Solute carrier family 39, member 14 (SLC39A14) is a transmembrane transporter that can mediate the cellular uptake of zinc, iron, and manganese (Mn). Studies of knockout () mice have documented that SLC39A14 is required for systemic growth, hepatic zinc uptake during inflammation, and iron loading of the liver in iron overload. The normal physiological roles of SLC39A14, however, remain incompletely characterized. Here, we report that mice spontaneously display dramatic alterations in tissue Mn concentrations, suggesting that Mn is a main physiological substrate for SLC39A14. Specifically, mice have abnormally low Mn levels in the liver coupled with markedly elevated Mn concentrations in blood and most other organs, especially the brain and bone. Radiotracer studies using Mn reveal that mice have impaired Mn uptake by the liver and pancreas and reduced gastrointestinal Mn excretion. In the brain of mice, Mn accumulated in the pons and basal ganglia, including the globus pallidus, a region susceptible to Mn-related neurotoxicity. Brain Mn accumulation in mice was associated with locomotor impairments, as assessed by various behavioral tests. Although a low-Mn diet started at weaning was able to reverse brain Mn accumulation in mice, it did not correct their motor deficits. We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues. The inability of Mn depletion to correct the motor deficits in mice suggests that the motor impairments represent lasting effects of early-life Mn exposure.
Postoperative mortality, morbidity, and length of stay in octogenarians are comparable to younger patients, while the overall survival is worse. With appropriate patient selection, good outcomes can be accomplished in octogenarians undergoing esophagectomy for cancer.
HighlightsMyoepithelial carcinoma of the vulva and epithelioid sarcoma has overlapping histological, immunohistochemical and genetic features.Similarities between two diagnoses in aggressive vulvar cancer should be noted as a sarcoma-based chemotherapy regimen should be considered.We recommend immediate surgical resection with bilateral superficial and deep inguinal lymph node dissections in these aggressive cancers.Identification of SMARCB1-deficiency trials of targeted therapies such as EZH2 inhibitors which show promise in halting further progression.
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