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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
10 Kasım 2012 Cumartesi
9 Kasım 2012 Cuma
Heart disease in pedigreed cats
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Trehiou-Sechi E, Tissier R, Gouni V, et al. Comparative echocardiographic and clinical features of hypertrophic cardiomyopathy in 5 breeds of cats: a retrospective analysis of 344 Cases (2001–2011). J Vet Intern Med. 2012; 26: 532-41.
A common form of heart disease in cats is hypertrophic cardiomyopathy (HCM) and it is associated with risk of sudden death. HCM has been shown to be inherited in some breeds though few studies have looked at comparisons of HCM phenotype and survival according to breed. The authors performed a retrospective study of 344 cats from 5 different breeds (Persian, Domestic Shorthair, Sphynx, Maine Coon, and Chartreux) having primary HCM diagnosed by conventional echocardiography. In this group, 266 cats were asymptomatic and 78 were symptomatic. Most of the symptomatic cats exhibited congestive heart failure, aortic thromboembolism, syncope, and weakness.
The age at the first cardiac event was significantly lower in Maine Coons (2.5 years) versus other breeds (7 years). In Sphynx, the age at the time of diagnosis was 3.5 years. Concerning sudden death solely, Maine Coon cats died younger than other breeds. No sudden deaths were reported in Chartreux and Persian cats in this study. Sudden death was observed in only 3 breeds—Maine Coon, Domestic Shorthair, and Sphynx. All cats surviving longer than 15 years of age were Domestic Shorthair, Persians, or Chartreux. From the results of this study, it appears that feline HCM is characterized by marked phenotypic variability with several breed-dependent features with regard to epidemiological characteristics, left ventricular geometric patterns, age at the time of diagnosis, and decompensation events. [VT]
See also: Silverman SJ, Stern JA and Meurs KM. Hypertrophic cardiomyopathy in the Sphynx cat: A retrospective evaluation of clinical presentation and heritable etiology. J Feline Med Surg. 2012; 14: 246-9.
For more information: Other blog articles on hypertrophic cardiomyopathy
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A common form of heart disease in cats is hypertrophic cardiomyopathy (HCM) and it is associated with risk of sudden death. HCM has been shown to be inherited in some breeds though few studies have looked at comparisons of HCM phenotype and survival according to breed. The authors performed a retrospective study of 344 cats from 5 different breeds (Persian, Domestic Shorthair, Sphynx, Maine Coon, and Chartreux) having primary HCM diagnosed by conventional echocardiography. In this group, 266 cats were asymptomatic and 78 were symptomatic. Most of the symptomatic cats exhibited congestive heart failure, aortic thromboembolism, syncope, and weakness.
The age at the first cardiac event was significantly lower in Maine Coons (2.5 years) versus other breeds (7 years). In Sphynx, the age at the time of diagnosis was 3.5 years. Concerning sudden death solely, Maine Coon cats died younger than other breeds. No sudden deaths were reported in Chartreux and Persian cats in this study. Sudden death was observed in only 3 breeds—Maine Coon, Domestic Shorthair, and Sphynx. All cats surviving longer than 15 years of age were Domestic Shorthair, Persians, or Chartreux. From the results of this study, it appears that feline HCM is characterized by marked phenotypic variability with several breed-dependent features with regard to epidemiological characteristics, left ventricular geometric patterns, age at the time of diagnosis, and decompensation events. [VT]
See also: Silverman SJ, Stern JA and Meurs KM. Hypertrophic cardiomyopathy in the Sphynx cat: A retrospective evaluation of clinical presentation and heritable etiology. J Feline Med Surg. 2012; 14: 246-9.
For more information: Other blog articles on hypertrophic cardiomyopathy
More on cat health:
Winn Feline Foundation Library
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Let's immune system help
To contact us Click HERE
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
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
5 Kasım 2012 Pazartesi
Let's immune system help
To contact us Click HERE
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
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
FIV and kidney disease
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Baxter KJ, Levy JK, Edinboro CH, Vaden SL and Tompkins MB. Renal disease in cats infected with feline immunodeficiency virus. J Vet Intern Med. 2012; 26: 238-43.
In people infected with human immunodeficiency virus (HIV), renal disease is the fourth most common cause of death. Feline immunodeficiency virus (FIV) causes similar clinical syndromes to HIV in humans (e.g., immune dysregulation, opportunistic infections, inflammatory diseases, and neoplasia). The seroprevalence of FIV in cats in North America is estimated to be 3.6-4.3%, with the highest prevalence found in adult male, sick, and free-roaming cats. The authors used a mixed retrospective/prospective cross-sectional study of client-owned cats (153 FIV-infected, 306 FIV-uninfected) and specific-pathogen-free (SPF) research colony cats (95 FIV-infected, 98 FIV-uninfected). The researchers hypothesized that cats infected with FIV are at increased risk of proteinuria, and that proteinuria is associated with advanced FIV infection and comorbidity factors contribute to the prevalence of renal disease.
Comparisons were made by evaluating blood urea nitrogen, serum creatinine, urine specific gravity, and urine protein-creatinine (UPC) ratio between infected and uninfected cats. Also CD4+ and CD8+ T lymphocytes were measured and the ratio was calculated. Renal azotemia was defined as a serum creatinine > 1.9 mg/dL with urine specific gravity < 1.035. Proteinuria was defined as a UPC ratio > 0.4 with an inactive urine sediment. The results indicated that the prevalence of proteinuria was higher in client-owned FIV-infected cats than in FIV-uninfected cats. Yet, there was no significant difference in the prevalence of azotemia. The authors believe that using their classification system, being considered “diseased” was not a risk factor for proteinuria in FIV-infected cats. The primary conclusion from the study was that client-owned cats with naturally acquired FIV infection were at increased risk of proteinuria, but not renal azotemia. The cause and pathogenesis of this proteinuria is uncertain. [VT]
See also: Poli A, Abramo F, Matteucci D, et al. Renal involvement in feline immunodeficiency virus infection: p24 antigen detection, virus isolation and PCR analysis. Vet Immunol Immunopathol. 1995; 46: 13-20.
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In people infected with human immunodeficiency virus (HIV), renal disease is the fourth most common cause of death. Feline immunodeficiency virus (FIV) causes similar clinical syndromes to HIV in humans (e.g., immune dysregulation, opportunistic infections, inflammatory diseases, and neoplasia). The seroprevalence of FIV in cats in North America is estimated to be 3.6-4.3%, with the highest prevalence found in adult male, sick, and free-roaming cats. The authors used a mixed retrospective/prospective cross-sectional study of client-owned cats (153 FIV-infected, 306 FIV-uninfected) and specific-pathogen-free (SPF) research colony cats (95 FIV-infected, 98 FIV-uninfected). The researchers hypothesized that cats infected with FIV are at increased risk of proteinuria, and that proteinuria is associated with advanced FIV infection and comorbidity factors contribute to the prevalence of renal disease.
Comparisons were made by evaluating blood urea nitrogen, serum creatinine, urine specific gravity, and urine protein-creatinine (UPC) ratio between infected and uninfected cats. Also CD4+ and CD8+ T lymphocytes were measured and the ratio was calculated. Renal azotemia was defined as a serum creatinine > 1.9 mg/dL with urine specific gravity < 1.035. Proteinuria was defined as a UPC ratio > 0.4 with an inactive urine sediment. The results indicated that the prevalence of proteinuria was higher in client-owned FIV-infected cats than in FIV-uninfected cats. Yet, there was no significant difference in the prevalence of azotemia. The authors believe that using their classification system, being considered “diseased” was not a risk factor for proteinuria in FIV-infected cats. The primary conclusion from the study was that client-owned cats with naturally acquired FIV infection were at increased risk of proteinuria, but not renal azotemia. The cause and pathogenesis of this proteinuria is uncertain. [VT]
See also: Poli A, Abramo F, Matteucci D, et al. Renal involvement in feline immunodeficiency virus infection: p24 antigen detection, virus isolation and PCR analysis. Vet Immunol Immunopathol. 1995; 46: 13-20.
More on cat health:
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New antiviral treatments for cats
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Robert-Tissot C, Ruegger VL, Cattori V, et al. Stimulation with a class A CpG oligonucleotide enhances resistance to infection with feline viruses from five different families. Vet Res. 2012; 43: 60. [free, full text article]
Viral pathogens commonly infect domestic cats, in particular in multi-cat environments such as shelters and catteries, often leading to increased morbidity and mortality. A promising addition to our armamentarium against viral infection along with vaccinations is the manipulation of innate immunity. Oligonucleotides (ODN) containing unmethylated cytosine-phosphate-guanosine motifs of class A (CpG-A) are recognized as pathogen-associated molecular patterns due to high abundance in viral genome (as well as bacterial genome) and, thus, are highly potent synthetic inducers of innate antiviral mechanisms.
This study tested in vitro CpG-A ODN ability to enhance innate immune responses and prevent viral replication. CpG-A ODN was shown to stimulate feline peripheral blood mononuclear cells (PBMCs), enhancing their proliferation, and shifting their gene expression in an antiviral orientation. In vivo, CpG-A ODN also induced a systemic antiviral state with astonishing effects of potent induction of IFNα and IFNω, with mRNA expression of these genes increased by up to 12 000 and 35 000-fold respectively in PBMCs of cats.
With regard to this, a recombinant feline type I IFN marketed in both Japan (Intercat®) and Europe (Virbagen Omega®) has made its way into therapeutic protocols for FCV, FHV, FeLV and canine parvovirus infections and has demonstrated preventive capacities in a cattery developing an outbreak of FPV. However, when compared to direct initiation of antiviral mechanisms by a recombinant IFNα protein, administration of CpG-A ODN holds the advantage of inducing the production of all type I IFN and their subtypes, which have been shown to possess differential antiviral properties and kinetics. On the other hand, CpG-A ODN stimulated PBMCs in kittens tended to develop an immunologic environment with a Th2 orientation (antibody response) corroborating the immature IFN system and impaired activation of mononuclear cells in neonates. This particular observation opens new perspectives on possible explanations for the qualitative discrepancy between innate immune responses in newborns and adults.
Overall, treatment with CpG-A ODN enhanced resistance against feline viruses from five distinct viral families, namely Coronavirdae, Herpesviridae, Caliciviridae, Parvoviridae, and Retrovridae. The data highlights the prophylactic potential of CpG-A ODN in domestic cats as a stand-alone agent and against a large range of viral pathogens simultaneously. Cats may highly benefit from such a molecule when placed in environments with strong infectious pressure such as catteries, shelters or pet shows. [GO]
See also: Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007; 449: 819-26.
More on cat health:
Winn Feline Foundation Library
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Viral pathogens commonly infect domestic cats, in particular in multi-cat environments such as shelters and catteries, often leading to increased morbidity and mortality. A promising addition to our armamentarium against viral infection along with vaccinations is the manipulation of innate immunity. Oligonucleotides (ODN) containing unmethylated cytosine-phosphate-guanosine motifs of class A (CpG-A) are recognized as pathogen-associated molecular patterns due to high abundance in viral genome (as well as bacterial genome) and, thus, are highly potent synthetic inducers of innate antiviral mechanisms.
This study tested in vitro CpG-A ODN ability to enhance innate immune responses and prevent viral replication. CpG-A ODN was shown to stimulate feline peripheral blood mononuclear cells (PBMCs), enhancing their proliferation, and shifting their gene expression in an antiviral orientation. In vivo, CpG-A ODN also induced a systemic antiviral state with astonishing effects of potent induction of IFNα and IFNω, with mRNA expression of these genes increased by up to 12 000 and 35 000-fold respectively in PBMCs of cats. With regard to this, a recombinant feline type I IFN marketed in both Japan (Intercat®) and Europe (Virbagen Omega®) has made its way into therapeutic protocols for FCV, FHV, FeLV and canine parvovirus infections and has demonstrated preventive capacities in a cattery developing an outbreak of FPV. However, when compared to direct initiation of antiviral mechanisms by a recombinant IFNα protein, administration of CpG-A ODN holds the advantage of inducing the production of all type I IFN and their subtypes, which have been shown to possess differential antiviral properties and kinetics. On the other hand, CpG-A ODN stimulated PBMCs in kittens tended to develop an immunologic environment with a Th2 orientation (antibody response) corroborating the immature IFN system and impaired activation of mononuclear cells in neonates. This particular observation opens new perspectives on possible explanations for the qualitative discrepancy between innate immune responses in newborns and adults.
Overall, treatment with CpG-A ODN enhanced resistance against feline viruses from five distinct viral families, namely Coronavirdae, Herpesviridae, Caliciviridae, Parvoviridae, and Retrovridae. The data highlights the prophylactic potential of CpG-A ODN in domestic cats as a stand-alone agent and against a large range of viral pathogens simultaneously. Cats may highly benefit from such a molecule when placed in environments with strong infectious pressure such as catteries, shelters or pet shows. [GO]
See also: Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007; 449: 819-26.
More on cat health:
Winn Feline Foundation Library
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Dental Did You Know: Obesity and Dental Health
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Men and women with a BMI over 30 regardless of smoking or diabetes status had a greater risk of developing periodontal disease than those with a healthy body weight.
Source: Ward W and Fritz P, Obesity and Periodontal Health: What's the Link? Should I be Concerned? Oral Health, Oct 2012, Vol 102, No 10, pg 80-83.
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
Source: Ward W and Fritz P, Obesity and Periodontal Health: What's the Link? Should I be Concerned? Oral Health, Oct 2012, Vol 102, No 10, pg 80-83.
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
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