OREGON STATE UNIVERSITY

heath and nutrition

Richard van Breemen named director of Linus Pauling Institute at Oregon State University

CORVALLIS, Ore. – Oregon State University has named Richard van Breemen as the director of the university’s Linus Pauling Institute.

Van Breemen, professor of pharmacy at the University of Illinois at Chicago, will succeed Balz Frei as director and endowed chair of the institute, which studies the role of vitamins and other micronutrients in enhancing health and preventing disease.

Van Breemen characterized his new role as director of the Linus Pauling Institute as a “dream job.”

“Richard brings the prestige and accomplishments we were looking for in a new director,” said Cynthia Sagers, vice president for research at OSU. “He runs a National Institutes of Health-funded center for botanical dietary supplement research and is someone who makes things happen. He is very collaborative and people here already know his work. Richard feels a real passion for the work we do here at OSU and at the Linus Pauling Institute in particular.”

Van Breemen has a Ph.D. in pharmacology from Johns Hopkins University and was a post-doctoral scholar at Johns Hopkins in mass spectrometry. His undergraduate degree in chemistry is from Oberlin College.

His research includes clinical trials regarding prostate cancer prevention, and the safety and efficacy of botanical dietary supplements used by women.

At the University of Illinois at Chicago, where he has worked since 1994, van Breemen is the founding academic director of the Mass Spectrometry, Metabolomics and Proteomics Facility for the university’s Research Resources Center. He is also the director of the Botanical Center for Dietary Supplements Research, which has NIH funding through 2020 and has been continually funded since 1999.

From 1986 to 1993, van Breemen was a faculty member at North Carolina State, where he founded and directed the Mass Spectrometry Laboratory for Biotechnology Research.

Linus Pauling, who died in 1994 at age 93, was an Oregon State alumnus and is the only person to win two unshared Nobel Prizes – for chemistry in 1954 and for peace in 1962. A chemistry professor at California Institute of Technology, he founded what would become the Linus Pauling Institute in 1973.

Pauling bequeathed his vast scientific archives to OSU, and in 1996 the institute moved from Palo Alto, Calif., to Oregon State. The following year, Frei became director and endowed chair, a position he held until his retirement in June 2016.

Van Breemen met Pauling shortly before his death when the Nobel laureate spoke at a symposium at North Carolina State.

“Of course I had followed his work with dietary supplements for years, and I also got to know Balz upon visits to Oregon State,” van Breemen said. “I have visited several times and gotten to know the investigators and other faculty and have always known it to be a wonderful place to live and work. OSU and the Linus Pauling Institute offer a wealth of infrastructure and support that is unparalleled. The institute can help the work I have been doing be even more productive and make a bigger imprint and footprint on society.”

Van Breemen will start Jan. 1, 2018. Fred Stevens, professor of medicinal chemistry in the Oregon State College of Pharmacy, will continue as the interim director until then.

Van Breemen’s appointment at OSU will also be in the College of Pharmacy. 

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Richard van Breemen

Vitamin E-deficient embryos are cognitively impaired even after diet improves

CORVALLIS, Ore. – Zebrafish deficient in vitamin E produce offspring beset by behavioral impairment and metabolic problems, new research at Oregon State University shows.

The findings are important because the neurological development of zebrafish is similar to that of humans, and nutrition surveys indicate roughly 95 percent of women in the U.S. have inadequate intakes of this critical micronutrient.

The problem may be exacerbated in women of child-bearing age who avoid high-fat foods and may not have a diet rich in oils, nuts and seeds, which are among the foods with the highest levels of vitamin E, an antioxidant necessary for normal embryonic development in vertebrates. 

Corresponding author Maret Traber and collaborators at OSU compared offspring from fish on vitamin E-deficient diets – the E-minus group – with those on vitamin E-adequate diets, the E-plus fish.

The E-minus embryos had more deformities and greater incidence of death as well as an altered DNA methylation status through five days after fertilization; five days is the time it takes for a fertilized egg to become a swimming zebrafish.

For the next seven days, all of the normal-looking fish, irrespective of diet history, were fed a vitamin E-adequate diet.

Both groups grew normally and showed similar DNA methylation, but the E-minus fish failed to learn and were afraid. They also continued to have metabolic defects and indications of mitochondrial damage.

Because insufficient vitamin E reached the E-minus embryos’ brains, those brains continued to lack choline and glucose and simply did not develop correctly, said Traber, a professor in the OSU College of Public Health and Human Sciences, and Ava Helen Pauling Professor in the Linus Pauling Institute.

“They managed to get through the critical period to get the brain formed, but they were stupid and didn’t learn and didn’t respond right,” Traber said. “They had so much oxidative damage they essentially had a screwed-up metabolism. These outcomes suggest embryonic vitamin E deficiency in zebrafish causes lasting impairments that aren’t resolved via later dietary vitamin E supplementation.

“What that means for people is that many people are walking around with inadequate intakes, and how is their metabolism being affected and especially the brain, which is highly polyunsaturated and has specific mechanisms for retaining vitamin E? It takes awhile to get vitamin E into the brain to protect it, and this has me concerned about teenage girls who eat inadequate diets and get pregnant.”

Traber said a lack of vitamin E causes a chain reaction that dramatically changes cell metabolism.

“It’s the secondary ripples of having inadequate vitamin E that are really causing the problems, and it takes a fair amount of time to correct all of those things that go wrong,” she said. “It’s very frightening is what it really comes down to.”

Traber’s collaborators included OSU colleagues Melissa McDougall, Jaewoo Choi, Lisa Truong and Robert Tanguay.

Findings were recently published in Free Radical Biology and Medicine. The National Institutes of Health and the National Institute of Environmental Health Sciences supported this research.

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Maret Traber, 541-737-7977
maret.traber@oregonstate.edu

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Participants sought for study on family dogs and physical activity for kids with disabilities

CORVALLIS, Ore. – Oregon State University researchers are recruiting children with disabilities and their family dogs for a research study that will test a new intervention to see if pairing the dog and the child can help the child become more physically active.

The project is led by Megan MacDonald of OSU’s College of Public Health and Human Sciences and Monique Udell of OSU’s College of Agricultural Sciences. The researchers recently received a two-year, $375,000 grant from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development to support the project.

Children with disabilities spend less time participating in physical activity compared to their peers and are considered a health disparity group, meaning they generally face more health concerns than their peers. And physical activity tends to drop among all children around age 12. The goal of the study is to see if the partnership with the family dog leads to improvements in children’s physical activity levels, which in turn could lead to other health improvements.

“We need to find creative ways to engage kids in physical activity,” MacDonald said. “And beyond physical activity, animal companionship can have a significant impact on health and well-being.” 

The new study builds on the researchers’ earlier work exploring how a family dog might serve as a partner to help a child with disabilities become more active. In a recent case study of one 10-year-old boy with cerebral palsy and his family’s dog, the researchers found the intervention program led to a wide range of improvements for the child, including physical activity as well as motor skills, quality of life and human-animal interactions. They also found that the dog’s behavior and performance on cognitive and physical tasks improved alongside the child’s.

The new intervention is aimed at children with disabilities who are 10 to 16 years old and have a family dog that also could participate in the study. The children will learn how to train their dog in new behaviors with the “Do As I Do” method, which uses positive reinforcement. “Do As I Do” is similar to the game “Simon Says,” in which the dog follows the lead of the child.

“It’s really about the child and the dog being active together as a team,” MacDonald said. “The program also could help the relationship between the child and the dog grow.”

Families will come to OSU for one hour daily for two weeks during the study, which is expected to begin later this summer. There is some flexibility to the schedule depending on families’ needs. The children also will have homework such as walking the dog each day at home. Not all families selected for the study will participate in the “Do as I Do” training this year but all families will have a chance to participate in the training over the course of the two-year study.

“Participating children need to be able to follow basic instructions but beyond that, we want to be as inclusive as possible,” MacDonald said. “Parents who have questions about whether their child and their pet are a good fit for the study should feel free to give me a call so we can discuss their individual needs.”

Families interested in learning more about the study or participating in it should contact MacDonald at 541-737-3273 or Megan.MacDonald@oregonstate.edu

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New gonorrhea treatment targets enzyme needed for respiration

CORVALLIS, Ore. – Researchers have identified a possible new treatment for gonorrhea, using a peptide that thwarts the infection-causing bacterium by interfering with an enzyme the microbe needs to respirate.

The findings are especially important since Neisseria gonorrhoeae is considered a “superbug” due to its resistance to all classes of antibiotics available for treating infections.

Gonorrhea, a sexually transmitted disease whose numbers grow by 78 million new cases worldwide each year, is highly damaging to reproductive and neonatal health if untreated or improperly treated.

It can lead to endometritis, pelvic inflammatory disease, ectopic pregnancy, epididymitis and infertility. And babies born to infected mothers are at increased risk of blindness.

“The infections very often are silent,” said Oregon State University researcher Aleksandra Sikora. “Up to 50 percent of infected women don’t have symptoms, but those asymptomatic cases can still lead to some very severe consequences for the patient’s reproductive health, miscarriage or premature delivery.”

The need for better antibiotic therapy, and a vaccine, is pressing. N. gonorrhoeae strains resistant to the last effective treatment options have emerged, and failures in treatment are occurring.

Researchers led by Sikora, an associate professor in the OSU College of Pharmacy, have identified a new therapy target, an enzyme known as AniA. The bacteria need the surface-exposed enzyme to respirate without oxygen, or anaerobically, which is their preferred method of respiration in the biofilms of the genitourinary tract.

A biofilm is a group of one or more types of microorganisms that grow on a wet surface, such as dental plaque on teeth.

Sikora and her team identified a peptide – multiple amino acids linked in a chain – that inhibits the AniA enzyme’s nitrite reductase activity. That in turn damages the bacteria’s ability to grow in the oxygen-poor biofilm environment.

“Bacteria in biofilms display increased resistance to antimicrobials,” Sikora said. “The enzyme is only necessary for cell viability when these bacteria grow under anaerobic conditions, including when they grow in the biofilm. Most antibiotics target essential cell functions; this one doesn’t. It’s only at a certain stage of growth that the bacteria are affected, which means the development of resistance won’t be as fast.”

Through a technique known as biopanning, OSU scientists and collaborators at the University of Kentucky found 29 unique peptides that bound with the targeted enzyme. One of them, C7-3, was identified as most promising for inhibiting the protein’s interaction with nitrite, necessary for anaerobic respiration.

“Imagine this research approach as having a pond with a lot of fish, and you’re using the protein as the bait,” Sikora said. “The peptides bind with the protein, and you go through multiple rounds to identify the peptides that have the strongest binding ability. You start with a billion peptides and end up with one that strongly inhibits the enzyme and ultimately kills the bacteria.”

Findings were recently published in Antimicrobial Agents and Chemotherapy, and Sikora has applied for a provisional patent. The National Institutes of Health and the Medical Research Foundation of Oregon partially supported this research.

The research team included five undergraduate students, four of whom were from Oregon State University.

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Neisseria gonorrhoeae cells

Neisseria gonorrhoeae cells

Patients nearing end of life receptive to having cholesterol medicine ‘deprescribed’

PORTLAND, Ore. – New research suggests patients nearing the end of their lives because of a “life-limiting illness” such as cancer or heart disease may not feel medically abandoned if their doctor wants to take them off the statins that control their cholesterol.

The findings are important because little is known about the best way to manage chronic medications for patients with a life-limiting condition, including data regarding patient attitudes toward “deprescribing.”

Deprescribing medications has the potential to improve outcomes in some cases, but patient concerns over being taken off statin drugs have not been reported.

Statins are a class of drugs that work by blocking the liver enzyme responsible for cholesterol production, thus reducing the buildup of plaque on artery walls that can lead to a stroke or heart attack. The drugs are highly effective but not without side effects for some patients, the most common being muscle pain that ranges from mild to severe.

Jon Furuno, an associate professor in of the Oregon State University/Oregon Health & Science University College of Pharmacy, joined collaborators from around the United States in a study that included nearly 300 patients whose average age was 72 and whose life expectancy was one to 12 months. The patients were participants in a clinical trial to determine the safety and benefit of discontinuing statin therapy.

Fifty-eight percent were cancer patients, 8 percent had cardiovascular disease, and 30 percent had some other life-limiting diagnosis. The patients gave responses to a nine-item questionnaire designed to quantify potential benefits and concerns associated with discontinuing statins.

“We know these patients are on a lot of medications,” Furuno said. “There’s a lot of concern that patients will feel like doctors are giving up on them if they start to discontinue some of their medications, that there’s something comforting about continuing to take their medications, and this gives us some indication of what patients feel about the risks and benefits of deprescribing.”

Less than 5 percent of study participants expressed concern that deprescribing statins indicated being abandoned by their doctor, and many could see benefits of going off their statin, including spending less on medications (63 percent); the potential for being able to stop taking other meds also (34 percent); and having a better overall quality of life (25 percent).

Cardiovascular patients were particularly likely to envision quality-of-life benefits arising from statin discontinuation.

“Hopefully this will help inform prescribers who might be tentative to address this topic with their patients,” Furuno said. “As a patient’s prognosis changes and we think they have a relatively short lifespan left, it really requires risk/benefit re-examination of everything we’re doing for them, medications and everything else. There may still be benefits, but have the benefits changed or has the risk/benefit ratio changed?

“A lot of our work is trying to better inform the evidence base for medication use at the end of life, and patient perceptions are really important in trying to honor what the patient wants and what the family wants.”

Furuno notes that the primary limitation of this study is that all of the questionnaire respondents had also agreed to participate in a trial that involved possibly being chosen at random to go off statins – thus, they were all at least somewhat open to the idea of deprescribing.

“So this group is likely not completely representative of all people, because they might be foreseeing some benefits to stopping that other people hadn’t considered,” he said. “But while we don’t want to overlook that limitation, given the lack of information about patient perceptions regarding deprescribing, these data are important and useful as a stepping stone.”

The Palliative Care Research Cooperative Group, funded by the National Institute of Nursing Research, supported this study. Collaborators included researchers from the University of Massachusetts, the University of Colorado, Case Western Reserve University, Duke University, the University of Maryland, the University of California-San Francisco, Mayo Clinic, and Flatiron Health, a health care technology company.

Findings were recently published in the Journal of Palliative Medicine.

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New modified toy car designs offer children with disabilities more options

CORVALLIS, Ore. – Researchers at Oregon State University have developed two new modified toy car designs for children with disabilities in an effort to encourage them to further explore, play, and engage in physical and social activities.

The new cars were developed under the umbrella of the “Go Baby Go” program at OSU, which provides modified, ride-on toy cars to young children with disabilities so they can move around independently. Independent movement has been linked to a wide range of developmental benefits in young children. 

The sit-to-stand car is a modified version of the original Go Baby Go car, but encourages the child to stand up in order to activate the switch that makes the car move. The goal is to encourage the physical skills of pulling up to stand, bear weight and balance, while also fostering more interaction with peers.

The “Throw Baby Throw” car is a modified toy car that uses a toy pitching machine to throw foam balls. The goal is to provide a way for children who have upper extremity limits to participate in throwing, a fundamental motor skill, while also facilitating socialization. 

“Both of these devices are designed to encourage movement and social interaction, which are critical developmental skills for all young children,” said Sam Logan, an assistant professor of kinesiology in the College of Public Health and Human Sciences at OSU and leader of the university’s Go Baby Go program.

“Movement and socialization are very often combined early and continually as children develop.” 

The two new car designs were featured in a technical report published recently in the journal Frontiers in Robotics and AI. A study of a child using the sit-to-stand car also was recently published in the journal Pediatric Physical Therapy; researchers found the child was more engaged with peers when using the sit-to-stand car.

Modified toy cars are an inexpensive way to help toddlers with mobility issues get around, experts say. Power wheelchairs can be costly and typically aren’t available for children until they are older, and may not always be an option for children who are expected to eventually be able to walk. Toy cars and their modifications start at about $200, while motorized wheelchairs can run thousands of dollars. 

The sit-to-stand car was designed for children who may or are expected to walk eventually but their walking is delayed. In the study of the sit-to-stand car in use, researchers found that a child with disabilities spent about 10 percent more time engaging with his peers on the playground or in the gym at school when he used the sit-to-stand car, compared to using his forearm crutches.

“That’s exactly what you want to see,” Logan said. “This car gets you up and gets you moving. It’s also a way to introduce some fun around the practice of these skills that will help a child stand and walk on their own.” 

In developing the new car, researchers found the process takes just a few different steps than the original car. The “go” switch is located under the car’s seat, rather than on the steering wheel or elsewhere. Training others to modify cars for sit-to-stand would be fairly simple and could be done in a few hours in a workshop, Logan said.

The Throw Baby Throw car uses the same “go” technology as the original car, with the added element of the pitching machine, which is also activated by a switch that a child could press. 

“With the switch, kids with upper-extremity limits can throw the same as other kids,” Logan said. “The design is really about facilitating this interaction with other kids. You also need someone to catch, retrieve or dodge the balls being thrown.”

The engineering behind the throwing car is more complex and needs more refinement before the design could be shared more widely across the Go Baby Go network, Logan said. The throwing car also has not been studied in action. There is one car in use by clinicians in Portland now but the design is still considered a prototype, he said. 

The overarching goal of the new car designs is to find more ways to encourage children with disabilities to move, play and engage with their peers from a young age, Logan said.

“We encourage families, clinicians and teachers to embrace a ‘right device, right time, right place’ approach that takes into account each child’s specific needs and abilities,” he said. “Whatever typically-developing kids do should be the gold standard for all children, including those with disabilities.”

Co-authors of the technical report include Kathleen Bogart, William D. Smart, Brianna Goodwin, Samantha M. Ross, Michele Ann Catena, Austin A. Whitesell and Zachary J. Sefton of OSU; Heather Feldner of the University of Washington and Cole Galloway of the University of Delaware. The research was supported by the National Institutes of Health.

Co-authors of the study of the sit-to-stand car include Megan MacDonald and Haylee Winden of OSU; Feldner of UW; Galloway, Michele Lobo and Tracy Stoner of University of Delaware; and Melynda Schreiber of the University of Utah. The research was supported by the Unidel Foundation.

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Sam Logan, 541-737-3437, sam.logan@oregonstate.edu

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GoBabyGo at Oregon State

Throw Baby Throw car

Throw baby throw

Researcher Sam Logan

Sam Logan

Want to better comply with dietary guidelines, and save money? Cook dinner at home

CORVALLIS, Ore. – The best culinary paths to better health are not always paved with cash, new research shows, and cooking at home can provide the best bang-for-the-buck nutritionally as well as  financially.

A study by Arpita Tiwari, a health systems researcher at Oregon State University, and collaborators at the University of Washington confirms what many mothers and grandmothers have said for decades: that habitually eating dinner at home means a better diet and lower food expenditures compared with regularly dining out.

“Traditionally better socioeconomic status – more money – means healthier people,” said Tiwari, a graduate student at OSU's College of Public Health and Human Sciences. “That’s the trend. This research goes against that; it shows a resilience to that trend. It’s not spending more but how you spend that’s important. What you eat is important.”

“Cooking at home reduces that expenditure, and our research empirically quantifies that when we regularly eat dinner at home, our nutrition intake is better.”

Tiwari is quick to point out, though, that researchers understand the barriers to home-cooked meals.

“A mother who has two jobs and four children, even if she knows the value of home-cooked dinners, doesn’t have time to cook,” Tiwari said. “Government policy needs to be mindful of things like that when states create programs to help Medicaid populations achieve nutritional goals. Right now our system really does not allow for it. What can the government do about that? That’s what needs to be explored in the near future.”

The research involved more than 400 Seattle-area adults who were surveyed regarding a week’s worth of cooking and eating behaviors. Participants also provided various types of sociodemographic information, and their weekly food intake was graded using the Healthy Eating Index (HEI).

HEI scores range from 0 to 100, with higher scores indicating better diet quality. An index score over 81 indicates a “good” diet; 51 to 80 means “needs improvement”; and 50 or less is “poor.”

Households that cooked at home three times per week showed an average score of about 67 on the Healthy Eating Index; cooking at home six times per week resulted in an average score of around 74.

“Higher HEI scores are generally associated with higher socioeconomic status, education and income,” Tiwari said. “By contrast, cooking dinner at home depends more on the number of children at home. The study showed no association between income or education and eating at home or eating out.”

The findings also suggested that regularly eating home-cooked dinners, associated with diets lower in calories, sugar and fat, meant meeting more of the guidelines for a healthy diet as determined by the Department of Agriculture.

Eighty percent of U.S. residents fail to meet at least some of the federal dietary guidelines, the study notes, and about half the money spent on eating in the U.S. is on food not cooked at home. From the 1970s to the late 1990s, the percentage of home-cooked calories consumed fell from 82 to 68.

“HMOs should have ancillary programs to really encourage people to eat healthier,” Tiwari said. “It’s a benefit for insurance companies to get involved; eating is really the source of most of the issues that the insurance system has to deal with down the road.”

The National Institutes of Health supported this research. Findings were published in the American Journal of Preventive Medicine.

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Adolescents with frequent PE more fit, more informed about physical activity’s role in health

CORVALLIS, Ore. – Frequent, long-term instruction in physical education not only helps adolescents be more fit but also equips them with knowledge about how regular physical activity relates to good health, research at Oregon State University shows. 

The findings are important for several reasons. One is that regular physical education, which is on the decline nationwide, strongly correlated with students meeting the federal recommendation of at least 60 minutes per day of moderate to vigorous physical activity.

The results also showed more than one adolescent in five reported no physical education at all; nearly 40 percent of the students in the 459-person sample, whose ages ranged from 12 to 15, were obese or overweight; and only 26.8 percent met the federal government’s physical activity guidelines.

“Perhaps some were not meeting the guidelines because fewer than 35 percent actually knew what the guidelines were for their age group,” said study co-author Brad Cardinal, a professor in OSU’s School of Biological and Population Health Sciences and a nationally recognized expert on the benefits of exercise.

The guidelines call for an hour or more of physical activity at least five days a week.

The findings by OSU’s College of Public Health and Human Sciences indicate that a trend of decline in physical education mandates for middle-school students is detrimental to developing the knowledge, interests and skills that serve as a foundation for a lifelong healthy lifestyle.

Physical activity also has been shown to improve cognitive function and academic performance, Cardinal said.

“We have the physical activity guidelines for a reason, and they’re based on good science,” he said. “With only slightly more than one in four adolescents meeting the guidelines, today’s youth are being shortchanged in terms of their holistic development. They are not being prepared to live the proverbial good life.”

Cardinal notes that new guidelines will be released in 2018.

“Because of a growing propensity toward inactivity in daily life, such as increased media consumption and screen time, the guidelines very well may have to be ratcheted up to compensate,” Cardinal said.

Like physical education, participation in sports also correlated with more accurate student perceptions of the amount of physical activity necessary for good health, as well as better performance on a variety of muscular fitness-related tests.

“This underscores the importance of quality physical education in schools and the added value of sports participation,” Cardinal said. “The junior high/middle school years are a vulnerable and pivotal time in which students are typically required to take at least some physical education for at least part of the year, whereas after their freshman year in high school, most students aren’t required to take any. It’s a time when experiences in physical education and sports, whether positive or negative, can make or break whether an adolescent chooses to continue a physically active lifestyle.”

Cardinal points out that in Oregon, 2017 is supposed to represent the final year in a decade-long, statute-mandated ramp-up of physical education in public schools, but the reality is something different.

Portland Public Schools, he noted, just announced a cutback to 30 minutes of physical education every other week, whereas the law calls for 225 minutes per week for middle school students and 150 for elementary school students.

“In the federal Every Student Succeeds Act, physical education is a core subject, on par with language, math and science. Its status was elevated for a reason,” Cardinal said. “If you’re physically active, you’re going to be healthier and stronger and have fewer behavioral problems, and your cognitive function is going to be better.

“Physical education trumps sports in a head-to-head comparison of the two,” he added, “and when you have physical education plus sports, that’s when you have students who are the healthiest, fittest, strongest and most active.”

Findings were published in the American Journal of Health Promotion.

OSU alumnus Paul Loprinzi, now with the University of Mississippi, is the lead author, and the other co-authors are Marita Cardinal of Western Oregon University and Charles Corbin of Arizona State University.

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Brad Cardinal

New drug delivery system shows promise for fighting solid tumors

PORTLAND, Ore. – A new cancer-drug delivery system shows the ability to exploit the oxygen-poor areas of solid tumors that make the growths resistant to standard chemotherapy and radiation treatment.

Carcinomas that affect the breast, lung, prostate and colon are among the solid-tumor cancers, as are malignancies in the lymphatic system, known as lymphomas, and the much less common sarcomas that arise in connective tissue.

These solid masses often contain hypoxic regions, where the concentration of oxygen in the tissue is low. Hypoxic cancer cells grow slowly, and that makes them less susceptible to the drugs prescribed to kill or damage them.

Researchers at Oregon State University have found a way to turn the tables on those cells using a “prodrug” loaded into nanostructured platforms.

A prodrug is a pharmacologically inactive compound that the body metabolizes into an active drug, in this case the cancer drug vinblastine.

Provided with the prodrug vinblastine-N-oxide by research partners at Cascade Prodrug Inc. of Eugene, Ore., OSU scientists developed two different lipid-based platform formulations known as liposomes to carry the prodrug to the tumor’s hypoxic regions. There, the lack of oxygen triggers its metabolic conversion to vinblastine.

In both formulations – one with polyethylene glycol on its surface, one without – the prodrug proved both safe and much more effective against non-small cell lung cancer than when it was delivered without a liposome.

“One of the hallmarks of these solid tumors is their hypoxic regions,” said the study’s lead author, Adam Alani of the OSU College of Pharmacy. “One reason these cancers become very aggressive is the development of this hypoxia. Since the late 1990s, researchers have been trying to take advantage of the hypoxia. The tumor model we chose, lung cancer, is one of the very well established tumors and there’s a very strong hypoxia associated with that – as well as, lung cancer is one of these cancers that in its advanced stages, it’s a terminal disease, and there’s a need for new treatments.”

By itself, vinblastine-N-oxide had shown less than optimal efficacy in testing by Cascade Prodrug because of how fast the body clears it from the system – it has a half-life of less than half an hour.

“When it was tested in mice and dogs, it did not have a chance to assimilate in the cancer tissue to produce the desired pharmacological effect,” Alani said.

But the liposomes – both the “pegylated” one containing polyethylene glycol, and the non-pegylated one – increased the half-life dramatically: to 9.5 and 5.5 hours, respectively.

“The nano carriers performed much better than the prodrug itself,” Alani said. “We were able to literally cure the tumor.”

Alani’s research began with laboratory cultures and progressed to safety and efficacy testing in animals.

“We made sure the nanostructure platform worked properly against lung cancer in vitro, then looked at the safety of the formulation in healthy mice and looked at the maximum tolerated dose – the biggest dose you can use without producing side effects,” Alani said. “Then we determined how long the nano carriers could keep the drug in the blood compared to the drug without the nanostructures.”

When those data were “very encouraging,” Alani’s team assessed the efficacy of the formulations in mice that had tumors grafted into them.

Without any liposome, the drug showed some tumor suppression, but the mice that had received the drug alone had to be euthanized after 70 days because of tumors that were no longer being controlled.

Mice that had received the drug with one of the liposomes were healthy and tumor-free for the nearly 100-day run of the experiment.

“The formulations clearly performed better than the unformulated drug as well as much better than Cisplatin, the standard-of-care drug for this research,” Alani said. “Now we’re collaborating with Cascade Prodrug and the College of Veterinary Medicine to assess safety and efficacy in dog models, and trying to look at other tumors, like bladder cancer, associated with dogs.”

One goal, Alani said, is to develop a new treatment for cancer in dogs, and another is to look at dogs as a model for drug development – “to get data Cascade can use to move the process forward for approval for use in dogs, as well as preliminary data for a new drug application with the FDA,” Alani said.

The Oregon Nanoscience and Microtechnologies Institute supported this research. Findings were recently published in the Journal of Controlled Release.

Co-authors on the paper were Alani’s colleagues in the Department of Pharmaceutical Sciences, Vidhi Shah, Duc Nguyen and Adel Alfatease, and Shay Bracha of the OSU veterinary college’s Department of Clinical Sciences.

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Elevated blood pressure not a high mortality risk for elderly with weak grip

CORVALLIS, Ore. – A study of nearly 7,500 Americans age 65 or older suggests that elevated blood pressure is not related to high mortality risk among people in that age group with weak grip strength.

New research by Oregon State University builds on an earlier OSU study that showed the relationship between high blood pressure and risk of death is largely dependent on elders’ frailty status as measured by walking speed.

The findings are important because they suggest that treating high blood pressure in older patients should not follow a one-size-fits-all approach. When an older person is still functioning at a high level physically, high blood pressure indicates mortality risk; however, when the person is not physically robust, high blood pressure is not a marker for mortality risk.

“If people are very frail, they typically don’t respond well to anti-hypertensive therapy and they are not benefiting from having a low blood pressure,” said lead author Chenkai Wu, a graduate student in OSU’s College of Public Health and Human Sciences. “The research is basically saying older adults are not one single group, they’re very different in terms of their health status, and drugs may not have the same benefits for everyone. This is consistent with the idea of precision medicine, where you don’t just look at age, you look at other things like functional status.”

Measured in millimeters of mercury, blood pressure is the force of blood against the vessel walls. Systolic blood pressure, the higher number, is the force during a heartbeat, and diastolic refers to when the heart is at rest.

Most people’s diastolic blood pressure goes down with age. Systolic blood pressure, though, tends to rise, and high blood pressure – hypertension – can put extra strain on the heart and arteries, causing greater risk of heart attack and stroke.

But as Wu’s research suggests, an elderly patient’s level of physical functionality should be considered in determining whether anti-hypertensive therapy is warranted.

Grip strength, easily measured by an inexpensive device known as a dynamometer, is a common way to gauge functionality in the elderly. Another often-used measuring stick is walking speed.

Wu looked at data from 7,492 people age 65 or older who had taken part in the nationally representative Health and Retirement Study. Six years after being surveyed, 25 percent of those people had died.

The study showed that elevated systolic blood pressure (150 or greater) and diastolic blood pressure (90 or greater) correlated with a substantially higher likelihood of dying for those with normal grip strength, which is 26 kilograms or more for men and 16 kilograms or more for women.

“We did three analyses,” Wu said. “One was to look at gait speed to separate people into two groups, normal and slow. The second part was grip strength – weak grip and normal grip. Third, we looked at the combinations, and the strongest inverse association between high blood pressure and mortality was for slow walkers with weak grip strength.

“Both measures are markers of functional status, a multidimensional concept. Considering both might be better than considering each measure alone for identifying subgroups of elders for whom high blood pressure is potentially beneficial.”

OSU public health epidemiologist Michelle Odden, senior author on the study and the lead author on the earlier gait-speed research, explained how high blood pressure might actually help in some cases.

“As we age, our blood vessels lose elasticity and become stiff,” said Odden, an assistant professor in the College of Public Health and Human Sciences. “Higher blood pressure could be a compensatory mechanism to overcome this loss of vascular elasticity and keep fresh blood pumping to the brain and heart.

“And everyone ages differently – there is a profound difference between the physiological age of an 80-year-old man who golfs every day and someone who needs a walker to get around. So with fast walkers, high blood pressure may be more indicative of underlying disease and not just a symptom of the aging process.”

In addition to the connection with weak grip strength, Wu said there was a “very clear” inverse association between high blood pressure and mortality among those who weren’t physically able to finish the gait-speed test in the latest study, measured over a 98.5-inch walk.

Put another way, among those who couldn’t walk a little over 8 feet, high blood pressure was associated with less mortality risk.

“It’s a small group but not negligible – 6 percent – of people who were not able to complete the test,” he said. “Compared to grip strength, it’s a harder test to complete, an integration of a lot of physiological systems: balance, vision, lower-extremity muscle strength, etc.”

The National Institute on Aging supported this research. Findings were recently published in the Journal of the American Geriatrics Society.

Ellen Smit, associate professor of epidemiology in the College of Public Health and Human Sciences, served as a co-author.

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