Homes for Animal Heroes partnership to augment robust adoption program at MU

The University of Missouri has a robust adoption program for animals involved in research; since 2007, 394 dogs and 294 cats have been adopted at Mizzou. Recently, the Office of Research announced that in an effort to expand its adoption program, it has partnered with Homes for Animal Heroes (HAH), a national program dedicated to placing retired research animals in loving homes.

“Homes for Animal Heroes is a program of the National Animal Interest Alliance that helps establish and expand animal adoption programs at research institutions and facilities such as Mizzou,” said Jeff Henegar, director of animal care and quality assurance at MU. “We’re excited about partnering with Homes for Animal Heroes and look forward to helping place even more of our animals in loving homes.”

These animals have helped researchers to discover key factors in a variety of human and companion animal conditions, including cancer, joint and musculoskeletal disorders, heritable genetic disorders, neurodegenerative diseases and muscular degenerative conditions. In many cases, dogs are the final step to testing lifesaving therapies and diagnostics needed for human clinical trials.

“Animal research on the MU campus, and throughout the country, has led to discoveries that have saved the lives of both humans and animals,” said Mark McIntosh, MU interim vice chancellor for research, graduate studies and economic development. “MU researchers take the utmost care of their research animals, follow all federal and state laws, and must go through a rigorous approval process before beginning their studies. It’s through these adoption programs that we can recognize the contributions these animals make and help place them with loving families.”

Through the HAH project, several foster caregivers have been approved to prepare research animals for adoption. These foster families have an opportunity to raise and socialize their foster dogs while evaluating them for permanent placement with the families that are right for them.

“Our foster team took care of five dogs earlier this year,” Henegar said. “We were able to find them homes in late April, and all reports are that our dogs are making wonderful pets in their new homes.

Once an animal has been placed in a foster home, adoption applications are evaluated by both the HAH regional coordinator and the foster caregiver to ensure potential adopters are a good fit for the animal. Additional information regarding the adoption process may be found at http://animalheroes.naiaonline.org/giving-homes/adoption-process/.

For information about possible adoptions, contact Pat Wiese, the Missouri HAH regional coordinator, at (971) 212-7490, or pat.wiese@naiaonline.org.

Story Contact: Jeff Sossamon, sossamonj@missouri.edu, 573-882-3346

Protein testing could aid clinicians in the proper diagnosis and treatment of the disease

In 2016, more than 181,000 new cases of prostate cancer were reported in the U.S., according to the American Cancer Society. The prostate-specific antigen (PSA) test is one of the earliest ways clinicians can detect prostate cancers in their patients. Sometimes, a high PSA level may be a sign of benign conditions such as inflammation; therefore, more reliable tests are under investigation to help urologists diagnose and treat the disease in an aging population. Now, researchers at the University of Missouri have explored how a specific protein’s status may allow clinicians to better identify prostate cancer progression while helping them to make rational decisions in treating the disease.

“Our research is focused on finding genetic biomarkers that help identify prostate cancer patients at risk for more aggressive diseases as well as candidates who may have successful drug treatment or response,” said Senthil Kumar the assistant director of the Comparative Oncology, Radiology and Epigenetics Laboratory (COREL) at the MU College of Veterinary Medicine and the principal investigator of the study.

The team identified that the testis-specific Y-like protein (TSPYL5) varied between normal patients and tumor tissues with different Gleason scores (which can range from 2-10), a tool used by pathologists and urologists to categorize the stages of cancer. This score can categorize patients based on disease aggressiveness, helping to define subsequent treatment options.

The multidisciplinary team, including members from the MU School of Medicine, collected human prostate cancer samples at various stages of the disease as described by the Gleason score. The researchers discovered that TSPYL5 was present in the tissues with Gleason score of 7, but was diminished or absent in some patients with Gleason score of 7 and above, which could predict a more aggressive course of prostate cancer progression. Moreover, they identified that the presence of TSPYL5 could facilitate better drug response as tested in the prostate carcinoma cells.

“TSPYL5 testing could become one of the tools in our fight against prostate cancer,” Kumar said. “The anticipation is that we can use this biomarker for patients before they undergo any unnecessary and invasive surgeries or drug therapy plans.”

Kumar mentioned that this study needs to be conducted in large patient cohorts to further validate its potential for clinical translation. Studies along this line are in progress, Kumar added.

The study was published in February 2017 issue of BMC Cancer. The interdisciplinary team included Jeffrey N. Bryan, associate professor of  veterinary oncology; James Amos-Landgraf, assistant professor of veterinary pathobiology in the MU College of Veterinary Medicine; Magda Esebua, associate professor of pathology and anatomical sciences and director of cytopathology in the MU School of Medicine; and Tanner J. May, a veterinary student at Mizzou. Funding was provided in part by an award from the Jay Dix Challenge to Cure prostate cancer fund from the Ellis Fischel Cancer Center at MU.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Story Contact(s):
Jeff Sossamon, sossamonj@missouri.edu, 573-882-3346

The rate of American men with prostate cancer saw a surge in the 1990s following the development of the prostate-specific antigen test. While the spike may have seemed alarming, there is no evidence that there was an increase in the number of men developing prostate cancer; rather the PSA test allowed doctors to diagnose the disease earlier and more accurately.

In 2005, Jeffrey N. Bryan, DVM, MS, PhD, DACVIM (Oncology), had recently completed a residency in medical oncology and was working as a research assistant professor at the University of Missouri College of Veterinary Medicine. To further examine the role of dogs as models for human disease, Bryan investigated whether there was any correlation between the rate of prostate cancer diagnoses in dogs and that of people.

“Following the attention on prostate cancer of the late 1990s, the veterinary profession became more aware of the disease in dogs,” Bryan said. “It was interesting to look at that parallel.”

Bryan, now an associate professor at MU, focused on whether there was an association between castration and the risk of prostate cancer development. To gather the data needed to investigate his theory, he turned to the Veterinary Medical Database (VMDB). The VMDB allowed him to examine the medical records of more than 2,000 dogs.

William Priester, DVM, MPH, of the National Institutes of Health National Cancer Institute started the VMDB in 1964. The original goal was to track cancer occurrences among domestic animals seen at schools and colleges of veterinary medicine in the United States and Canada. Michigan State University was the first institution to submit data, which at the time was manually re-entered onto punch cards and stored on the computer system of the era.

The University of Missouri was the next veterinary program to join the effort in 1965, with an additional 27 programs joining during subsequent years. Member institutions contributed information about all species of animals treated in their hospitals for all diseases and conditions. Information gathered included the age, sex, location, symptoms, treatments and outcomes of the animal patients.

In 1975 with Priester about to retire, a consortium of schools met and formed the Association of Veterinary Medical Program Participants to administer the database. Allen Hahn, a professor of Veterinary Medicine and Surgery at the University of Missouri College of Veterinary Medicine (CVM), who had been involved with the VMDB since its inception, was elected president and began the work of finding a new home for the growing volume of veterinary medical data.

The VMDB was transferred from the NIH to Cornell University in New York. In 1987 the database was moved to Purdue University in Indiana, and in 2006, it was moved again, this time to servers housed at the University of Illinois at Urbana-Champaign. A budget cut and loss of office space at Illinois in 2014 prompted another relocation of the VMDB to the MU CVM, where it remains.

Wayde Shipman, DVM, who also possesses a master’s degree in computer information systems, of Virginia-Maryland College of Veterinary Medicine, was the association’s president at the time. He worked with Matthew Keeler, associate director of Information Technology at MU, to coordinate the transfer of data from the old servers to newer equipment that was available at the CVM.

“The old servers were at risk of failing so we moved the data to more stable equipment available here at MU.” Keeler said. “We have plans to get everything on the most current-generation hardware and operating systems this summer. Other than the ones in our hospital and diagnostic lab information systems, VMDB is the largest database we administer in the college.”

MU CVM Associate Teaching Professor Loren Schultz, DVM, is serving as the president of the association for a two-year term. Hahn, now an emeritus professor at the MU CVM, serves as the program director.

Since the database was moved to MU, the existing interface has been refined. Lingxue Wu, an MU graduate student working in the office of the director of informatics, developed software to automate online inquiries for case information. Previously, requests for information had to be managed by an individual.

Schultz said his goals as association president are to expand the number of universities with veterinary colleges submitting case information and develop software to collect that data so that submission of information can also be expedited. There are currently about a dozen veterinary hospitals still involved with the VMDB.

“The problem now is submitting information is not automated,” Schultz said. “Someone has to collect it and code it. We want to make that easier so it’s seamless, which will encourage more veterinary hospitals to come on board.”

The information collected to date is actually divided between two databases: The older coding version is in Standard Nomenclature of Veterinary Medicine (SNVDO) and the newer Systemized Nomenclature of Medicine (SNOMED). The two databases now comprise records from 30 institutions on 3.5 million patients and 7.8 million hospital visits. The records are searchable for free to member institutions whose faculty are conducting research.

Researchers seeking canine candidates for a pilot study testing drugs to treat the wasting disease often associated with cancer

According to the National Cancer Institute, nearly one-third of cancer deaths can be attributed to a wasting syndrome known as cachexia. Cachexia, an indicator of the advanced stages of disease, is a debilitating disorder that causes loss of appetite, lean body mass and can lead to multi-organ failure. Now, researchers at the University of Missouri in partnership with Tensive Controls, Inc. have developed a drug that could reverse cachexia. The team currently is seeking canine candidates for a pilot study to test the new drug.

According to the National Cancer Institute, nearly one-third of cancer deaths can be attributed to a wasting syndrome known as cachexia. Cachexia, an indicator of the advanced stages of disease, is a debilitating disorder that causes loss of appetite, lean body mass and can lead to multi-organ failure. Now, researchers at the University of Missouri in partnership with Tensive Controls, Inc. have developed a drug that could reverse cachexia. The team currently is seeking canine candidates for a pilot study to test the new drug.

Promising New Drug Development Could Help Treat Cachexia from MU News Bureau on Vimeo.

This video is available for broadcast quality download and re-use. For more information, contact Nathan Hurst: hurstn@missouri.edu

“The goal of this drug trial is to extend and improve the quality of life of cancer patients who are suffering from cachexia,” said Sandra Bechtel, associate professor of medical oncology at the MU Veterinary Health Center and principal investigator for the drug clinical trial. “The clinical trial is targeting a disease that significantly decreases quality of life. We are working to improve end-stage quality of life for our veterinary patients with the hopes of translating the improvements to human patients.”

Cachexia is caused by inflammatory cytokines, or small proteins that when released have an effect on the behavior of the cells around them. Certain cytokines in the brain cause the body to be hyperactive, decreasing appetite and causing weight loss in individuals with cachexia.

Kenneth A. Gruber, principal investigator at the MU Dalton Cardiovascular Research Center and president and founder of Tensive Controls, Inc., and his team have developed a drug that is able to cross the blood brain barrier, a protective barrier that typically prevents drugs, toxins or microbes from entering the brain, and inhibits overstimulation of the melanocortin system. The drug is administered via a subcutaneous, below the skin, injection.

“Preliminary results of the trial are promising,” said Gruber, who also holds an appointment as a professor of pharmacology and physiology in the MU School of Medicine. “Three dogs have already received the drug therapy and have gained an average of 7.5 percent of their body weight back over a 28-day trial. Dogs who have taken the drug for longer periods of time have improved to ideal body condition.”

The clinical trial is taking place at the MU Small Animal Hospital and is the first site to offer the drug as part of a clinical trial to patients. The trial is currently enrolling dogs for treatment. To inquire about enrolling a dog, call (573) 882-7821 and ask to speak to Deb Tate or Sandra Bechtel or email Deb Tate at tated@missouri.edu or Sandra Bechtel at bechtels@missouri.edu.

The early-stage results of this research are promising. If additional studies are successful within the next few years, MU and Tensive Controls officials will request authority from the federal government to begin human drug development (this is commonly referred to as the “investigative new drug” status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for cancer cachexia in people.

The startup company associated with this research, Tensive Controls, Inc., highlights the university’s impact on the state’s economic development efforts, including commercialization of research conducted at Mizzou, workforce development and job growth, quality of life improvements for residents, and attracting corporations and businesses to the state. During the past five years, companies commercializing MU technologies have secured hundreds of millions of dollars in investments and grants to advance their commercialization efforts. In 2016, the Office of Technology Management and Industry Relations reported that Mizzou received $14.9 million in revenue from more than 40 technology licenses.

Story Contact(s):
Jeff Sossamon, sossamonj@missouri.edu, 573-882-3346

Mutant mice aren’t just a plot device for science fiction or apocalyptic disaster tales. The value of genetically engineered mice to scientific research is immeasurable. Since 1901, nearly every Nobel Prize in medicine has been awarded for work that is heavily dependent on data from research animals – most of them mice. According to the Foundation for Biomedical Research, 95 percent of all laboratory animals are mice.

The importance of selectively bred research mice and the dramatic growth of genetically modified mouse strains led the National Institutes of Health (NIH) to establish the Mutant Mouse Resource and Research Center (MMRRC) in 1999 to serve the scientific community. The MMRRC is a consortium of four centers, one of which is located at the University of Missouri.

“Understanding the biology of mutant rodents is really our expertise,” says James Amos-Landgraf, PhD, assistant professor of veterinary pathobiology. “With the presences of the MMRRC along with its partner center, the Rat Resource and Research Center (RRRC), we have a very strong rodent biology background.  Moreover with the MU Metagenomics Center here as well, we are really at the forefront of understanding the effects of genetics and the microbiota — complex microbial communities that live in and on many parts of the body — on health and disease,” Amos-Landgraf stated.

*****

The MMRRC became necessary after developments during the past 20 years allowed researchers to create custom-made mice by making specific, intentional changes to the DNA sequence of a gene in mouse embryonic stem cells in order to research specific conditions. The mouse genome contains more than 23,000 protein-encoding genes, and researchers have produced thousands of genetically modified mice that differ in terms of which gene has been manipulated. Typically, each type has a different gene that has been knocked out, or deactivated.

The Center for the Genetics of Host Defense is a prolific producer of mice with many different mutations and phenotypes. Located at the University of Texas Southwestern Medical Center in Dallas, the center is commonly known as the Beutler lab, after its director Bruce Beutler, MD, a prominent immunologist and geneticist. Beutler shared the 2011 Nobel Prize in Physiology or Medicine for discoveries he made using mutant mice.

The staff at the Beutler lab has produced more than 3,550 mutant strains, and counting. The Beutler lab and its collection, however, are not affiliated with the MMRRC.

“We had a few of Beutler’s lines coming in to the MMRRC and we realized that he was doing something much bigger – much bigger than any mouse center had pursued,” Amos-Landgraf said.

“Our director, Craig Franklin, had approached him several years ago about trying to get this entire collection,” Amos-Landgraf said. “We had received a few of his lines, and we have some of the same interests in immunology, understanding cancer, and so forth. At the time, Dr. Beutler was interested in trying to maintain and distribute animals himself. But, he soon realized it was too big of a job to generate animals and do the distribution. That wasn’t the focus of their mission; they just wanted researchers around the world to have access to live animals to study.”

As a cost saving measure, all of the Beutler mice are cryopreserved as sperm samples and brought back to life through artificial reproduction techniques like in vitro fertilization.

“MU ended up nurturing a relationship with the Beutler lab and was assigned most of these strains,” said Franklin, DVM, PhD, DACLAM, professor of veterinary pathobiology. “Subsequently, Joe Waterman, our project manager, and Jim Amos-Landgraf, one of our co-investigators, worked tirelessly to find a way to obtain the whole collection and get it here in good order.”

“I had met up with Bruce at a mouse meeting and had said that we were really interested in trying to get this all together and keep it as one collection, so the resource wasn’t lost,” Amos-Landgraf said. “That’s where Joe came in and facilitated all of that.”

*****

MMRRC & RRRC Project Manager Joe Waterman served as MU’s boots on the ground for the operation.

“Once we got the go-ahead to bring the collection here, I worked with Dr. Beutler’s group to put together a list of strains,” Waterman recalled. “And then, we started working with our informatics group to transfer all the data; we’re talking about genetic data for more than 3,000 lines.”

Compatibility issues were almost immediate and impossible to ignore.

“We had to find a way to get the data from their system into our system,” Waterman said. “That took a while, even with IT guys from both groups working on it. There were even some communications trending toward our need to manually enter all the information. That would have been problematic. Finally, the IT guys figured out a way to make it work.”

“After we got all the data figured out, it just became a matter of getting them transported,” according to Waterman. “We’re talking approximately 3,000 strains, and each strain has a half-dozen or so straws of sperm, so we were dealing with nearly 20 thousand straws.”

“Getting them here was a challenge,” Amos-Landgraf interjected. “All of the strains are stored in liquid nitrogen, so it wasn’t a simple task.”

Liquid nitrogen temperatures range from minus 346 to minus 321 degrees Fahrenheit; its boiling temperature is minus 320 degrees. The substance presents a freezing hazard to humans. The material can also act as an asphyxiant. Small amounts of liquid can evaporate into very large volumes of gas, which can simply displace the oxygen in air to levels below that required to support life. Heat leak, and the resulting vaporization, is always present.

And Waterman was heading to hot, sunny Texas the week before the Fourth of July.

“I went down to Dallas to help get the materials organized and to arrange all of these samples,” Waterman said. “I spent a week in Texas working on this. It was a lot of work because we had so many samples to organize. Their cryopreservation structure — or, freezer organization — is different than ours. We had to adapt ours to theirs. We were very meticulous in getting it all organized.

“Then, we had to get those lines up here,” Waterman continued. “That was kind of a big deal. We hired a transportation company to send a truck capable of transporting up to 20,000 sperm straws in liquid nitrogen for us, and we shipped 2,931 strain samples from Dallas to our lab.”

*****

A comprehensive collection of the Beutler lines now resides inside MU’s Discovery Ridge facility. The MMRRC considers the lines to be one of its major collections.

Beutler still resides in Dallas, continuing his research in immunology and genetics in his lab at the University of Texas Southwestern Medical Center.

”He is a really nice guy; very easy going.” Waterman said. “I met with him about some of the nuts-and-bolts of the move, and he was very accommodating.”

“He’s a true visionary,” Amos-Landgraf observed. “I think it required a lot of bold foresight and enterprise to make the big investment he made. The Beutler lines are unique: 3,000 lines, they all carry multiple mutations, and they’ve all been sequenced to identify the mutations in the genome.”

“The reason why that’s really so important, or why that’s fundamentally different than all other mouse collections, is that when you think about humans, we all have lots of different variants in our genomes — that’s why we’re all different. No two people, except for twins, are genetically identical.

“So, the genetics and the genetic variation between people are really important to understand,” Amos-Landgraf said. “Understanding how variants — not necessarily mutations, just variations of a certain gene — can influence whether or not you get a disease. They may influence the disease process only very slightly, or only under certain conditions, but that can make all the difference. These lines are on the forefront of the effort to understand precision medicine. In other words, how multiple mutations interact or how very subtle variations in a gene can affect the phenotype of disease. That’s one way we are trying to understand personalized medicine. Here at Mizzou we can look at these mice to gain a better understanding of why certain people get diseases like cancer. This makes Mizzou truly a unique research institution.”