Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.

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Twenty-four lactating ewes (Manchega, n = 12; Lacaune, n = 12) in mid lactation were used to assess the short-term effects of different machine milking intervals (4, 8, 12, 16, 20, and 24 h) on milk yield, milk composition, and tight junction (TJ) permeability of mammary epithelia. Milk samples were analyzed for chemical composition, somatic cell count (SCC), and plasmin activity. Plasma lactose, and milk Na and K concentrations were used as indicators of TJ permeability. Milk accumulated linearly for up to 24 h, showing a different rate according to the milk yield of the breed (Manchega, 38 mL/h; Lacaune, 87 mL/h). Milking interval affected milk fat content, which decreased markedly from 4 to 24 h in both breeds, but no differences were observed in milk protein content. The milk contents of casein, true protein, lactose, and total solids also varied according to milking interval. Values of SCC did not vary by breed (175 x 10(3) cells/mL, on average), showing the lowest log(10) values for the 4-and 24-h milking intervals in both breeds. Plasmin activity in milk increased with milking interval until 20 h of udder filling in both breeds, and was poorly but positively correlated with SCC content (r = 0.39). Plasma lactose increased dramatically after 20 h of milk accumulation, indicating enhanced permeability of mammary TJ. As a result, an increase in Na concentration and in the Na:K ratio, and a decrease in K concentration, were observed in the milk of Manchega ewes. On the contrary, no differences in Na and K concentrations in milk were detected in Lacaune ewes. In conclusion, our results proved that Manchega and Lacaune dairy sheep could maintain high rates of milk secretion during extended milking intervals in the short term, with no effects on udder health and few negative effects on milk yield. Increased TJ permeability, caused by the effect of udder filling, induced changes in milk composition that were more marked in Manchega than in Lacaune ewes.

Aberrant expression of cell division cycle 20 (CDC20) is associated with malignant progression and poor prognosis in various types of cancer. The development of specific CDC20 inhibitors may be a novel strategy for the treatment of cancer with elevated expression of CDC20. The aim of the current study was to elucidate the role of CDC20 in cancer cell invasiveness and to identify novel natural inhibitors of CDC20. The authors found that CDC20 knockdown inhibited the migration of chemoresistant PANC-1 pancreatic cancer cells and the metastatic MDA-MB-231 breast cancer cell line. By contrast, the overexpression of CDC20 by plasmid transfection promoted the metastasizing capacities of the PANC-1 cells and MCF-7 breast cancer cells. It was also identified that a triterpene mixture extracted from the mushroom Poria cocos (PTE), purified triterpenes dehydropachymic acid, and polyporenic acid C (PPAC) downregulated the expression of CDC20 in PANC-1 cells dose-dependently. Migration was also suppressed by PTE and PPAC in a dose-dependent manner, which was consistent with expectations. Taken together, the present study is the first, to the best of our knowledge, to demonstrate that CDC20 serves an important role in cancer metastasis and that triterpenes from P. cocos inhibit the migration of pancreatic cancer cells associated with CDC20. Further investigations are in progress to investigate the specific mechanism associated with CDC20 and these triterpenes, which may have future potential use as natural agents in the treatment of metastatic cancer.

The aim of this work was to evaluate the effects of milking interval (4, 8, 12, 16, 20, and 24 h) on cisternal size and milk partitioning (cisternal and alveolar) in the udders of dairy ewes. Twenty-four dairy ewes (Manchega, n = 12; Lacaune, n = 12) were used in a 2-wk experiment during mid-lactation. Cisternal and alveolar milk yields were measured and milk samples from each udder fraction were collected for analysis. Cisternal milk was obtained after i.v. injection of an oxytocin receptor antagonist, and alveolar milk was obtained after i.v. injection of oxytocin. Enlargement of the cisternal compartment due to milking intervals was measured by ultrasonography for each half udder. Volumes of cisternal and alveolar milk differed according to breed, being greater in Lacaune (888 +/- 43 and 338 +/- 25 mL, respectively) than in Manchega ewes (316 +/- 43 and 218 +/- 25 mL, respectively). Alveolar milk increased linearly to 16 h in Manchega and 20 h in Lacaune and remained constant thereafter. Cisternal milk accumulated linearly to 24-h milking intervals in both breeds. Cisternal area (values per udder half) increased as milking interval increased, reaching a plateau at 20 h in Manchega (21 +/- 1 cm(2)) and 16 h in Lacaune (37 +/- 1 cm(2)). Correlation between cisternal area and cisternal milk was the greatest at 8 h (Manchega: r = 0.70 and Lacaune: r = 0.56). Cisternal area correlated with total milk (r = 0.80). Milk fat content varied markedly with milking intervals, increasing in alveolar milk (until 12 h in Manchega, 8.90 +/- 0.18%; and 20 h in Lacaune, 8.67 +/- 0.19%) and decreasing until 24 h in cisternal milk (5.74 +/- 0.29% and 4.85 +/- 0.29%, respectively). Milk protein content increased in alveolar milk until 24 h (Manchega, 6.46 +/- 0.11%; Lacaune, 5.95 +/- 0.11%), but did not vary in cisternal milk. Milk lactose content only decreased at the 24-h milking interval in the cisternal milk of Manchega ewes (4.60 +/- 0.04%). In conclusion, our results suggest that cisterns play an important role in accommodating secreted milk during extended milking intervals. Thus, long milking intervals could be a recommended strategy for large-cisterned dairy sheep. Evidence indicates that ultrasonography provides accurate estimations of udder cistern size and could be used as an indicator for selecting large-cisterned dairy ewes.

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