Steatoapoptosis is a hallmark of non-alcoholic fatty liver disease (NAFLD) and is an important factor in liver disease progression. We hypothesized that increased reactive oxygen species resulting ...

Testicular germ cell tumors (TGCTs) are among the most responsive solid cancers to conventional chemotherapy. To elucidate the underlying mechanisms, we developed a mouse TGCT model featuring germ cell-specific Kras activation and Pten inactivation. The resulting mice developed malignant, metastatic TGCTs composed of teratoma and embryonal carcinoma, the latter of which exhibited stem cell characteristics, including expression of the pluripotency factor OCT4. Consistent with epidemiological data linking human testicular cancer risk to in utero exposures, embryonic germ cells were susceptible to malignant transformation, whereas adult germ cells underwent apoptosis in response to the same oncogenic events. Treatment of tumor-bearing mice with genotoxic chemotherapy not only prolonged survival and reduced tumor size but also selectively eliminated the OCT4-positive cancer stem cells. We conclude that the chemosensitivity of TGCTs derives from the sensitivity of their cancer stem cells to DNA-damaging chemotherapy.

The hypotheses that endophyte (Neotyphodium coenophialum)-infected tall fescue (TF) seed causes vasoconstriction in horses in vivo and that ground seed would cause more pronounced vasoconstriction than whole seed were tested. Ten horses each received 1 of 3 treatments: endophyte-free ground (E–G; n = 4 horses) seed, endophyte-positive whole (E+W; n = 3) seed, or endophyte-positive ground (E+G; n = 3) seed. There were two 14-d periods, P1 and P2. During P1, animals were adapted to a concentrate (0.2% BW, as fed, twice daily) and alfalfa cubes. During P2, the seed was mixed into the concentrate portion of the diet and alfalfa cubes were offered ad libitum. Fescue seed was fed in increasing amounts ranging from 0.02% BW on d 1 (averaging 76 ug/kg ergovaline + ergovalinine) to 0.22% BW on d 11 to 14 (averaging 713 ug/kg ergovaline + ergovalinine). The distal palmar artery of the left foreleg of each horse was scanned via Doppler ultrasonography for 4 d during each period, with 5 replicate scans performed on each scanning day. The measurements taken at each scan included artery luminal diameter, area, and circumference, peak systolic velocity, end diastolic velocity and blood flow variables. Animal temperature, heart rate, and respiration rate and ambient temperature and humidity were also recorded. Blood samples were taken on each scanning day to measure inflammatory cytokine mRNA abundances, and blood samples were collected on d 0, 4, 8, and 14 of P2 to measure prolactin concentrations. Consumption of E+G TF seed caused decreased artery lumen diameter (P = 0.0033), area (P = 0.0406), and circumference (P = 0.0480) compared with E–G seed, and E+W seed produced an intermediate response. Blood flow volume was reduced (P < 0.05) during P2 in horses receiving E+G seed compared with horses receiving E–G seed. Other ultrasound variables were not different (P > 0.05) among treatment groups, and neither were cytokine mRNA or prolactin concentrations. Treatment did not alter (P > 0.05) animal temperature, heart rate, or respiration rate, and neither ambient temperature nor relative humidity was consistently correlated with any response variable measured. Taken together, these data confirm that consumption of E+G fescue seed caused vasoconstriction in horses, which could be readily measured by Doppler ultrasonography. Use of Doppler ultrasound to monitor the diameter of the palmar artery of horses grazing endophyte-infected (E+) fescue pastures may provide a convenient and satisfactory biomarker to determine premonitory signs of fescue toxicosis. Copyright © 2013. American Society of Animal Science .

Defects in the Fanconi anemia (FA) DNA damage–response pathway result in genomic instability, developmental defects, hematopoietic failure, cancer predisposition, and metabolic disorders. The endogenous sources of damage contributing to FA phenotypes and the links between FA and metabolic disease remain poorly understood. Here, using mice lacking the Fancd2 gene, encoding a central FA pathway component, we investigated whether the FA pathway protects against metabolic challenges. Fancd2^−/− and wildtype (WT) mice were fed a standard diet (SD), a diet enriched in fat, cholesterol, and cholic acid (Paigen diet), or a diet enriched in lipid alone (high-fat diet (HFD)). Fancd2^−/− mice developed hepatobiliary disease and exhibited decreased survival when fed a Paigen diet but not a HFD. Male Paigen diet–fed mice lacking Fancd2 had significant biliary hyperplasia, increased serum bile acid concentration, and increased hepatic pathology. In contrast, female mice were similarly impacted by Paigen diet feeding regardless of Fancd2 status. Upon Paigen diet challenge, male Fancd2^−/− mice had altered expression of genes encoding hepatic bile acid transporters and cholesterol and fatty acid metabolism proteins, including Scp2/x, Abcg5/8, Abca1, Ldlr, Srebf1, and Scd-1. Untargeted lipidomic profiling in liver tissue revealed 132 lipid species, including sphingolipids, glycerophospholipids, and glycerolipids, that differed significantly in abundance depending on Fancd2 status in male mice. We conclude that the FA pathway has sex-specific impacts on hepatic lipid and bile acid metabolism, findings that expand the known functions of the FA pathway and may provide mechanistic insight into the metabolic disease predisposition in individuals with FA.

Testicular germ cell tumors (TGCTs) are exceptionally sensitive to genotoxic chemotherapy, resulting in a high cure rate for the young men presenting with these malignancies. However, this treatment is associated with significant toxicity, and a subset of malignant TGCTs demonstrate chemoresistance. Mixed nonseminomas often contain pluripotent embryonal carcinoma (EC) cells, the cancer stem cells (CSCs) of these tumors. We hypothesized that differentiation therapy, a treatment strategy which aims to induce differentiation of tumor-propagating CSCs to slow tumor growth, could effectively treat mixed nonseminomas without significant toxicity. The FDA-approved antipsychotic thioridazine and the agricultural antibiotic salinomycin are two drugs previously found to selectively target CSCs, and here we report that these agents differentiate EC cells in vitro and greatly reduce their tumorigenic potential in vivo. Using a novel transformed induced pluripotent stem cell allograft model and a human xenograft model, we show that thioridazine extends the survival of tumor-bearing mice and can reduce the number of pluripotent EC cells within tumors. These results suggest that thioridazine could be repurposed as an alternative TGCT treatment that avoids the toxicity of conventional chemotherapeutics.

Ambrosia beetles (Coleoptera: Curculionidae: Scolytinae) are among the most devastating pests of orchards, nurseries, and forest ecosystems. Anisandrus maiche (Kurentzov) has been regularly captured in ethanol-baited traps along woody edges of apple (Malus domestica (Suckow) Borkh.) orchards in western New York alongside a known apple pest, Xylosandrus germanus (Blandford). However, this species has yet to be a confirmed pest of apple trees. In winter 2024, we conducted a series of dissections of potted apple trees with visible ambrosia beetle attacks (i.e. entry holes, exit holes). Our examination revealed the presence of active A. maiche galleries housing mainly larvae, a few adults, and the fungal symbiont Ambrosiella cleistominuta C. Mayers & T.C. Harr This is a first report of Anisandrus maiche attacking apple trees.