Preeclampsia (PE) is a multisystemic disease of pregnancy affecting 2–8% of women worldwide. PE-induced liver disease is a rare but important complication of pregnancy. The pathogenesis of liver dysfunction in PE is poorly understood, but is correlated with dysregulated angiogenic, inflammatory, and hypoxic events in the early phase of placental development. Because BPH/5 mice develop the maternal and fetal hallmarks of PE during pregnancy, we hypothesized that they may also share the clinicopathologic findings of the human PE-associated hemolysis elevated liver transaminases low platelets (HELLP) syndrome. Using this model, we determined that microangiopathic hemolysis, thrombocytopenia, and elevated liver enzymes do not occur in mid to late gestation. Pregnant BPH/5 mice do not develop histologic evidence of hepatic inflammation, but they do have increased microsteatosis scores at preconception and in mid to late gestation that progress to macrosteatosis in a subset of mice in late gestation. The transcriptional upregulation of TNF-α, CXCL-10, and TLR-2 occurs in mid gestation prior to the onset of macrosteatosis. The BPH/5 female mouse is not a model of HELLP syndrome, but may be a model of fatty liver disease associated with pregnancy.

Hepatobiliary neuroendocrine neoplasms are rare cancers in humans and dogs. To date, no large-scale primary hepatobiliary neoplasm omics analyses exist in any species. This limits the development of diagnostic biomarkers and targeted therapeutics. Neuroendocrine cancers are a heterogenous group of neoplasms categorized by their tissue-of-origin. Because the anatomic niche of neuroendocrine neoplasms shapes tumor phenotype, we sought to compare the proteomes of 3 canine hepatobiliary neoplasms to normal hepatobiliary tissue and adrenal glands with the objective of identifying unique protein signatures. Protein was extracted from formalin-fixed paraffin-embedded samples and submitted for tandem mass spectroscopy. Thirty-two upregulated and 126 downregulated differentially expressed proteins were identified. Remarkably, 6 (19%) of the upregulated proteins are correlated to non-hepatobiliary neuroendocrine neoplasia and 16 (50%) are functionally annotated within the exosome cellular compartment key to neuroendocrine signaling. Twenty-six (21%) downregulated proteins are enriched in metabolic pathways consistent with alterations in cancer. These results suggests that characteristic neoplastic protein signatures can be gleaned from small data sets using a comparative proteomics approach.

BPH/5 mice represent a superimposed model of preeclampsia that spontaneously develop maternal and fetal characteristics of preeclamptic pregnancies. In women, the development of preeclampsia is associated with pre‐existing dysregulation of lipid metabolism including hepatic steatosis. The study objective was tocharacterize the basal hepatic health of the female BPH/5 mouse to determine if hepatic steatosis precedes the preeclampsia‐like syndrome. We hypothesized that non‐pregnant female BPH/5 mice have an excess of hepatocellular lipid that promotes intrahepatic pro‐inflammatory cytokine production. Blood and liver samples were collected from 8–10‐week‐old BPH/5 non‐pregnant females (n=10) and 8–10‐week‐old C57Bl/6 non‐pregnant females (n=6). Liver and body weight were recorded. Biochemical markers of hepatocellular function (albumin, ALT, BUN, and bilirubin) were quantified. Hepatic RNA was isolated, and qPCR was used to evaluate pro‐inflammatory markers. H&E staining was used to evaluate hepatic histomorphology and lipid accumulation. There was no significant difference in albumin, ALT, BUN, or bilirubin between BPH/5 and C57Bl/6 mice. There was significantly higher hepatic CXCL‐2, CXCL‐10, IL‐1ß, TLR2, and TLR7 mRNA expression in BPH/5 versus C57Bl/6 mice (p<0.05). There was a significantly greater liver weight in BPH/5 mice compared to C57Bl/6 mice (p=0.05). The histologic microsteatosis score was significantly increased in the BPH/5 mice (2.5) compared to C57Bl/6 mice (0.98, p=0.025). The BPH/5 mouse has basal hepatic steatosis and a pro‐inflammatory hepatic phenotype that precedes pregnancy. Dysregulated lipid metabolism in the liver may contribute to the development of preeclampsia.

Hepatobiliary neuroendocrine neoplasia is an extremely rare cancer in humans and other species. In humans, neuroendocrine neoplasia of the liver and gallbladder represents less than 2% of all gastroenteropancreatic neuroendocrine neoplasia. In the veterinary literature, there is a paucity of information on hepatobiliary neuroendocrine cancer with only a small number of published studies. Improved characterization of these tumors is needed to identify additional biomarkers for diagnosis and generate informed treatment protocols for human and veterinary patients. Here, we applied a proteomics strategy to identify differentially expressed proteins in canine hepatobiliary neoplasia as compared to normal canine adrenal and liver tissue from formalin‐fixed paraffin‐embedded samples. Our objective was to identify unique protein biomarkers and possible chemotherapeutic targets. Thirty‐four up‐regulated, differentially expressed proteins were identified in the hepatobiliary neuroendocrine neoplasia samples. Galectin‐1, a multivalent carbohydrate binding protein known to play a role in lung and pancreatic neuroendocrine neoplasia development and progression, was among them. Drugs targeting the galectin family have shown promise as anticancer therapeutics in cervical cancer, prostate cancer, lung and pancreatic neuroendocrine neoplasia. Galectin‐1 may represent a novel treatment target in hepatobiliary neuroendocrine neoplasia in both humans and dogs.