just as if
it was a foreign invader.
Watson’s father, George Watson Sr., had prostate and lung cancer,
but there is no known history of pancreatic cancer in his family.
After the diagnosis, Watson and his wife, Kathleen, decided to
seek treatment eight hours from home at UNMC’s hospital partner,
The Nebraska Medical Center.
“You have to get to a place that deals with pancreatic cancer,” he
said. “We’re fortunate here in Nebraska that we have a place.”
Jean Grem, M.D., a nationally known expert in gastrointestinal
malignancies, explores novel therapeutic approaches in both colon
and pancreatic cancer. She has developed a clinical trial that uses
a patient’s molecular profile to determine the best drug therapy for
metastatic colorectal cancer.
Plans are underway for a clinical trial to determine whether there
is an advantage to using the peptide inhibitor of N-cadherin to reduce
Aaron Sasson, M.D.
Surinder Batra, Ph.D.
the growth and spread of tumors and the incidence of metastasis. UNMC researchers
have evidence that expression of N-cadherin by human cancer cells results in tumors
that are highly aggressive. The peptide inhibitor, however, has reduced the severity of
tumors in mice, said UNMC researcher Keith Johnson, Ph.D., who works on the project
with Peggy Wheelock, Ph.D., and Dr. Grem.
Another clinical trial will study the effects of a telomerase inhibitor at three levels: in
cultured pancreatic cancer cells, in mice bearing pancreatic tumors and in patients with
advanced pancreatic cancer.
In cancer cells, an enzyme called telomerase prevents the protective caps at the end
of chromosomes, or telomeres, from shortening, which, in normal cells, naturally occurs
as we age. Once telomeres get too short, a healthy human cell stops dividing. Cancer
cells are immortal, said UNMC researcher Michel Ouellette, Ph.D., because they tend to
express telomerase, which prevents the shortening process and allows malignant cells
to grow out of control. Researchers hope the telomerase inhibitor limits the lifespan of
cancer cells and blocks the regrowth of residual disease after conventional therapy.
That’s the type of news patients like Watson want to hear.
Cancer treatments forced Watson – for the first time in 33 years – to miss this past
summer’s student excursion to London. During his career, he has taken more than 800
Chadron State College students abroad on international study programs.
“The trips give students a different perspective of life in general,” he said.
Cancer does the same.
“The diagnosis changes the reality of your life almost immediately,” Watson said. “I
have tried to take the outlook that cancer should not alter my life plans, but it does make
you more aware of the things that are important and the things that are peripheral.”
Whipple procedure gives hope to people with pancreatic cancer
George Watson was fortunate, in that, his cancer
had not spread beyond the pancreas.
That silver lining gave him the only chance for
a cure.
“The gold standard is to have the Whipple
procedure, if possible,” said the father of three.
Only 15 to 20 percent of pancreatic cancer
patients are eligible for surgery and, of those, only 15
to 20 percent live five years, said Aaron Sasson, M.D.,
associate professor of general surgery at UNMC, and
chief of GI surgical oncology.
Prior to surgery, Watson underwent an intensive
treatment regiment to shrink the tumor that sat
near an artery. The regiment included three months
of chemotherapy and radiation therapy under the
guidance of Jean Grem, M.D., and Chi Lin, M.D.
On July 8, Dr. Sasson surgically removed the rest
of the growth in a Whipple operation.
Dr. Sasson and his team (Drs. Quan Ly and
Chandrakanth Are) are specialists with advanced
training in the management of pancreas and
hepatobiliary malignancies.
His team takes an intensive approach to surgery,
often removing blood vessels that surround the
pancreas in order to eradicate the tumor. “Surgery can
be quite complicated and last five to seven hours,” Dr.
Sasson said.
In the Whipple operation, the head of the pancreas,
a portion of the bile duct, the gallbladder and the small
intestine is removed. A portion of the stomach also may
be removed. Then, the remaining pancreas, bile duct and
intestine are sutured back into the intestine.
To ensure the best outcome, the American
Cancer Society recommends the Whipple operation
be performed in experienced centers, such as The
Nebraska Medical Center, that do a high volume of
these complex surgical procedures. Dr. Sasson and his
team perform more than 50 pancreas operations each
year, the majority being Whipples.
The death rate is significantly lower in hospitals
that perform a high volume of these procedures, Dr.
Sasson said.
“Everything, so far, is good,” Watson said, later
during a four-week cycle of chemotherapy. “The
prognosis is only as good as the next test.”
UNMC
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25
Clinical researcher co-authors
largest study on HIV drugs
Susan Swindells, M.D., diagnosed common illnesses and
injuries in an indigent, city-run clinic in Columbus, Ohio, when
HIV first emerged in the early 1980s.
“Patients started to turn up with symptoms we didn’t know
about and there was no one to ask,” she said. “At that time, if you
treated three people, you became an expert.”
Thousands of patients later, Dr. Swindells is now an
internationally renowned expert in human immunodeficiency
virus, or HIV, and co-author of the largest study ever conducted to
evaluate commonly used HIV drugs.
The study, which was led by researchers at the University of
Pittsburgh School of Medicine and published in the New England
Journal of Medicine this past summer, confirmed that one of the
most frequently prescribed triple-drug combinations for initial HIV
infection is the most effective for suppressing HIV, but that a twodrug regimen is comparable.
“The study showed that the triple-drug therapy currently
preferred by clinicians is indeed the most effective treatment
for HIV disease. It also is the simplest treatment regimen as all
three drugs can be given once a day as one pill, compared to
the two-drug regimen that requires seven pills a day. For those
with prescription insurance, this means only one copayment
each month,” said Dr. Swindells, the Terry K. Watanabe Professor
of Internal Medicine in the section of infectious diseases and
medical director of the UNMC HIV Clinic.
Although, the one-a-day, three-drug regimen is preferred,
it doesn’t work with all patients, Dr. Swindells said, including
pregnant women and individuals with viral resistance.
The study focused in part on nucleoside reverse transcriptase
inhibitors (NRTIs), which are one of the first class of HIV drugs
approved by the U.S. Food and Drug Administration. Although
effective and commonly prescribed, NRTIs can produce severe
side effects in some patients.
The study, which included 753 participants at 55 centers,
found that the popular three-drug combination of efavirenz plus
NRTI therapy was more effective at achieving and maintaining
reduction of the virus than another commonly prescribed drug
combination of lopinavir-ritonavir plus NRTI.
Interestingly, a two-drug combination of lopinavir-ritonavir plus
efavirenz had a similar level of effectiveness as each of the tripledrug regimens that contained NRTIs.
The study was conducted as part of the AIDS Clinical Trials
Group (ACTG) – the largest HIV clinical trials organization in the
With many patients, the goal
is to get them to function as
normal as possible
26
fall 2008
under the
microscope
by Karen Burbach
world – with funding from the National Institute of Allergy and
Infectious Diseases.
Dr. Swindells, whose main research interests are in
opportunistic infections, is chairwoman of ACTG’s Optimization of
Co-Infection and Co-Morbidity Management Committee.
The Manchester, England native also is involved with an
international research study to determine how best to treat HIV
and tuberculosis.
Unlike some health care workers who looked the other way,
Dr. Swindells embraced the challenges posed by HIV in the
1980s. “When you’re the clinic of last resort it’s difficult to say ‘go
somewhere else’ because there’s nowhere else to go,” she said.
In 2007, the UNMC HIV Clinic served 926 people, including
126 new cases. “We still see a steady trickle of new people – even
in 2008 when we know how not to get HIV,” she said.
But, unlike the early days, there is greater hope for
today’s patients.
“I tell my patients that HIV is a serious, chronic disease similar
to diabetes in that you have to take care of yourself, eat right, take
your medicine and go to the doctor,” she said. “You may develop
some complications, but the chances of living to 60 are good.”
who are we?
In 2000, a group of individuals formed a not-for-profit organization called
Nebraskans for Research (NFR). The group wanted to serve as a positive voice in
support of medical research in Nebraska.
In 2007, philanthropist, Richard Holland helped form Nebraska Coalition for
Lifesaving Cures (NCLC). This new organization was made up of business,
education, and community leaders who shared the same goals as Nebraskans for
Research. The two organizations joined and took the name Nebraska Coalition for
Lifesaving Cures.
what do we do?
We concentrate on two key areas: education and public advocacy. For the past eight
years we’ve worked to support the efforts and accomplishments of Nebraska-based
medical researchers, science educators and young collegiate scientists. In particular,
we have advocated for stem cell research, therapies and cures in Nebraska.
Under its new name, Nebraska Coalition for Lifesaving Cures continues to advocate
awareness across the state for the accomplishments of Nebraska-based medical
research and the improvement in people’s lives that research provides. Stem
cell research, a relatively new breakthrough, holds the promise of providing
treatments and cures for many diseases – including diabetes, Parkinson’s and
spinal cord injuries – that alone, affect thousands of Nebraskans.
how can you help?
We invite you to join our Coalition to help support and
protect lifesaving research and cures in Nebraska. Joining
will cost you nothing – but it could help save the life
of someone you love.
To join Just fill out the form attached and
return the self-addressed post card.
If you would prefer, go online to
www.NebraskaCures.com.
research today for healthier tomorrows.
8401 West Dodge Road • Suite 111 • Omaha, NE 68114 • 402.390.2461 • www.NebraskaCures.com
discover
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