Let's immune system help

Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido, 
Vinod P Balachandran, et al. Nature Medicine17 (2011) 


I would like to hilight this paper to our readership, as many of your are involved in the design of clinical trials and selection of potential biomarkers. This report is one of a handful of high impact papers that report the coperative role that inflammatory infiltrate and non cell autonomous effectors play in modulating response to established agents. This study demonstrates an interesting immunological mechanism of Imatininb  that contributes to the antitumor effect in a Gastrointestinal Stromal Tumor (GIST) mouse model. Inflammatory infiltrate is a known finding in GIST specimens (including intratumoral CD8+ Tcells, Treg cells and macrophages). Acording to the authors, Imatinib activates CD8+ T cells and induces Treg cells apoptosis within the tumor. Imatinib is therefore able to reduce the expression of 2,3-dioxygenase (Ido) of tumor cells. Ido enzyme is involved in the catayzation of immunosuppressive metabolites from tryptophan and therefore mediates downstream immunological response. Interestingly Imatininb resistant tumors, generally as a result of a second KIT mutation, restore the overexpression of IDO and combination of Imatinib with CTLA-4 blockade (a well established immunotherapeutic strategy) act synergistically. This insight provides some hints on something we have been suspecting for a long time. It is easy to predict consequences for rational design of combination therapies and strategies to overcome resistance in Imatinib resistant tumors.TweetShare

2012 Excellence in Feline Research Award

Niels Pedersen, DVM, PhD, is the winner of the 2012 Excellence in Feline Research Award from Winn Feline Foundation and the American Veterinary Medical Foundation (AVMF). Dr. Pedersen was recognized due in large part to his work as a pioneer in infectious diseases in cats having produced 220 research publications and authored a number of textbooks on feline husbandry and infectious diseases. As a member of the faculty at the School of Veterinary Medicine at University of California at Davis, Pedersen is currently a distinguished professor and director of both the Center for Companion Animal Health and Veterinary Genetics Laboratory.

Winn President, Vicki Thayer, DVM, DABVP, made the announcement and was at the presentation of the $2,500 award, given along with a crystal cat award at the annual convention of the American Veterinary Medical Association held August 7th in San Diego.

Dr. Thayer commented that “Dr. Pedersen is well known for his support for research into feline infectious peritonitis (FIP) and working with volunteers at SOCK FIP (Save Our Cats and Kittens) which currently focuses on FIP research. The Winn Board of Directors is pleased to honor Dr. Pedersen for a lifetime of achievement and as a long time friend of Winn and supporter of our mission. We were also pleased to have him present information on FIP research at Winn’s Annual Symposium in 2011 to excellent reviews.”

Dr. Pedersen, Winn past president Joan Miller, 1981

According to Dr. Pedersen, his most satisfying achievements have involved the creation of the Center for Comparative Medicine, The Center for Companion Animal Health and the Koret Shelter Medicine Program. His single most rewarding experience has been directing the Veterinary Genetics Laboratory (VGL) at UC-Davis  since 1997 and using the resources of the VGL to develop a broad based and internationally recognized veterinary genetics research program.

Pedersen graduated from UC Davis, School of Veterinary Medicine in 1967 and interned in small animal medicine and surgery at Colorado State University. He was awarded a PhD in Experimental Pathology and Immunology from the John Curtin School of Medical Research, Australian National University in 1972. Dr. Pedersen was active in clinics for 17 years, specializing in infectious and immunologic diseases of dogs and cats. He taught infectious diseases, clinical immunology and feline medicine for 22 years.

He holds honorary doctorates from the Universities of Zurich and Utrecht and has received several awards for his research on feline infectious diseases. Although he has worked on many different diseases of cats and dogs, his lifelong interest has been with feline infectious peritonitis, which continues to both excite and frustrate him with its complexities.

Winn Feline Foundation and the American Veterinary Medical Foundation are pleased to collaborate in this effort to focus attention on the importance of feline health studies and the committed researchers who conduct these lifesaving investigations into the prevention and care of feline disease for “Every Cat, Every Day.”

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Investigating new drugs for feline diabetes mellitus

Final report, Winn grant W10-020
Pharmacokinetics of pioglitazone in lean and obese cats
Investigators: Levent Dirikolu, Margarethe Hoenig, Duncan Ferguson; University of Illinois
 
Diabetes mellitus and hepatic lipidosis (fatty liver disease) are common problems in feline medicine. Both diseases are associated with obesity and may be prevented by maintaining an ideal body weight. However, weight control is difficult in many cats and once these diseases develop, specific treatment is needed. Current treatment for diabetes mellitus in cats is either insulin or drug therapy with glipizide, along with dietary modification. The only treatment available for hepatic lipidosis is aggressive nutritional support, often with a feeding tube. In human medicine, new anti-diabetic drugs called thiazolidinediones such as pioglitazone improve insulin sensitivity and reverse fatty changes in the liver. The purpose of this project was to begin investigation of pioglitazone in cats so that it may be evaluated in clinical trials in the future.

The investigators’ objectives in this study were to evaluate the pharmacokinetics of this drug in lean and obese cats in an effort to provide a foundation for assessment of its effects on insulin sensitivity and lipid metabolism. Pioglitazone was administered intravenously (median dose 0.2 mg/kg) or orally (3 mg/kg) to six healthy lean cats and six obese cats. There were no statistically significant differences in pharmacokinetic parameters between lean and obese cats subsequent to either oral or intravenous administration. No adverse effects were noted with oral dosing in any of the cats. It appears that achieving therapeutic concentrations of pioglitazone, potentially at a dose of 3 mg/kg, appears feasible. [VT]

Clark MH, Hoenig M, Ferguson DC and Dirikolu L. Pharmacokinetics of pioglitazone in lean and obese cats. J Vet Pharmacol Ther. 2012.

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Leptospirosis in cats

Arbour J, Blais M-C, Carioto L and Sylvestre D. Clinical leptospirosis in three cats (2001–2009). J Am Anim Hosp Assoc. 2012; 48: 256-60.

Leptospira species are an important zoonotic bacterium harbored by some species of wildlife, including rodents. The bacteria are shed in urine from infected animals. Infection of cats with the spirochete bacteria Leptospira occurs but cats have always been thought to be resistant to development of clinical signs following infection. This report describes three confirmed cases of leptospirosis in cats with disease. All three cases were indoor/outdoor cats that were known to hunt.

All three cases presented with kidney disease, but no involvement of the liver as is sometimes seen in dogs. Symptoms included lethargy, anorexia, frequent urination, and excessive drinking. One cat had blood in the urine, and also inflammatory involvement of the right eye. Two of the cats responded well to treatment, but one continued to deteriorate and had to be euthanized.

Interestingly, these cats developed disease several months after the known exposure to rodents, implying a longer incubation period than is seen in dogs, which is usually a few days. The authors conclude that while disease due to Leptospira infection in cats is rare, it must be considered in cases of kidney disease. Further work is needed to determine the ability of cats to carry and shed the bacteria asymptomatically. [MK]

See also: Markovich JE, Ross L and McCobb E. The prevalence of leptospiral antibodies in free roaming cats in Worcester County, Massachusetts. J Vet Intern Med. 2012; 26: 688-9.

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Cyclosporine in cats

Final report, Winn grant W09-028
Pharmacokinetics of cyclosporine after intravenous and subcutaneous administration in cats
Investigators: Sandra Diaz, David Panciera, James Meldrum; Virginia_Maryland Regional College of Veterinary Medicine

Cyclosporine A (CsA) is an immune-modulating drug that has traditionally been used for kidney transplantation in cats. In recent years, CsA has been reported to be effective in the management of several skin diseases, including allergic skin disease. CsA is typically given by mouth, but absorption of the drug is variable and not all owners can give oral medication to their cats long term. The objective of this study was to determine if subcutaneous administration of CsA would give predictable blood concentrations of the drug. If so, this route of drug administration could be easier for some cat owners, and may reduce side effects and reduce the need for blood monitoring of drug levels.

This study looked at the pharmacokinetic profile of CsA after intravenous (IV) and subcutaneous (SQ) administration. Five healthy adult cats were given a single IV bolus of CsA. After two weeks, they received a dose of CsA SQ every 48 hours for 14 days. Blood samples were taken and measured. No adverse effects were observed in any cat. The results indicated that SQ CsA bioavailability is very good. The SQ route could represent a promising route of administration in cats in the future. [VT]

See also: Heinrich NA, McKeever PJ and Eisenschenk MC. Adverse events in 50 cats with allergic dermatitis receiving ciclosporin. Vet Dermatol. 2011; 22: 511-20.

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Acromegaly in cats

Greco DS. Feline acromegaly. Top Companion Anim Med. 2012; 27: 31-5.

From Dr. Mark Peterson: endocrinevet.blogspot.com

Acromegaly (or hypersomatotropism) is a disease that derives its name from two Greek words: ‘acro’ (meaning extremity) and ‘megale’ (meaning great). The disease has been known in humans for at least 100 years, and has been identified in cats starting in the 1980s. The disease is caused by a tumor (adenoma) of the pituitary gland in the brain that leads to excessive secretion of growth hormone. The effects of excessive growth hormone include the development of diabetes mellitus and increase in size of certain parts of the body (e.g., jaw, skull, limbs). Internal organs (e.g., heart, liver, kidney) may also be increased in size. 

The typical feline patient is an older male cat with diabetes mellitus that is difficult to manage. The disease is diagnosed by finding increased blood levels of growth hormone and/or insulin-like growth factor as well as demonstration of a pituitary mass using magnetic resonance imaging or computed tomography. Few treatments are available for this disease in cats; to date, the most effective approach has been radiation therapy. Most affected cats eventually die of congestive heart failure, chronic kidney failure, or complications of the growing pituitary tumor. [SL]

See also: 

• Niessen SJM. Feline acromegaly: An essential differential diagnosis for the difficult diabetic. J Feline Med Surg. 2010; 12: 15-23.
• Final report, Winn grant W10-017: Evaluation of a long-acting somatostatin receptor ligand for the treatment of feline acromegaly
• Insights into veterinary endocrinology: Dr. Mark E. Peterson

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Dental Did You Know: The Price of John Lennon's Tooth.

Apparently, John Lennon's molar was sold for about $31000 at the Omega Auction House on November 4th. It went for double its listed price and was originally given by him to his former housekeeper. It is also reported to be now in the possession of a Canadian dentist (not confirmed and not me :)

Source: Rolling Stone Magazine (Online), November 6th, Read November 7th, http://www.rollingstone.com/music/news/john-lennons-tooth-sells-for-more-than-31-000-at-auction-20111106


Hans Skariah, B.Sc., DMD
Promenade Court Dental Health Group in Mississauga
2233 Hurontario St., Mississauga, ON, Canada
(1/2 km north of the QEW in the Dome Building)
(905) 273-7100