Could additives in hot dogs affect incidence of colon cancer?

ScienceDaily (Oct. 25, 2011) — The addition of ascorbate (vitamin C) or its close relative, erythorbate, and the reduced amount of nitrite added in hot dogs, mandated in 1978, have been accompanied by a steep drop in the death rate from colon cancer, according to data presented at the 10th AACR International Conference on Frontiers in Cancer Prevention Research, held Oct. 22-25, 2011.

However, the incidence rate for colon cancer has apparently not changed much since 1978, according to 2011 data from the SEER Cancer Statistics Review from the National Cancer Institute.

"It was proposed that N-nitroso compounds in hot dogs and other processed meats can cause colon cancer," said Sidney S. Mirvish, Ph.D., professor emeritus at the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center in Omaha. "We found that the level of total apparent N-nitroso compounds in hot dog links prepared in our laboratory fell as increasing levels of sodium erythorbate were included in the hot dog links."

Mirvish and colleagues discussed the view that colon cancer was induced by components of the apparent nonvolatile N-nitroso compounds that occur in processed (nitrite-preserved) meat. Hence, Mirvish and colleagues investigated the effect of varying the erythorbate level on the N-nitroso compound content of hot dogs.

They found that the current level of erythorbate (500 milligrams per kilogram) added to hot dogs reduces the N-nitroso compounds to 2 nanomoles per gram compared with 180 nanomoles per gram when erythorbate was not used.

"When erythorbate was not added, 80 percent of the apparent N-nitroso compounds were found to be due to nitrosothiols, which are probably harmless, still leaving 40 nanomoles per gram that were attributed to possibly carcinogenic N-nitroso compounds," Mirvish said.

If the level of N-nitroso compounds was an important cause of colon cancer, "the drop in N-nitroso compound content caused by the mandated changes in processed meat should have been accompanied by a drop in the incidence of colon cancer," Mirvish said.

In fact, since the mandated changes were introduced 33 years ago, the death rate for colon cancer has dropped sharply. "This may have been due mostly to earlier detection and better treatment of this disease," Mirvish said.

Mirvish concluded that the role of hot dog-derived N-nitroso compounds in the causation of colon cancer remains unclear.

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Scientists aim to put a pox on dog cancer

ScienceDaily (Sep. 10, 2012) — Researchers report that myxoma -- a pox virus that afflicts rabbits but not humans, dogs or any other vertebrates so far studied -- infects several different types of canine cancer cells in cell culture while sparing healthy cells. The study adds to the evidence that viruses or modified viruses will emerge as relatively benign cancer treatments to complement or replace standard cancer therapies.

The new study, reported in the American Journal of Veterinary Research, is unique in that it focused on spontaneously occurring cancers in dogs. This allowed the researchers to avoid a common practice: testing viral therapies on mice or rats with induced human cancers. Such animals must be immunosuppressed to prevent their immune systems from rejecting the foreign tissue, complicating the results.

Treating cancers with viruses could offer several advantages over standard cancer therapies, said University of Illinois veterinarian and pathobiology professor Amy MacNeill, who led the new study. Many cancers have impaired anti-viral defenses, which allow viruses to target tumors while sparing healthy cells. And under the right conditions, infection with an oncolytic (cancer-killing) virus exterminates cancer cells and elicits an anti-cancer immune response without spurring a harmful inflammatory response, she said. Chemotherapy and radiation kill healthy cells along with cancer cells and radiation can cause abrupt cell death that spurs inflammation and pain, she said.

"Ideally, what would happen is the virus would get into a few cancer cells, cause cell death and then spread to the other tumor cells nearby," she said.

Recent studies have shown that oncolytic viral therapies can be used successfully in conjunction with traditional approaches, MacNeill said.

"There was a study in cats where they removed the tumor surgically and then they put a viral therapy in the area where the tumor had been removed," she said. The animals that received the viral therapy had significantly less regrowth of the cancer than those that weren't exposed to the virus after surgery.

"Other studies (1, 2, 3, 4) have shown that once you've eliminated a cancer with an oncolytic virus, if you re-challenge that animal with the same cancer cells, they don't develop tumors," MacNeill said. Viral infection of the cancer cells appears to train the immune system to better recognize the cancer, she said.

In the new study, the researchers wanted to see if spontaneously occurring cancers in dogs were responsive to infection with a virus that is not a pathogen in humans or dogs. They found that cancerous and healthy canine cells respond as human cells do to myxoma infection: The virus invades cancer cells and leaves healthy cells alone. The team also showed that a version of the myxoma virus with a single gene deleted was four times better at killing cancer cells than the unmodified virus. The deleted gene codes for a protein that hinders cell death in infected cells.

More preliminary tests are needed and researchers have many more years of tests and trials ahead, but if all goes well they will eventually test the virus or a modified version of the virus in dogs with cancer, MacNeill said.

"We wanted to make sure that the dog cells were like the human cells because we want to use these viruses not only to cure dogs of cancer but also to use the dogs as better models for humans with cancer," she said. "People are beginning to see the logic of this approach. These dogs have spontaneous tumors just like humans, they're living in the same environment as humans, they're exposed to the same carcinogens in the water if there are any and they sometimes even share our food."

She calls this approach a "win-win" for dogs and humans.

"This way we can test the therapy in dogs while at the same time treating them," she said. "Other researchers can take our results and use them to develop therapies for human patients."

The study team also included researchers from the University of Florida.

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Ashlee S. Urbasic, Stacy Hynes, Amy Somrak, Stacey Contakos, Masmudur M. Rahman, Jia Liu, Amy L. MacNeill. Oncolysis of canine tumor cells by myxoma virus lacking the serp2 gene. American Journal of Veterinary Research, 2012; 73 (8): 1252 DOI: 10.2460/ajvr.73.8.1252

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New genetic evidence confirms coyote migration route to Virginia and hybridization with wolves

ScienceDaily (Oct. 25, 2011) — Changes in North American ecosystems over the past 150 years have caused coyotes to move from their native habitats in the plains and southwestern deserts of North America to habitats throughout the United States. In a new study, published Oct. 17 in the Journal of Mammalogy, researchers from the Smithsonian Conservation Biology Institute's Center for Conservation and Evolutionary Genetics used DNA from coyote scat (feces) to trace the route that led some of the animals to colonize in Northern Virginia. The researchers also confirmed that, along the way, the coyotes interbred with the native Great Lakes wolves.

According to the study, coyotes migrated eastward via two main routes -- one that went through the northern United States, and one that went through the south. Using DNA samples, the researchers found that Virginian coyotes were most closely related to coyote populations in western New York and Pennsylvania. It appears the northern trekkers eventually encountered the Great Lakes wolves and interbred before converging again on the East Coast. They then gradually headed south along the Appalachian Mountains toward what is considered the Mid-Atlantic region, to an area centered around Virginia.

"The Mid-Atlantic region is a particularly interesting place because it appears to mark a convergence in northern and southern waves of coyote expansion," said Christine Bozarth, an SCBI research fellow and lead author on the paper. "I like to call it the Mid-Atlantic melting pot."

Bozarth and her colleagues collected scat samples in Northern Virginia from local coyote populations. They were then able to extract DNA from the intestinal cells in the scat and compare it to the DNA from preserved historic wolf specimens that had lived in the Great Lakes region before coyotes colonized the area. They shared some of the same genes, supporting the hybridization theory. Hybridization between canid species usually occurs when one species is rare. Those individuals may have trouble finding mates and therefore breed instead with closely related species.

"This does not mean that we have massive, wolf-like coyotes roaming around here in Virginia," Bozarth said. "Coyotes with wolf ancestry have differently shaped jaws, which may allow them to fill different ecological niches. They tend to hunt small prey and scavenge large game, so hybrid coyotes might be helpful in controlling the overly abundant deer population."

While coyote populations have been expanding, wolf populations have become endangered. Hybridization with coyotes is now a major threat to the recovery of wolves.

"For the past decade, our lab has developed and used noninvasive techniques to monitor and survey rare and endangered species in various regions of the world and in this study, we were able to show that noninvasive techniques can also be an effective tool for tracking the origins and movement patterns of this elusive canid," Jesús Maldonado, SCBI research geneticist and paper co-author. "The admixed coyotes have also been found further south, into North Carolina, which brings the hybridized coyote into the range of the critically endangered red wolf, further complicating the issue."

The study's authors from SCBI are Bozarth, Maldonado and Frank Hailer (now a postdoctoral researcher at the Biodiversity and Climate Research Center in Frankfurt, Germany). Bozarth is currently an assistant professor in the science, technology and business division at Northern Virginia Community College. The additional authors are Larry Rockwood and Cody Edwards from the department of environmental science and policy at George Mason University.

The Smithsonian Conservation Biology Institute plays a key role in the Smithsonian's global efforts to understand and conserve species and train future generations of conservationists. Headquartered in Front Royal, Va., SCBI facilitates and promotes research programs based at Front Royal, the National Zoo in Washington, D.C., and at field research stations and training sites worldwide.

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Christine A. Bozarth, Frank Hailer, Larry L. Rockwood, Cody W. Edwards, Jesús E. Maldonado. Coyote colonization of northern Virginia and admixture with Great Lakes wolves. Journal of Mammalogy, 2011; 92 (5): 1070 DOI: 10.1644/10-MAMM-A-223.1

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How motherhood behavior is influenced by alterations in brain function

ScienceDaily (Oct. 29, 2011) — Instinctive mothering behavior towards care of newborns has long been recognized as a phenomenon in humans and animals, but now research at the Hebrew University of Jerusalem has shown that motherhood is associated with the acquisition of a host of new behaviors that are driven, at least in part, by alterations in brain function.

The research, by Dr. Adi Mizrahi of the and Edmond and Lily Safra Center for Brain Sciences and the Silberman Institute of Life Sciences at the Hebrew University, has just been published in the journal Neuron. It provides insight into how neural changes integrating odors and sounds lie behind a mouse mother's ability to recognize and respond to distress calls from her pups.

"We know that distinct brain changes are linked with motherhood, but the impact of these changes on sensory processing and the emergence of maternal behaviors are largely unknown," explains Mizrahi. "In mice, olfactory and auditory cues play a major role in the communication between a mother and her pups. Therefore, we hypothesized that there may be some interaction between olfactory and auditory processing so that pup odors might modulate the way pup calls are processed in the mother's brain."

Dr. Mizrahi and his post-doctoral colleague Dr. Lior Cohen examined whether the primary auditory cortex, a brain region that is involved in the recognition of sounds, might serve as an early processing region for integration of pup odors and pup calls. The primary auditory cortex is known as a site that undergoes functional changes in response to sensory input from the environment.

In their study, the researchers exposed regular mice, mice that had experienced interaction with their pups, and lactating mother mice to pup odors, and then monitored both spontaneous and sound-evoked activity of neurons in the auditory cortex. The odors triggered dramatic changes in auditory processing only in the females that had interacted with pups, while the lactating mothers were the most sensitive to pup sounds. The olfactory-auditory integration appeared in lactating mothers shortly after they had given birth and had a particularly strong effect on the detection of pup distress calls.

Taken together, the findings suggest that motherhood is associated with a previously un-described form of multisensory processing in the auditory cortex.

"We have shown that motherhood is associated with a rapid and robust appearance of olfactory-auditory integration in the primary auditory cortex occurring along with stimulus-specific adaptation to pup distress calls," says Dr. Mizrahi. "These processes help to explain how changes in neocortical networks facilitate efficient detection of pups by their caring mothers."

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Lior Cohen, Gideon Rothschild, Adi Mizrahi. Multisensory Integration of Natural Odors and Sounds in the Auditory Cortex. Neuron, 2011; 72 (2): 357 DOI: 10.1016/j.neuron.2011.08.019

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Chromosomal 'breakpoints' linked to canine cancer

ScienceDaily (Nov. 3, 2011) — North Carolina State University researchers have uncovered evidence that evolutionary "breakpoints" on canine chromosomes are also associated with canine cancer. Mapping these "fragile" regions in dogs may also have implications for the discovery and treatment of human cancers.

When new species evolve, they leave genetic evidence behind in the form of "breakpoint regions." These regions are sites on the genome where chromosomes broke during speciation (when new species of dogs developed). Dr. Matthew Breen, professor of genomics at NC State, and graduate student Shannon Becker looked at the breakpoint regions that occurred when the canid (dog) species differentiated during evolution. They compared the genomes of several wild canine species with those of the domestic dog. By overlaying the genomes, they found shared breakpoints among 11 different canid species -- the so-called evolutionary breakpoints.

"The interesting thing about the breakpoint areas in the canid chromosome is that they are the same regions that we have shown to be associated with chromosome breaks in spontaneously occurring cancers," Breen says. "It is possible that the re-arrangement of chromosomes that occurred when these species diverged from one another created unstable regions on the chromosome, and that is why these regions are associated with cancer."

The researchers' results appear in Chromosome Research.

"As species evolve, genetic information encoded on chromosomes can be restructured -- resulting in closely related species having differently organized genomes," says Becker. "In some cases, species acquire extra chromosomes, called B chromosomes. We looked at these extra B chromosomes in three canid species and found that they harbor several cancer-associated genes. Our work adds to the growing evidence that there is an association between cancer-associated genomic instability and genomic rearrangement during speciation."

"The presence of clusters of cancer- associated genes on canid B chromosomes suggests that while previously though to be inert, these chromosomes may have played a role in sequestering excess copies of such genes that were generated during speciation," adds Breen. "We now need to determine whether these stored genes are active or inert -- that information could give us new tools in cancer detection and treatment."

The research was funded by the Morris Animal Foundation. The Department of Molecular Biomedical Sciences is part of NC State's College of Veterinary Medicine.

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Shannon E. Duke Becker, Rachael Thomas, Vladimir A. Trifonov, Robert K. Wayne, Alexander S. Graphodatsky, Matthew Breen. Anchoring the dog to its relatives reveals new evolutionary breakpoints across 11 species of the Canidae and provides new clues for the role of B chromosomes. Chromosome Research, 2011; 19 (6): 685 DOI: 10.1007/s10577-011-9233-4

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Wolf mange part of nature's cycle, ecologists say

ScienceDaily (Sep. 9, 2012) — Mange and viral diseases have a substantial, recurring impact on the health and size of reintroduced wolf packs living in Yellowstone National Park, according to ecologists.

Following the restoration of gray wolves to Yellowstone in 1996, researchers collected blood from the animals to monitor parasite-induced disease and death. They also tracked the wolves in each pack to follow their survival and allow additional data-gathering.

"Many invasive species flourish because they lack their native predators and pathogens, but in Yellowstone we restored a native predator to an ecosystem that had other canids present that were capable of sustaining a lot of infections in their absence," said Emily S. Almberg, graduate student in ecology, Penn State. "It's not terribly surprising that we were able to witness and confirm that there was a relatively short window in which the reintroduced wolves stayed disease-free."

The researchers found that within a year after the wolves were reintroduced to Yellowstone, 100 percent of the wolves tested had at least one infection, but mange did not infect wolves living in the park until 2007.

"We can look at the biology of the diseases and predict which ones will come in first," said Peter J. Hudson, Willaman Professor of Biology and director of the Huck Institutes of the Life Sciences, Penn State. "What was surprising was that so many diseases came in so fast, but those were the ones we expected to come in first. It wasn't really a sequence, they were almost there immediately. That's very interesting in itself. "

The diseases that infected the wolves quickly were all viral, including canine distemper and canine parvovirus -- both contractible through bodily secretions. Mange, however, is a skin infection, caused by scabies mites, that makes the wolves scratch and lose fur. An infected wolf can lose enough body heat in the winter to freeze to death. Mange is spread by direct contact with another mite-infected animal or by contact with the mites themselves, as they can survive away from a host for several days, depending on the temperature.

"Where did those diseases come from?" asked Hudson. "Most of them initially came from other canid species, like coyotes or foxes. Wolves are animals that disperse far and move around fast, and once the wolves were established the diseases were spread from pack to pack."

Almberg and Hudson tracked how quickly mange spread from pack to pack after the disease entered the population. The number of infected wolves in a pack did not affect the likelihood of a neighboring pack to contract mange, but distance was a factor -- for every six miles of distance between an infected pack and an uninfected pack, there was a 66 percent drop in risk for the uninfected pack. Some wolves and packs were not severely affected by mange, while other packs were decimated, the researchers report in the current issue of Philosophical Transactions of the Royal Society B.

In January 2007, Mollie's pack was the first in Yellowstone to show signs of mange infection. As of March 2011, they had recovered. The Druid pack, which had been one of the most stable and visible packs in the park, according to Almberg, started to show signs of mange in August 2009.

"It was in a very short amount of time that the majority of the animals [in Druid] became severely infected," Almberg said. "The majority of their hair was missing from their bodies and it hit them right in the middle of winter. The summer before it got really bad, we saw that many of the pups had mange."

The Druid pack was gone by the end of the winter in 2010.

The researchers note that the wolf population in Yellowstone experienced several phases -- from 1995 to 2003 the wolves experienced rapid growth, from 2003 to 2007 the number of wolves stabilized, and the most recent data from 2007 to 2010 shows a decline.

"We're down to extremely low levels of wolves right now, we're down to [similar numbers as] the early years of reintroduction," said Almberg. "So it doesn't look like it's going to be as large and as a stable a population as was maybe initially thought."

Also working on this research were Paul C. Cross, disease ecologist, Northern Rocky Mountain Science Center; Andrew P. Dobson, professor of ecology and evolutionary biology, Princeton University; and Douglas W. Smith, director, Yellowstone Wolf Project.

The research was supported through the U.S. Geological Survey/National Park Service Park-Oriented Biological Support (POBS); the Yellowstone Wolf Project of the National Park Service; and the National Institutes of Health, Research and Policy for Infectious Disease Dynamics (RAPIDD).

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E. S. Almberg, P. C. Cross, A. P. Dobson, D. W. Smith, P. J. Hudson. Parasite invasion following host reintroduction: a case study of Yellowstone's wolves. Philosophical Transactions of the Royal Society B: Biological Sciences, 2012; 367 (1604): 2840 DOI: 10.1098/rstb.2011.0369

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Scientists unlock the mystery surrounding a tale of shaggy dogs

ScienceDaily (Nov. 27, 2011) — Researchers from the University of York have produced the first clear evidence that textiles made by the indigenous population of the Pacific coast of North America contained dog hair.

In recent years, scientists have hotly debated whether textiles such as blankets and robes made by the skilful Coast Salish weavers before contact with Europeans were made of dog hair as oral histories have claimed.

Coast Salish oral tradition refers to a special dog which was bred locally until the mid 19th century for its woolly hair or fleece for use in the textile industry.

Using highly sensitive equipment at the University's Centre for Excellence in Mass Spectrometry, York researchers from BioArCh (Departments of Biology, Archaeology and Chemistry) analysed the protein composition of 11 textiles in different locations, representing 25 samples in total.

The samples were taken from artefacts in the Smithsonian's National Museum of Natural History and National Museum of the American Indian collections and included blankets, a sash and a robe of fur. Some of the textiles were collected during the American expeditions to the West Coast, including the Lewis and Clark (1803-1806) and Wilkes (1838-1842) expeditions. The samples dated mainly from early to mid 19th century.

Researchers found evidence of dog hair in the robe of fur and six of the woven textiles, primarily in a blend with goat hair.

However, the results published in the journal Antiquity, show there is no real proof of a preference for dog hair in high status fabrics and the researchers did not find any textiles made entirely of dog hair. Instead, researchers conclude that dog hair appears to have been used to supplement mountain goat hair, possibly as a bulking material.

Surprisingly too, the results also indicate that commercial sheep wool was also incorporated into textiles in the 19th century. Previous investigations had implied that sheep wool was not used in Salish weaving.

The research was led by Dr Caroline Solazzo, a Marie Curie Research Fellow from York's Department of Archaeology, and a former Postdoctoral Fellow at the Museum Conservation Institute at the Smithsonian Institution.

Dr Solazzo said: "Dogs have a long history of interaction with humans, from companionship to guarding and hunting; but raising dogs for fibre production was a unique cultural adaptation in the Pacific Northwest. It is perhaps the unusual strategy that has led some to doubt the use of dog wool.

"We found dog hair in all textiles produced before 1862, but it was absent from blankets woven in the late 19th century to early 20th century. Noticeably, dog hair is absent from all plain twill-woven ceremonial-type blankets, indicating a strong preference for mountain goat hair, in both aesthetic and technical aspects."

Bio-archaeologist Professor Matthew Collins, from York's Department of Archaeology, said: "Protein mass spectrometry is a useful new tool for the study of textiles, and indeed cultural artefacts composed of proteins, such as silk, wool, ivory, leather, bone and parchment, in which the original source of production is difficult to identify.

"Despite the minute quantities of fibres used, the analytical sensitivity of the instrumentation at York was able to reveal the use of dog hair in Salish weaving."

The Coast Salish peoples are indigenous to the Pacific Northwest coastal areas of northern Washington and southern British Columbia, and are particularly notable for their large, finely woven blankets. In pre-contact times, the blankets were important items and their gift and distribution were present in all aspects of social life. As well as having a functional use, they were important in ceremonies such as marriages and funerals.

Co-author Susan Heald, Senior Textile Conservator, from the Smithsonian's National Museum of the American Indian, said: "Salish weaving is undergoing a resurgence. With this revival it is crucial to have the use of dog hair in older blankets confirmed.

"The research at York has finally provided confirmation for the Coast Salish oral history of the use of dog hair. It appears that dog hair mixed with goat wool was used in every day textiles, with goat hair alone being used in ceremonial textiles."

The existence of a woolly dog is supported by historic accounts of 18th century European explorers. The dogs were reported to be corralled on small islands off the coast to prevent inter-breeding with short-haired village dogs. The dog disappeared less than 100 years after the first contact with Europeans.

Dr Solazzo said: "Based on our results, the description of textiles in museum collections as 'dog hair blankets' should be reconsidered; in no case did we find a textile made solely of this fibre. It may have been the case that pure dog hair blankets were once more common, but considered of lower value and consumed in use and lost."

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Russian and US veterinarians collaborate to solve mysterious wild tiger deaths

ScienceDaily (Oct. 3, 2011) — A team of Russian veterinary colleagues and health experts from the Wildlife Conservation Society's Bronx Zoo are collaborating to understand how distemper -- a virus afflicting domestic dogs and many wildlife species -- may be a growing threat to Siberian (Amur) tigers.

The team presented its results at the first-ever Russian symposium on wildlife diseases recently held in the Russian Far East city of Ussurisk. The symposium underscores the growing recognition of the importance of the health sciences to successful wildlife conservation efforts.

Working at WCS's Wildlife Health Center at the Bronx Zoo, Russian health experts and WCS pathologists used histology along with PCR and DNA sequencing to confirm and characterize the infection in two wild Siberian tigers from the Russian Far East. This diagnosis provides long-awaited genetic confirmation of the fact that distemper is impacting wild tigers, which WCS and Russian colleagues first documented in 2003.

The collaboration will enable conservationists to formulate health measures to counter this latest threat to the world's largest cat.

The participants in the partnership included: Drs. Irina Korotkova and Galina Ivanchuk from the Primorskaya State Agricultural Academy; Elena Lyubchenko, county veterinarian for Ussuriski County, Drs. Anastasia Vysokikh and Mikhail Alshinetskiy from the Moscow Zoo; and Drs. Denise McAloose and Tracie Seimon from WCS.

Last year a tigress "Galia" -- studied by WCS researchers for eight years in Sikhote-Alin Biosphere Reserve in the Russian Far East -- walked into the village of Terney. Galia displayed abnormal neurologic signs, seemingly unfazed by the new surrounding, appeared gaunt, and was searching for dogs as an easy meal. The tiger was shot by local police after several capture attempts failed. In November 2003, a similar event occurred when an otherwise healthy looking wild tigress walked into the village of Pokrovka in Khabarovski Krai. WCS staff working in the area immobilized the animal and worked with local Russian veterinarian Evgeny Slabe in treating the tiger, which later died in captivity. Samples for the diagnosis of distemper were collected only from these two animals.

Several other examples of tigers entering villages or stalling traffic on major roadways -- behavior possibly indicative of distemper -- have been reported in recent years.

"This exchange provides a foundation for elucidating potential disease threats to tigers in the Russian Far East," said Irina Korotkova of the Primorskaya Agricultural Academy. "Understanding the role of distemper in our wild Amur tiger population is vitally important."

Distemper is found worldwide in domestic dogs and has caused infection and death in wild species such as lynx and bobcats in Canada, Baikal seals in Russia, lions in the Serengeti ecosystem in Africa, and raccoons and the endangered black footed ferret in the United States.

"With all the threats facing Siberian tigers from poaching and habitat loss, relatively little research has been done on diseases that may afflict tigers," said Dale Miquelle, WCS Director of Russia Programs. "There are no records of tigers entering villages and behaving so abnormally before 2000, so this appears to be a new development and new threat. Understanding whether disease is a major source of mortality for Siberian tigers is crucial for future conservation efforts."

Anatoly Astafiev, Director of Sikhote-Alin Reserve, said, "We have seen a fall in tiger numbers within our reserve, so it is very important to know that at least one of the causes is a recognizable disease, something we may be able to address and potentially prevent."

Canine distemper is controlled in domestic dogs through vaccination. In Africa, massive vaccination campaigns of dogs in villages surrounding the Serengeti appear to have been effective in reducing the disease's impact on lions.

Dr. Denise McAloose, WCS's Chief Pathologist and leader of the investigation, said, "This is a great example of what international collaboration can achieve. Without our Russian associates there on the spot, knowing what samples to collect and how to preserve these specimens, samples would never have made it to our lab, and the cause of death would remain unknown. It's great that we're all here together to work on this issue as a team."

WCS is working with staff from the Primorskaya Agriculture Academy and other partners to establish a wildlife lab in Ussurisk to facilitate local diagnostic testing, although it will take several years until the lab is adequately funded and fully functional.

McAloose added: "Until then, there's still much to do including identifying the source of the disease."

It is still uncertain how tigers may have contracted the disease and whether it originated in another wild animal species or domestic dogs, both of which can act as reservoirs for the infection.

Latest reports suggest that fewer than 3,500 tigers remain in the wild; 1,000 are breeding females.

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For common toy breed dog windpipe issue, veterinarians use technology and precision

ScienceDaily (Oct. 5, 2011) — Jack, a 12-year-old Yorkshire terrier, was lethargic and gasping for air when he arrived at the University of Missouri Veterinary Hospital. His tongue and gums were a bluish-purple. But, just one day following an innovative procedure, Jack bounced back to his former youthful exuberance.

Jack was suffering from tracheal collapse. Tracheal collapse occurs when the cartilage comprising the c-shaped rings of the trachea collapse, leaving dogs to breathe through a trachea that resembles a narrowed or closed straw. Standard treatment involves medical management with lifestyle changes and drugs aimed at minimizing the consequences of a smaller airway. For many dogs, medical management ultimately ceases to work.

In Jack's case, MU veterinarians inserted an intra-luminal stent, like a tiny spring, within the trachea. Carol Reinero, associate professor of small animal internal medicine, performed the procedure on Jack, which required no incision.

"This condition is very common in toy breeds, but not all dogs with this condition have such severe symptoms," Reinero said. "We start with medical management, but because this is a degenerative disease, further measures are sometimes necessary. The procedure that Jack received is generally considered a last-ditch effort. It takes a great deal of planning and precision. But its success can be seen -- and heard -- almost immediately."

The life-giving treatment Jack received was performed at the MU Veterinary Medical Teaching Hospital, the only facility in Missouri known to offer the particular procedure that allowed Jack to breathe again so quickly. The MU College of Veterinary Medicine's success in the placement of these stents can be attributed to the teaching hospital's high-tech equipment and a full team of skilled veterinary medicine specialists, including board certified internists, anesthesiologists, radiologists and veterinary students.

"When Jack first came to us, he was wheezing and coughing, and we had to carry him around because of his condition," said Heather Wise, a fourth-year veterinary medical student. "At his follow up, we didn't even hear him coming down the hall for his appointment."

Jack's two-week follow-up examination showed remarkable results. The team found that his oral membranes had returned to a healthy pink color and his tracheal and lung sounds were normal. The radiographs show the tracheal areas once absent of air are now propped fully open with the stent.

"We didn't realize how serious his condition was, but it was a great relief to know that it could be treated," said Connie Miller, Jack's owner.

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Mushroom-derived compound lengthens survival in dogs with cancer, study suggests

ScienceDaily (Sep. 10, 2012) — Dogs with hemangiosarcoma that were treated with a compound derived from the Coriolus versicolor mushroom had the longest survival times ever reported for dogs with the disease. These promising findings offer hope that the compound may one day offer cancer patients -- human and canine alike -- a viable alternative or complementary treatment to traditional chemotherapies.

The study was conducted by two University of Pennsylvania School of Veterinary Medicine faculty. Dorothy Cimino Brown is professor and chair of the Department of Clinical Studies and director of the Veterinary Clinical Investigation Center. Jennifer Reetz is an attending radiologist in the Department of Clinical Studies. They published their findings in an open-access article in the journal Evidence-Based Complementary and Alternative Medicine.

The Coriolus versicolor mushroom, known commonly as the Yunzhi mushroom, has been used in traditional Chinese medicine for more than 2,000 years. The compound in the mushroom that is believed to have immune-boosting properties is polysaccharopeptide, or PSP. In the last two decades, some studies have suggested that PSP also has a tumor-fighting effect.

"There have been a series of studies looking at groups of people with cancer," Cimino Brown said. "The issue with those studies is that they weren't necessarily measuring what most people would think is the most clinically important result, which is, do people taking PSP live longer?"

To address this critical question, Cimino Brown and Reetz pursued a study in dogs with naturally occurring hemangiosarcoma, an aggressive, invasive cancer that arises from the blood cells and typically affects the spleen. It commonly strikes golden retrievers and German shepherds.

Fifteen dogs that had been diagnosed with hemangiosarcoma participated in the trial. Divided into three groups of five, each group received a different dose -- 25, 50 or 100 mg/kg/day -- of I'm-Yunity, a formulation of PSP that has been tested for consistency and good manufacturing processes.

The owners were instructed to give their dog capsules of I'm-Yunity, compounded by Penn pharmacists, daily. Each month, the owners brought their dogs to Penn's Ryan Veterinary Hospital for follow-up visits. There, the researchers took blood samples and conducted ultrasounds to determine the extent that tumors developed or grew and spread in the dogs' bodies.

Based on the ultimate endpoints -- how quickly the tumors progressed and how long the dogs actually lived -- the results of the researchers' trial suggest that the I'm-Yunity was effectively fighting the tumors.

"We were shocked," Cimino Brown said. "Prior to this, the longest reported median survival time of dogs with hemangiosarcoma of the spleen that underwent no further treatment was 86 days. We had dogs that lived beyond a year with nothing other than this mushroom as treatment."

There were not statistically significant differences in survival between the three dosage groups, though the median survival time was highest in the 100 mg group, at 199 days, eclipsing the previously reported median survival time.

The results were so surprising, in fact, that the researchers asked Penn Vet pathologists to recheck the dogs' tissue biopsies to make sure that the dogs really had the disease.

"They reread the samples and said, yes, it's really hemangiosarcoma," Cimino Brown said.

Chemotherapy is available for treating hemangiosarcoma, but many owners opt not to pursue that treatment once their dog is diagnosed.

"It doesn't hugely increase survival, it's expensive and it means a lot of back and forth to the vet for the dog," Cimino Brown said. "So you have to figure in quality of life."

While I'm-Yunity is not inexpensive, if proven effective, it would offer owners a way of extending their pet's life without regular trips to the vet. As an added benefit, Cimino Brown and Reetz have found no evidence of adverse effects from the PSP treatment.

The researchers are now getting ready to pursue further trials of I'm-Yunity in dogs with hemangiosarcoma to confirm and refine their results. One trial will compare I'm-Yunity to a placebo for those owners who opt not to pursue chemotherapy in their pet and another will compare the compound to standard-of-care chemotherapy.

Depending on those results, veterinarians could eventually prescribe the compound for treating hemangiosarcoma, and perhaps other cancers, in dogs. The company that manufacturers I'm-Yunity may also pursue large-scale clinical trials in humans.

"Although hemangiosarcoma is a very sad and devastating disease," Cimino Brown said, "in the long term, if we prove that this works, this treatment can be a really nice alternative for owners to have increased quality time with their pet at the end of its life."

The study was funded by a grant from Chinese Medicine Holdings LTD.

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Journal Reference:

Dorothy Cimino Brown, Jennifer Reetz. Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma. Evidence-Based Complementary and Alternative Medicine, 2012; 2012: 1 DOI: 10.1155/2012/384301

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First dogs came from East Asia, genetic study confirms

ScienceDaily (Nov. 28, 2011) — Researchers at Sweden's KTH Royal Institute of Technology say they have found further proof that the wolf ancestors of today's domesticated dogs can be traced to southern East Asia -- findings that run counter to theories placing the cradle of the canine line in the Middle East.

Dr Peter Savolainen, KTH researcher in evolutionary genetics, says a new study released Nov. 23 confirms that an Asian region south of the Yangtze River was the principal and probably sole region where wolves were domesticated by humans.

Data on genetics, morphology and behaviour show clearly that dogs are descended from wolves, but there's never been scientific consensus on where in the world the domestication process began. "Our analysis of Y-chromosomal DNA now confirms that wolves were first domesticated in Asia south of Yangtze River -- we call it the ASY region -- in southern China or Southeast Asia," Savolainen says.

The Y data supports previous evidence from mitochondrial DNA. "Taken together, the two studies provide very strong evidence that dogs originated in the ASY region," Savolainen says.

Archaeological data and a genetic study recently published in Nature suggest that dogs originate from the Middle East. But Savolainen rejects that view. "Because none of these studies included samples from the ASY region, evidence from ASY has been overlooked," he says.

Peter Savolainen and PhD student Mattias Oskarsson worked with Chinese colleagues to analyse DNA from male dogs around the world. Their study was published in the scientific journal Heredity.

Approximately half of the gene pool was universally shared everywhere in the world, while only the ASY region had the entire range of genetic diversity. "This shows that gene pools in all other regions of the world most probably originate from the ASY region," Savolainen says.

"Our results confirm that Asia south of the Yangtze River was the most important -- and probably the only -- region for wolf domestication, and that a large number of wolves were domesticated," says Savolainen.

In separate research published recently in Ecology and Evolution, Savolainen, PhD student Arman Ardalan and Iranian and Turkish scientists conducted a comprehensive study of mitochondrial DNA , with a particular focus on the Middle East. Because mitochondrial DNA is inherited only from the mother in most species, it is especially useful in studying evolutionary relationships.

"Since other studies have indicated that wolves were domesticated in the Middle East, we wanted to be sure nothing had been missed. We find no signs whatsoever that dogs originated there," says Savolainen.

In their studies, the researchers also found minor genetic contributions from crossbreeding between dogs and wolves in other geographic regions, including the Middle East.

"This subsequent dog/wolf hybridisation contributed only modestly to the dog gene pool," Savolainen explains.

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Journal Reference:

Z-L Ding, M Oskarsson, A Ardalan, H Angleby, L-G Dahlgren, C Tepeli, E Kirkness, P Savolainen, Y-P Zhang. Origins of domestic dog in Southern East Asia is supported by analysis of Y-chromosome DNA. Heredity, 2011; DOI: 10.1038/hdy.2011.114

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Tail chasing in dogs resembles obsessive compulsive disorders in humans

ScienceDaily (Aug. 20, 2012) — A new research led by Professor Hannes Lohi at the University of Helsinki, Finland, revealed several similarities between compulsive behavior in dogs and humans: early onset, recurrent compulsive behaviors, increased risk for developing different types of compulsions, compulsive freezing, the beneficial effect of nutritional supplements, the effects of early life experiences and sex hormones and genetic risk.

The genetics research group, based at the University of Helsinki and the Folkhälsan Research Center and led by Professor Hannes Lohi, has in collaboration with an international group of researchers investigated the characteristics and environmental factors associated with compulsive tail chasing in dogs. A questionnaire study covering nearly 400 dogs revealed several similarities between compulsive behavior in dogs and humans: early onset, recurrent compulsive behaviors, increased risk for developing different types of compulsions, compulsive freezing, the beneficial effect of nutritional supplements, the effects of early life experiences and sex hormones and genetic risk. The study shows that dogs offer an excellent animal model for studying the genetic background and environmental factors associated with human obsessive compulsive disorders (OCD). The study has been published in the journal PLoS ONE on July 27, 2012.

Stereotypical behavior in pets has not been studied extensively, even though several different types of compulsive behavior occur in different species including dogs. A dog may recurrently chase lights or shadows, bite or lick its own flank, pace compulsively or chase its own tail. Different environmental and genetic factors have been suggested to predispose to compulsive behavior. Many stereotypes are breed-specific, which emphasizes the role of genes. Compulsive tail chasing occurs in several dog breeds, but worldwide it is most common in breeds such as Bull Terriers and German Shepherds. The aim of this study was to describe the characteristics of tail chasing in dogs, to identify possible environmental risk factors, and to find out whether a previously discovered gene region associated with compulsive behavior is also linked to tail chasing.

Could vitamins have an influence?

Nearly 400 Finnish dogs participated in this study, including Bull Terriers, Miniature Bull Terriers, German Shepherds and Staffordshire Bull Terriers respectively. Blood samples were taken from the dogs participating in the study, and their owners filled out a questionnaire about their dogs' stereotypic behavior. The questionnaire included questions about different stereotypic behaviors, as well as aspects of each dog's puppyhood and the routines of the dog's current daily life. In addition to this the owners evaluated their dogs' personality based on the questions in the questionnaire.

The study included dogs that chased their tails daily for several hours, dogs that chased their tails a few times a month, and dogs that had observably never chased their tails. With most of the dogs, the tail chasing had begun at the age of 3 to 6 months, before reaching sexual maturity.

One of the most interesting findings of this study is the connection with stereotypic behavior and vitamins and minerals. Dogs that received nutritional supplements, especially vitamins and minerals, with their food, chased their tails less. "Our study does not prove an actual causal relationship between vitamins and lessened tail chasing, but interestingly similar preliminary results have been observed in human OCD" says researcher, Katriina Tiira, PhD. Follow-up studies will aim to prove whether vitamins could be beneficial in the treatment of tail chasing.

Early separation from the mother and the mother's poor care of the puppy were also found in the study to predispose dogs to tail chasing. Early separation from the mother has been discovered to predispose also other animals to stereotypic behavior, but this is the first time this connection has been made with dogs.

The amount of exercise the dogs received or the number of activities they engaged in did not, however, seem to have a connection with tail chasing. This could be comforting news to many owners of dogs with compulsive behaviors, since often the owners themselves or the dogs' living environment may be blamed for these behaviors. Although frustration and stress are likely to be significant causes of the occurrence of stereotypic behavior in for example zoo animals, they may be of lesser significance when it comes to Finnish dogs that are walked regularly.

Tail chasing in dogs can be used as an animal model for studying the genetic background of OCD in humans

Compared to the control dogs, tail chasers suffered more from also other stereotypic behaviors. In addition, tail chasers were more timid and afraid of loud noises. "Different types of compulsive behavior occur simultaneously in humans suffering from obsessive compulsive disorder or other diseases such as autism" explains the head of the study, Professor Hannes Lohi. Dogs may turn out to be of significant use in investigating the causes of human psychiatric diseases. "Stereotypic behavior occurs in dogs spontaneously; they share the same environment with humans, and as large animals are physiologically close to humans. Furthermore, their strict breed structure aids the identification of genes."

The gene region previously associated with compulsive flank licking and biting in Dobermans was not found to be associated with tail chasing in any of the breeds in this study. The next aim of this research project is thus to discover new gene regions connected to tail chasing. The study is part of a larger DOGPSYCH project, funded by the European Research Council, in which the genetic background of different anxiety disorders, such as timidity, compulsive behavior and sound sensitivity are investigated, as well as their similarities with corresponding human diseases.

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Journal Reference:

Katriina Tiira, Osmo Hakosalo, Lauri Kareinen, Anne Thomas, Anna Hielm-Björkman, Catherine Escriou, Paul Arnold, Hannes Lohi. Environmental Effects on Compulsive Tail Chasing in Dogs. PLoS ONE, 2012; 7 (7): e41684 DOI: 10.1371/journal.pone.0041684

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University opens obesity clinic for pets

ScienceDaily (Sep. 6, 2012) — The United States' obesity epidemic reaches far beyond adults and children to our pets, who share our homes and often our dietary habits and lack of exercise. To address this, the Cummings School of Veterinary Medicine at Tufts University has created the nation's first obesity clinic geared especially for pets and overseen by a full-time, board-certified veterinary nutritionist.

The clinic taps the strength of the Cummings School's nutrition service, a 15-year-old clinical, teaching and research service located at its Grafton, Mass., Foster Hospital for Small Animals and featuring three board-certified clinical nutritionists. Such experts are a rarity, since fewer than 100 veterinarians have been boarded by the American College of Veterinary Nutrition.

Studies have suggested that up to 60 percent of dogs and cats are obese or overweight. A recent survey of client-owned animals at the Foster Hospital, one of the nation's busiest teaching hospitals for pets, put the number even higher -- nearly 70 percent.

Overseeing the clinic will be Deborah E. Linder, DVM, DACVN, a graduate of the Cummings School's Doctor of Veterinary Medicine program and its two-year residency in clinical nutrition.

"By employing sound, research-proven methods, Tufts' Veterinary Obesity Clinic will help owners achieve safe and effective weight loss for their pets," said Dr. Linder. "While the common perception leans toward overweight pets being happy, research has proven otherwise, and we hope to effect change in the obesity epidemic among companion animals."

Studies done both at the Cummings School and elsewhere suggest that obesity can be a complicated topic for pet owners. Although dogs and cats are not prone to coronary artery disease -- a leading killer of humans and a common side-effect of human obesity -- being overweight can lead to complications such as diabetes, orthopedic problems and respiratory complications, as well as reduced quality of life and life expectancy.

The clinic, which aims to see more than 600 clients per year by 2015, will focus on three areas: providing effective weight loss programs for pets deemed to be overweight and obese, especially hard-to-manage cases and pets with multiple medical conditions, educating veterinary professionals and the lay public on how to prevent, identify and combat obesity within pets, and conducting state-of-the art clinical research on optimal methods for its treatment and prevention.

Weight loss can be as tricky for pets as it is for people. A 2010 study done by Dr. Linder and Lisa M. Freeman, DVM, PhD, found a wide variety in calorie density and feeding instructions for foods marketed for canine and feline weight loss. Freeman's research on dogs and cats with medical conditions such as kidney or heart disease has shown that optimal body condition plays an important role in survival. This and other studies emphasize the importance of a carefully designed weight loss program, especially for pets with medical conditions. Tufts' clinic caters to these complex cases that require the attention and intensive intervention required for weight loss.

The clinic may offer hidden benefits, as well. A 2006 study conducted at Northwestern Memorial Hospital's Wellness Institute suggested that overweight pets can encourage overweight people to exercise with them -- and lose weight simultaneously.

Dr. Linder's faculty appointment is funded by a grant from Royal Canin USA.

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Apply public trust doctrine to 'rescue' wildlife from politics

ScienceDaily (Sep. 29, 2011) — When a species recovers enough to be removed from the federal endangered species list, the public trust doctrine -- the principle that government must conserve natural resources for the public good -- should guide state management of wildlife, scientists say.

In the Sept. 30 issue of the journal Science, the researchers note that the public trust doctrine holds that certain natural resources, including wildlife, have no owners and therefore belong to all citizens. So, they add, when federal statutory law no longer offers protection to a species, the public trust doctrine imposes upon states an obligation to conserve the species for their citizens.

The researchers cite the case of the gray wolf, which lost federal protection in the northern Rocky Mountains last spring under a rare Congressional legislative rider. This rider was passed after courts had reversed three previous U.S. Fish and Wildlife Service attempts to delist the wolf in the region, which includes Idaho, Montana and parts of Oregon, Washington and Utah.

The merits of protecting gray wolves have been hotly debated for years in the northern Rocky Mountains, where public opinion varies considerably among livestock owners, hunters and wildlife advocates. Idaho and Montana have launched public hunts aimed at reducing wolf populations since federal protections were lifted. Wolf advocates fear that heavy-handed "lethal management" of wolves could deplete the population so rapidly that the species will require federal protections again. Under the Endangered Species Act, the federal government monitors a species for at least five years after it is delisted, but state wildlife agencies take over management.

Lost in these bitter arguments is any attempt to clarify state agencies' obligation to their citizens, said Jeremy Bruskotter, assistant professor in Ohio State University's School of Environment and Natural Resources and lead author of the Science paper.

The wildlife trust doctrine, a branch of the public trust doctrine, defines that obligation, the paper's authors argue. The public trust doctrine has roots in ancient Roman and English common law, but its application to wildlife in the United States dates to the late 19th century. In an 1896 case, Geer vs. Connecticut, the U.S. Supreme Court ruled that the wildlife trust doctrine imposed on states a duty "to enact such laws as will best preserve the subject of the trust and secure its beneficial use in the future to the people of the state."

"If you recognize a wildlife trust doctrine, and that the state has the obligation to maintain these populations in perpetuity not just for current residents but for future residents, then there is a degree of protection for species in the absence of the statutory protection," Bruskotter said.

The researchers note that natural resource agency professionals are likely to be aware that all wildlife are communally owned by each state, but western politicians' open hostility toward this formerly protected species raises the question: What are states actually going to do?

"Some of the rhetoric about the killing of wolves might be political showmanship. But when they make exaggerated claims -- for example, comparing wolf restoration to the resurrection of the T. rex, which was done in Utah -- that adds layers of ambiguity and fear. Conservationists wonder if they will try to eliminate wolves and wonder if they can do it," Bruskotter said. "But the public trust doctrine holds that if state politicians were to intervene to try to prevent the maintenance of a viable wolf population, they could be taken to court. There is a legal mechanism to prevent that type of action."

Traditionally, the conservation and management of wildlife resources in the United States has been driven by state governments, which established agencies to monitor wildlife populations and regulate activities like hunting and trapping. However, the federal government began to take an interest in imperiled species in the 1960s, culminating with the passage of the Endangered Species Act in 1973.

"This is where the conflict turns. Until then, the impetus for wildlife management had come primarily from the states. Then the feds came in and said, 'We're taking over the protection and, hopefully, the recovery,'" Bruskotter said.

The federally led reintroduction of gray wolves to western states didn't sit well with many of those states' officials, who characterized the action as an unwanted federal intervention. When the wolf population was deemed to have met federal recovery goals in the region in 2002, state politicians began "clamoring for management authority," Bruskotter said.

To date, wildlife advocates haven't had to rely on the wildlife trust doctrine to guide their management because states generally show a strong desire to conserve species. The case of gray wolves in the northern Rockies has been unusual, with western legislatures continually expressing the desire to minimize or even remove wolf populations altogether.

While case law exists to define the reach of the public trust doctrine, additional case law would be beneficial to firmly establish states' obligations in the management of species no longer covered by federal protection, the authors contend.

"If this obligation is going to be more than just understood, there will need to be case law established, which is going to require somebody to take things to court to see what those obligations are," said Sherry Enzler, a co-author of the paper and a public trust scholar at the University of Minnesota.

The authors note that this argument for the application of the wildlife trust doctrine should not be construed as an appeal on behalf of the gray wolf.

"It's not about protecting any particular species. It's about how we ensure we have adequate protection for all imperiled species under state-led management. Not all species are a perfect fit for federal protection, so this is a better long-term solution," Bruskotter said.

"There is a middle ground here, and there is a legal process for defining this middle ground. States have an obligation to maintain, at minimum, a viable population of a species that has been removed from the endangered species list."

Better clarity about state management could also apply to the case of the grizzly bear, which the U.S. Fish and Wildlife Service stands ready to delist in the greater Yellowstone region. As part of a recent plan to remove protection, federal officials asked states to agree to certain management practices under a series of memoranda of understanding. A federal court rejected the plan because the memoranda were not legally binding -- states could not be compelled to conserve.

"This court-made law could be that regulatory mechanism," Bruskotter said, noting that this represents how the wildlife trust doctrine's application could support delisting a previously threatened species. "This common law could have been used to help remove grizzly bears from protection because it could have provided the regulatory mechanism the court sought in that case."

Bruskotter and Enzler co-authored the article Adrian Treves of the University of Wisconsin-Madison.

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J. T. Bruskotter, S. A. Enzler, A. Treves. Rescuing Wolves from Politics: Wildlife as a Public Trust Resource. Science, 2011; 333 (6051): 1828 DOI: 10.1126/science.1207803

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Efficacy of non-Hodgkin's lymphoma vaccine demonstrated in dogs

ScienceDaily (Oct. 19, 2011) — An experimental vaccine developed by researchers at the University of Pennsylvania's schools of Medicine and Veterinary Medicine is the first veterinary cancer vaccine of its kind that shows an increase in survival time for dogs with spontaneous non-Hodgkin's lymphoma. The work shows for the first time the feasibility and therapeutic efficacy of this alternative cell-based vaccine, which could be employed in the treatment of a number of different cancer types.

The research was conducted by Nicola Mason, assistant professor of medicine at Penn Vet; Robert H. Vonderheide, associate professor of hematology and oncology at the Perelman School of Medicine; and Karin U. Sorenmo, associate professor of oncology at Penn Vet. Erika Krick, Beth Overley and Thomas P. Gregor of Penn Vet and Christina M. Coughlin of the School of Medicine also contributed to the research.

Their work was published in the open access journal PLOS ONE.

The team recruited dogs that were brought to Penn's Matthew J. Ryan Veterinary Hospital with newly diagnosed non-Hodgkin's lymphoma to receive the experimental vaccine following standard induction chemotherapy and confirmation of clinical remission. The goal of the study was to determine whether the vaccine would prevent or prolong time to a relapse, a common scenario in both humans and dogs with NHL.

"We vaccinated dogs, which were in clinical remission following chemotherapy, three times," Mason said. "We then tracked them over several years to see if the vaccine would prevent relapse and would prolong overall survival.

"We found that, although the vaccinated dogs still relapsed with clinical disease when they were treated with rescue chemotherapy, they had significantly increased overall survival times when compared to an unvaccinated control group. Some of these dogs are still alive and cancer free more than three years later.

"The results with these dogs indicate that our immunotherapy and rescue chemotherapy appear to act synergistically to prevent a second relapse -- a phenomenon that has been previously recognized in human patients treated with other types of immunotherapy," she said.

Previous cell based vaccines have utilized genetically engineering dendritic cells -- which are part of the immune system -- to stimulate immune responses against cancers. Similar to using weakened viruses in traditional vaccines, scientists load these cells with tumor proteins and inject the cells back into the patient's body. Such cell-based vaccines are already being used to treat prostate cancer in humans, but engineering these cells is expensive and time consuming. Furthermore, patients must also endure long, leukapheresis sessions in which the necessary dendritic cells are harvested from their blood.

The Penn team hypothesized that another kind of immune cell, B-cells, could work just as well under the right conditions. Unlike dendritic cells, many B-cells can be grown from a small blood sample, removing the requirement for leukapheresis.

Mason's team made the vaccine by culturing B-cells from the blood taken from the dogs with NHL. These cells were then loaded with RNA that had been isolated from the patient's own tumor.

The results were impressive.

"Though vaccinated and unvaccinated dogs relapsed with clinical disease at the same time, 40 percent of vaccinated dogs that relapsed experienced long-term survival after a second round of chemotherapy; only 7 percent of unvaccinated dogs that relapsed and were treated with the same rescue chemotherapy protocol survived long term," Mason said. "Furthermore, when the vaccinated long-term survivors did eventually die, they showed no evidence of lymphoma on full necropsy."

While the molecular mechanisms responsible for these observed synergistic effects are currently unknown, Mason believes that the vaccine-primed immune system may be boosted by the effects of rescue chemotherapy leading to long term second remissions.

Though the increases in long-term survival are already unprecedented and the proof-of-concept for B-cell-based cancer vaccines represents a step forward in cell-based vaccine development, future research could have even more exciting results.

"These dogs just received three doses of vaccine, three weeks apart. If we kept boosting the immune system in this way by vaccination, perhaps the dogs would not relapse in the first place" Mason said.

Work is now underway to streamline B-cell vaccine generation and initiate further clinical trials aimed at optimizing this novel cell-based approach.

This work was supported by the National Institutes of Health, Alliance for Cancer Gene Therapy, Onyx and Breezy Foundation, Barry and Savannah Poodle Memorial Fund, Mari Lowe Comparative Oncology Center, Immunobiology Program of the Abramson Cancer Center at the University of Pennsylvania and Oncology Research Fund at the Veterinary Hospital of the University of Pennsylvania.

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Karin U. Sorenmo, Erika Krick, Christina M. Coughlin, Beth Overley, Thomas P. Gregor, Robert H. Vonderheide, Nicola J. Mason. CD40-Activated B Cell Cancer Vaccine Improves Second Clinical Remission and Survival in Privately Owned Dogs with Non-Hodgkin's Lymphoma. PLoS ONE, 2011; 6 (8): e24167 DOI: 10.1371/journal.pone.0024167

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