- Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2014; 111 (37): 13373-13378
- PHD Inhibition Mitigates and Protects Against Radiation-Induced Gastrointestinal Toxicity via HIF2 SCIENCE TRANSLATIONAL MEDICINE 2014; 6 (236)
Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes
2013; 19 (10): 1325-?
Signaling initiated by hypoxia and insulin powerfully alters cellular metabolism. The protein stability of hypoxia-inducible factor-1 alpha (Hif-1α) and Hif-2α is regulated by three prolyl hydroxylase domain-containing protein isoforms (Phd1, Phd2 and Phd3). Insulin receptor substrate-2 (Irs2) is a critical mediator of the anabolic effects of insulin, and its decreased expression contributes to the pathophysiology of insulin resistance and diabetes. Although Hif regulates many metabolic pathways, it is unknown whether the Phd proteins regulate glucose and lipid metabolism in the liver. Here, we show that acute deletion of hepatic Phd3, also known as Egln3, improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2α, which then increases Irs2 transcription and insulin-stimulated Akt activation. Hif-2α and Irs2 are both necessary for the improved insulin sensitivity, as knockdown of either molecule abrogates the beneficial effects of Phd3 knockout on glucose tolerance and insulin-stimulated Akt phosphorylation. Augmenting levels of Hif-2α through various combinations of Phd gene knockouts did not further improve hepatic metabolism and only added toxicity. Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms.
View details for DOI 10.1038/nm.3294
View details for Web of Science ID 000325531700033
View details for PubMedID 24037093
- Chinese Box turtle (Cuora flavomarginata) with lymphoid leukemia characterized by immunohistochemical and cytochemical phenotyping. Veterinary Clinical Pathology 2013
Transient hyperlipidemia in a litter of kittens
JOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE
2012; 22 (6): 703-709
To describe an entire litter of kittens with severe hyperlipidemia and subsequent successful, low-cost treatment that included high protein enteral support and parasite control. Previous case studies of similarly affected kittens have focused on a genetic etiology and on advanced interventions. The role of negative energy balance and additional factors influencing hyperlipidemia, as well as treatment and prognosis are discussed.Three of 6 kittens died or were euthanized due to severe clinical signs attributable to multiorgan failure associated with subacute hyperlipidemia. The remaining 3 kittens, although subclinical, were found to have similar biochemical abnormalities, including severe anemia and hypertriglyceridemia. Flea treatment and weaning with assisted enteral support prevented the worsening of clinical signs and returned biochemical parameters to within reference intervals.Transient hyperlipidemia in kittens has been previously reported and successfully treated with administration of oxygen, blood transfusion, and diet change; these treatment recommendations may not always be financially feasible, resulting in euthanasia of affected kittens. In contrast, this report describes a successful, low-cost, outpatient approach of flea control, weaning, and introduction of a high protein enteral diet. It also highlights the importance of screening and treating seemingly unaffected littermates, provides new, previously unreported biochemical and histopathology findings, and proposes that negative energy balance is a significant factor in the development of transient hyperlipidemia in kittens.
View details for DOI 10.1111/j.1476-4431.2012.00797.x
View details for Web of Science ID 000312159200011
View details for PubMedID 23110600
Comparative Analysis of Peptidylarginine Deiminase-2 Expression in Canine, Feline and Human Mammary Tumours
JOURNAL OF COMPARATIVE PATHOLOGY
2012; 147 (2-3): 139-146
The peptidylarginine deiminase (PAD) enzyme family converts arginine residues in proteins to citrulline. In the canine mammary gland, PAD2 expression is first detected in epithelial cells in oestrus and becomes more widely expressed during dioestrus. PAD2 appears to modify nuclear histones, suggesting a role for the enzyme in chromatin remodelling and gene regulation. Recent evidence suggests that PAD2 plays a role in gene regulation in primary human breast epithelial cells. PAD2 may therefore be involved in gene regulation as it relates to mammary development, the oestrus cycle and potentially to neoplasia. The aim of the present study was to determine whether PAD2 expression was increased or decreased in mammary carcinoma compared with normal mammary tissue. A human mammary tissue microarray and archival surgical biopsy tissues from canine and feline mammary tumours were used to demonstrate differential expression of PAD2 in mammary carcinoma that appeared to be consistent across species. Normal human and canine mammary epithelium showed strong cytoplasmic and nuclear expression of PAD2, but there was reduced PAD2 expression in mammary carcinomas from both species. Feline mammary carcinomas had complete loss of nuclear PAD2 expression. Loss of nuclear PAD2 expression may therefore represent a marker of progression towards more aggressive neoplasia.
View details for DOI 10.1016/j.jcpa.2012.01.021
View details for Web of Science ID 000307796500006
View details for PubMedID 22520816
Pathology in Practice
JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION
2012; 240 (4): 391-393
View details for Web of Science ID 000300264700023
- Pathology in practice. Widespread, metastatic liposarcoma and moderate, acute, diffuse centrilobular hepatic necrosis. Journal of the American Veterinary Medical Association 2012; 240 (4): 391-393
Spinal cord nephroblastoma in dogs: 11 cases (1985-2007)
JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION
2011; 238 (5): 618-624
To evaluate clinical features and outcome of dogs with a confirmed spinal cord nephroblastoma and to describe the use of Wilms tumor-1 (WT-1) immunohistochemical staining to confirm a diagnosis of nephroblastoma in dogs.Retrospective case series. Animals-11 dogs with a spinal cord nephroblastoma.Medical records of dogs with a spinal cord nephroblastoma were reviewed. Information extracted included signalment, history, clinical signs, results of diagnostic testing, tumor location, treatment, and outcome. The diagnosis was confirmed through histologic review and WT-1 immunohistochemical staining of a tumor sample. In dogs with negative results for staining with WT-1, staining for cytokeratin, vimentin, and glial fibrillar acidic protein was performed.11 dogs had a spinal cord tumor with a histologic appearance and immunohistochemical staining consistent with a nephroblastoma. Positive results for staining with WT-1 were detected in 9 of 11 dogs. Age at admission ranged from 5 to 48 months (median, 14 months). Nine dogs were female. All had progressive paraparesis, paraplegia, or ataxia. Duration of clinical signs ranged from 2 to 60 days (median, 14 days). Median survival time was 30 days from the time of diagnosis. Median survival time in dogs treated via surgical resection was 70.5 days.The prognosis for dogs with a spinal cord nephroblastoma appeared to be poor, although combined surgical resection and radiation therapy may provide a good functional outcome. Results for staining with WT-1 can be used to support a diagnosis of nephroblastoma.
View details for Web of Science ID 000287680600017
View details for PubMedID 21355804