Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer

Background In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. Results Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. Conclusion Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC

Small-Molecule Procaspase‑3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics

[Image: see text] Conventional chemotherapeutics remain essential treatments for most cancers, but their combination with other anticancer drugs (including targeted therapeutics) is often complicated by unpredictable synergies and multiplicative toxicities. As cytotoxic anticancer chemotherapeutics generally function through induction of apoptosis, we hypothesized that a molecularly targeted small molecule capable of facilitating a central and defining step in the apoptotic cascade, the activation of procaspase-3 to caspase-3, would broadly and predictably enhance activity of cytotoxic drugs. Here we show that procaspase-activating compound 1 (PAC-1) enhances cancer cell death induced by 15 different FDA-approved chemotherapeutics, across many cancer types and chemotherapeutic targets. In particular, the promising combination of PAC-1 and doxorubicin induces a synergistic reduction in tumor burden and enhances survival in murine tumor models of osteosarcoma and lymphoma. This PAC-1/doxorubicin combination was evaluated in 10 pet dogs with naturally occurring metastatic osteosarcoma or lymphoma, eliciting a biologic response in 3 of 6 osteosarcoma patients and 4 of 4 lymphoma patients. Importantly, in both mice and dogs, coadministration of PAC-1 with doxorubicin resulted in no additional toxicity. On the basis of the mode of action of PAC-1 and the high expression of procaspase-3 in many cancers, these results suggest the combination of PAC-1 with cytotoxic anticancer drugs as a potent and general strategy to enhance therapeutic response

Safety and Efficacy of Sodium and Potassium Arachidonic Acid Salts in the Young Pig

Arachidonic acid (ARA; 20:4n6) and docosahexaenoic acid (DHA; 22:6n3) are polyunsaturated fatty acids (FA) naturally present in breast milk and added to most North American infant formulas (IF). We investigated the safety and efficacy of novel sodium and potassium salts of arachidonic acid as bioequivalent to support tissue levels of ARA comparable to the parent oil; M. alpina oil (Na-ARA and K-ARA) and including a Na-DHA group. Pigs of both sexes were randomized to one of five dietary treatments (n = 16 per treatment; 8 male and 8 female) from postnatal day 2 to 23. ARA and DHA were included as either triglyceride (TG) or salt. Target dietary ARA/DHA concentrations as percent of total FA by weight were as follows: TT (0.47 TG/0.32 TG), NaT (0.47 Na-salt/0.32 TG), KT (0.47 K-salt/0.32 TG), and Na0 (0.47 Na-salt/0.00), NaNa (0.47 Na-salt/0.32 Na-salt). The primary outcome in this study was bioequivalence of ARA brain accretion. Growth performance; blood and tissue fatty acid levels; liver histology; complete blood cell counts; and serum chemistries were all evaluated. Overall, diets containing test sources of ARA and DHA did not affect growth performance; liver histology; or substantially influence hematological outcomes as compared with TT. The results confirm that the use of Na and K salt forms of ARA yield bioequivalent ARA accretion in the cerebral cortex and retinal tissue compared to TG-ARA. These findings confirm that use of Na-ARA and K-ARA salts in the young pig was safe and nutritionally bioequivalent to TG-ARA for critical neural tissues

Small-Molecule Procaspase‑3 Activation Sensitizes Cancer to Treatment with Diverse Chemotherapeutics

Conventional chemotherapeutics remain essential treatments for most cancers, but their combination with other anticancer drugs (including targeted therapeutics) is often complicated by unpredictable synergies and multiplicative toxicities. As cytotoxic anticancer chemotherapeutics generally function through induction of apoptosis, we hypothesized that a molecularly targeted small molecule capable of facilitating a central and defining step in the apoptotic cascade, the activation of procaspase-3 to caspase-3, would broadly and predictably enhance activity of cytotoxic drugs. Here we show that procaspase-activating compound 1 (PAC-1) enhances cancer cell death induced by 15 different FDA-approved chemotherapeutics, across many cancer types and chemotherapeutic targets. In particular, the promising combination of PAC-1 and doxorubicin induces a synergistic reduction in tumor burden and enhances survival in murine tumor models of osteosarcoma and lymphoma. This PAC-1/doxorubicin combination was evaluated in 10 pet dogs with naturally occurring metastatic osteosarcoma or lymphoma, eliciting a biologic response in 3 of 6 osteosarcoma patients and 4 of 4 lymphoma patients. Importantly, in both mice and dogs, coadministration of PAC-1 with doxorubicin resulted in no additional toxicity. On the basis of the mode of action of PAC-1 and the high expression of procaspase-3 in many cancers, these results suggest the combination of PAC-1 with cytotoxic anticancer drugs as a potent and general strategy to enhance therapeutic response

Sylvatic Canine Morbillivirus in Captive Panthera Highlights Viral Promiscuity and the Need for Better Prevention Strategies

Canine Distemper Virus (CDV) is a multi-host morbillivirus that infects virtually all Carnivora and a few non-human primates. Here we describe a CDV outbreak in an exotic felid rescue center that led to the death of eight felids in the genus Panthera. Similar to domestic dogs and in contrast to previously described CDV cases in Panthera, severe pneumonia was the primary lesion and no viral antigens or CDV-like lesions were detected in the central nervous system. Four tigers succumbed to opportunistic infections. Viral hemagglutinin (H)-gene sequence was up to 99% similar to strains circulating contemporaneously in regional wildlife. CDV lesions in raccoons and skunk were primarily encephalitis. A few affected felids had at least one previous vaccination for CDV, while most felids at the center were vaccinated during the outbreak. Panthera sharing a fence or enclosure with infected conspecifics had significantly higher chances of getting sick or dying, suggesting tiger-tiger spread was more likely than recurrent spillover. Prior vaccination was incomplete and likely not protective. This outbreak highlights the need for further understanding of CDV epidemiology for species conservation and public health

Sylvatic Canine Morbillivirus in Captive Panthera Highlights Viral Promiscuity and the Need for Better Prevention Strategies

Canine Distemper Virus (CDV) is a multi-host morbillivirus that infects virtually all Carnivora and a few non-human primates. Here we describe a CDV outbreak in an exotic felid rescue center that led to the death of eight felids in the genus Panthera. Similar to domestic dogs and in contrast to previously described CDV cases in Panthera, severe pneumonia was the primary lesion and no viral antigens or CDV-like lesions were detected in the central nervous system. Four tigers succumbed to opportunistic infections. Viral hemagglutinin (H)-gene sequence was up to 99% similar to strains circulating contemporaneously in regional wildlife. CDV lesions in raccoons and skunk were primarily encephalitis. A few affected felids had at least one previous vaccination for CDV, while most felids at the center were vaccinated during the outbreak. Panthera sharing a fence or enclosure with infected conspecifics had significantly higher chances of getting sick or dying, suggesting tiger-tiger spread was more likely than recurrent spillover. Prior vaccination was incomplete and likely not protective. This outbreak highlights the need for further understanding of CDV epidemiology for species conservation and public health

Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer.

BACKGROUND: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. RESULTS: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. CONCLUSION: Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC

Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer

Background: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. Results: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. Conclusion: Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC

Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer

Background: In humans, muscle-invasive bladder cancer (MIBC) is highly aggressive and associated with a poor prognosis. With a high mutation load and large number of altered genes, strategies to delineate key driver events are necessary. Dogs and cats develop urothelial carcinoma (UC) with histological and clinical similarities to human MIBC. Cattle that graze on bracken fern also develop UC, associated with exposure to the carcinogen ptaquiloside. These species may represent relevant animal models of spontaneous and carcinogen-induced UC that can provide insight into human MIBC. Results: Whole-exome sequencing of domestic canine (n = 87) and feline (n = 23) UC, and comparative analysis with human MIBC reveals a lower mutation rate in animal cases and the absence of APOBEC mutational signatures. A convergence of driver genes (ARID1A, KDM6A, TP53, FAT1, and NRAS) is discovered, along with common focally amplified and deleted genes involved in regulation of the cell cycle and chromatin remodelling. We identify mismatch repair deficiency in a subset of canine and feline UCs with biallelic inactivation of MSH2. Bovine UC (n = 8) is distinctly different; we identify novel mutational signatures which are recapitulated in vitro in human urinary bladder UC cells treated with bracken fern extracts or purified ptaquiloside. Conclusion: Canine and feline urinary bladder UC represent relevant models of MIBC in humans, and cross-species analysis can identify evolutionarily conserved driver genes. We characterize mutational signatures in bovine UC associated with bracken fern and ptaquiloside exposure, a human-linked cancer exposure. Our work demonstrates the relevance of cross-species comparative analysis in understanding both human and animal UC