Pinpointing the genes involved in human brain cancer can be like looking for a needle in a haystack, and sometimes the needle you find may not be the right one. By comparing human and canine genomes, researchers at North Carolina State University have discovered that a gene commonly believed to be involved in meningiomas---tumors that affect the meninges, or thin covering, of the human brain and account for one out of four adult brain tumors---may not be as key for tumor formation as previously thought, and they've narrowed the search for the real culprit.

Meningiomas are intracranial tumors, meaning that they do not grow within brain tissue itself, but in the space between the brain and the skull. In humans, they are associated with genetic defects of large segments of chromosomes, which makes isolating the specific genes involved extremely difficult. Humans suffering from meningioma frequently lose one copy of almost the entire length of human chromosome 22. This chromosome is made of almost 50 million base pairs of DNA that code for more than 500 genes.

"The dog has been man's best friend for centuries, and now the genome of the dog could well be man's next best friend," says Dr. Matthew Breen, professor of genomics at NC State.

"With so much genetic material to consider, one can see why figuring out which genes play a key role in meningiomas is extremely difficult," says Dr. Breen, a scientist with the Department of Molecular Biomedical Sciences in the College of Veterinary Medicine (CVM).

Dr. Breen’s laboratory is part of the NC State Center for Comparative Medicine and Translational Research. "By looking at tumors seen in both humans and dogs we have a simple way to narrow the search: we compare the affected areas of a human chromosome with related areas on dog chromosomes,” says Dr. Breen. “This works because dogs and humans are genetically similar and both get the same kinds of cancers. While we share much of our genetic material, the DNA of a dog is organized differently to our own and this makes it possible to isolate smaller 'shared' regions of genetic data rather than looking at an entire chromosome."

Dr. Breen, CVM colleagues Dr. Rachael Thomas and veterinary neurologist Dr. Natasha Olby, along with researchers from the University of California-Davis and the Wellcome Trust Sanger Institute in Cambridge, UK collaborated on the project, sharing samples of canine meningiomas for research. Their results were published in the Journal of Neurooncology.

Previous researchers had pinpointed a particular tumor-suppressing gene on human chromosome 22, known as NF2, as a possible contributor to meningioma. They believed that the deletion of NF2, with its tumor suppressing abilities, could trigger tumor growth.

In looking at genetic changes across the whole genome, Dr. Breen's team compared human chromosome 22 to its canine counterpart. In dogs, the region shared with 22 is "split up" across three separate dog chromosomes - numbers 10, 26 and 27- with the NF2 gene appearing on dog chromosome 26. The researchers discovered that in dogs with meningioma, chromosome 26, and hence NF2, was rarely affected, casting doubt on this gene as playing a significant role in the disease. Instead, dogs with meningioma frequently showed loss of parts of dog chromosome 27. This led the researchers to focus on the portion of human chromosome 22 that corresponds to canine chromosome 27.

"Now, instead of looking at 50 million base pairs that contain several hundred genes, we can focus on the portion of human chromosome 22 that is evolutionarily conserved with dog chromosome 27," Dr. Breen says. "By looking at dog and human meningiomas together we reduce the amount of searching we need to do 50-fold. It's the old needle/haystack dilemma, except that using information from dog and human tumors allows us to concentrate our search on the two percent of the haystack that actually contains the needle, and not spend time and resources on the other 98 percent."

Dr. Breen also noticed that the other chromosome involved for canines that suffer from meningioma is dog chromosome 17, which correlates with part of human chromosome 1. Defects of this chromosome are involved in almost 70 percent of human meningioma cases and are associated with a poor patient outcome. He hopes that he can use this correlation to further narrow the search for specific genes involved with the disease.

In addition the team looked also at gliomas, another kind of brain tumor, and have shown common genetic features shared between human and canine tumors that are now under further investigation.

"The data support that dog and human tumors are very similar at the genetic level, so both species will benefit from this research," Dr. Breen says. "It's proof of the 'One Medicine' concept---the idea that human and animal health relies on a common pool of medical and scientific knowledge and is supported by overlapping technologies and discoveries."

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The Center for Comparative Medicine and Translational Research is a community of more than 100 scientists from five NC State University colleges. These investigators are involved in collaborative studies with government, private, and other academic researchers to advance the knowledge and practical applications that improve the health of animals and humans.

North Carolina State University’s College of Veterinary Medicine (CVM) is participating in a national clinical trial evaluating a new drug to treat canine idiopathic epilepsy—a chronic condition affecting some four million dogs that is characterized by recurring seizures for which an underlying cause has not been identified.

The largest clinical trial of its kind, the blinded study is sponsored by a major animal health pharmaceutical company and is regulated by the Food and Drug Administration. Hundreds of dogs at multiple investigator sites across the country are participating in the study, which will help build a body of evidence-based research that may lead to new insights into canine idiopathic epilepsy and its treatment.

“We are excited to take part in this study which may offer additional treatment options to pets with epilepsy,” says Dr. Karen Munana, associate professor of neurology.“We are constantly trying to research the causes, diagnostic options, and treatments for epilepsy in dogs. Epilepsy is one disease that can impact the human-animal bond to a huge extent.”

Breeds with evidence of genetic predisposition to seizures include beagles, Belgian Tervurens, British Alsatians, collies, dachshunds, golden retrievers, keeshonden, Labrador retrievers, vizslas, German shepherd dogs, and Bernese mountain dogs. Most epileptic dogs suffer their first seizure between the age of one and five years, and male dogs slightly outnumber females in most studies.

Qualifying canine patients must be at least four months old, not previously treated with anti-seizure medication, weigh at least 11 pounds, have no previous history of seizure clusters, and not be pregnant. Candidates must be seen by the clinical investigator within seven days of the most recent seizure. Dogs that meet the initial eligibility criteria receive free medical evaluations and diagnostic tests. Dogs that are enrolled in the treatment phase of the study receive free medication (no placebo) and monthly exams as well as a CT scan or MRI if over five years of age.

Owners of participating dogs are eligible to have funds credited to their accounts at their referring veterinary hospitals. The medication given to participants may or may not help their seizures. As with all medications, there are risks and benefits, all of which will be discussed with dog owners prior to enrollment. A consumer web site has been created to help answer dog owner questions at www.HelpForDogsWithSeizures.com .

Veterinarians receive financial rewards for referring qualified dogs for screening, and additional rewards if the dogs are enrolled into treatment. Veterinarians may call 888-598-7125, ext. 208 for additional information.

To learn more about epilepsy research at the NC State CVM visit: http://cvm.ncsu.edu/epilepsyresearch

The Canine Spinal Cord Injury Program at North Carolina State University's Veterinary Teaching Hospital is evaluating the efficacy of a drug being developed to improve hind limb function in chronically paralyzed dogs.

The drug, a novel potassium channel antagonist or blocker, showed promise in a preliminary trial in dogs with spinal cord injuries. The clinical trial is funded by NeuroMetrix, Inc. of Waltham, MA.

“Acute spinal cord injuries are a common problem in dogs and due to the poor regenerative capacity of the central nervous system, severely injured dogs make an incomplete recovery and can be left with permanent hind limb paralysis,” says Dr. Natasha Olby, Associate Professor of Neurology who is the study’s principle investigator. “In spite of the lack of recovery, these dogs may have intact, if dysfunctional, neural tissue at the level of the injury. We are interested in trying to restore function to this tissue.”

Axons (nerve processes) normally conduct impulses up and down the spinal cord at rapid rates to maintain communication between the brain and the rest of the body. This is made possible by the presence of a fatty insulating sheath called myelin. Severe spinal cord injuries cause destruction of these axons, resulting in paralysis. However, even after severe spinal cord injury dogs can be left with some intact but demyelinated axons extending across the injured area. The loss of myelin results in a failure to conduct impulses. Blockade of potassium channels on these exposed axons can restore conduction, with the potential for improving hind limb function.

A drug called 4-aminopyridine (4-AP) has been shown to improve function in this way, and a sustained release version is presently under review by the Food and Drug Administration to improve walking ability in people with Multiple Sclerosis. Unfortunately it can cause side effects such as anxiety, tremors, and seizures. The drug to be used in this study is a derivative of 4-AP and appears to have the same beneficial effect without the side effects.
 

The study will compare the efficacy of 4-AP with the derivative (T-BOC) and a placebo. In phase 1, participants will be hospitalized for a week while the optimal dose of both drugs is determined. Dogs with a positive response will participate in phase 2, which lasts 10 weeks. During this time the owner will administer a drug three times a day and neither owners nor investigators will know the identity of the drug treatment. Participants will be assessed and video taped walking at the Veterinary Teaching Hospital on a weekly basis.

Participating dogs must have suffered an acute thoracolumbar spinal cord injury at least six months previously that resulted in permanent inability to use the hind limbs and be free from any urinary tract infection. All costs associated with hospitalization, assessment, and drugs will be covered by the trial at no cost to the owner.

For more information, contact Dr. Natasha Olby at 919.513.7235 or e-mail ivddstudy@lists.ncsu.edu.

February is National Pet Dental Health Month and owners are reminded that a pet’s bad breath could signify a potentially serious dental or oral disease that could pose a health risk to the animal’s internal organs.
 
The American Veterinary Dental Society (AVDS), in fact, reports that 80% of dogs and 70% of cats have some form of oral or dental disease by age three. According to Dr. William Krug, who directs the dentistry service in the Veterinary Teaching Hospital at North Carolina State University's College of Veterinary Medicine, preventative health care does not have to be complicated.

“An early oral exam by a veterinarian is important to properly diagnose gum and dental disease,” Dr. Krug says. “Good oral health is an important component of an animal’s overall well-being. Oral disease can begin simply with bacteria and plaque on a tooth surface near the gum line and progress into a condition that can cause tooth decay, bleeding gums, tooth loss, potentially even damage to the heart and other internal organs.”

The signs of possible gum and dental issues include: bad breath; loose teeth or teeth that are discolored or covered in tartar; abnormal drooling, dropping food from the mouth or swallowing food whole; bleeding from the mouth; sensitivity in the mouth area; and loss of appetite or other changes in eating or chewing habits.

Trouble begins when food particles and bacteria form plaque and tartar, which can lead to gingivitis and periodontal disease. Periodontal disease, in turn, leads to tooth decay, bad breath, bleeding gums, and tooth loss. Further complications arise when the bacteria that cause periodontal disease travel into a pet's bloodstream, possibly resulting in damage to the heart, liver, kidneys and lungs.

Small breed dogs can develop severe problems with periodontal disease because of crowding, and it can lead to extreme discomfort and even problems like a broken jaw from the progressive loss of bone. Cats can develop marked inflammation called stomatitis, which can be painful enough to make them stop eating.

“There is discomfort associated with generalized periodontal disease,” says Dr. Krug. "If your pet is having oral discomfort, it’s likely that periodontal disease is present. Without regular dental cleanings by a veterinarian and daily preventive maintenance, the disease is almost guaranteed to progress.”

At the minimum, Dr. Krug suggests annual visits to the veterinarian for an anesthetized dental scale/ polish, a thorough oral examination, and dental radiographs if recommended. “If owners can brush their pet's teeth on a daily basis,” he says, “then they are taking huge strides towards slowing the progress of the periodontal degeneration.”

One word of warning: never use human toothpaste to brush your pet’s teeth. It can make the animal sick. Special foods, dental chews, rawhide, dental bones, and other healthy products can help keep teeth white and free of disease.

In addition to the AVDS, other organizations formally involved in promoting pet dental health include the American Veterinary Medical Association (AVMA), Academy of Veterinary Dentistry, American Veterinary Dental College, Academy of Veterinary Dental Technicians, Veterinary Oral Health Council, and Hill’s Pet Nutrition, Inc.

The American Veterinary Medical Association offers details on dental health care.

Dogs suffering from lymphoma are now able to receive the same medical treatment as their human counterparts through a new bone marrow transplant procedure offered by the Veterinary Teaching Hospital at North Carolina State University’s College of Veterinary Medicine.

NC State’s CVM is the first veterinary program in the nation to offer canine bone marrow transplants in a clinical setting. See NC State video.

The relatively new procedure involves the use of Leukophoresis machines—the same equipment used in human medicine—that are designed to harvest healthy stem cells from the peripheral blood. The machines are used in conjunction with drug therapy to harvest stem cells that have left the patient's bone marrow and entered the bloodstream.

Harvested cancer-free cells are then reintroduced into the patient after total body radiation is used to kill residual cancer cells left in the body. This treatment is called peripheral blood stem cell transplantation.

“Canine lymphoma is one of the most common types of cancer in dogs,” says Dr. Steven Suter, assistant professor of oncology. “While the survival rate with current treatments is extremely low—about 0 to 2 percent—the cure rate for dogs that have received a bone marrow transplant is at least 30 percent. We see from human medicine that peripheral blood stem cell transplantation, in conjunction with chemotherapy, has raised human survival rates considerably.”

The harvesting procedure itself takes six hours and the patient remains in the hospital for two weeks following the procedure. The bone marrow transplant process is completely painless for dogs, although the dogs do experience some GI distress, manifested mainly as diarrhea, from the total body radiation.
 

“This is not a new technology, it’s just a new application of an existing technology” says Dr. Suter. “Doctors have been treating human patients with bone marrow transplantation for many years, and there have been canine patient transplants performed in a research setting for about 20 years, but it’s never been feasible as a standard therapy until now.”

The canine bone marrow transplant unit has attracted international interest.

See Fox News video report.

See Reuters News Agency story.