TRIM24 (TIF1α), TRIM28 (TIF1β), and TRIM33 (TIF1γ) are three related cofactors belonging to the tripartite motif superfamily that interact with distinct transcription factors. TRIM24 interacts with the liganded retinoic acid (RA) receptor to repress its transcriptional activity. Germ line inactivation of TRIM24 in mice deregulates RA-signaling in hepatocytes leading to the development of hepatocellular carcinoma (HCC). Here we show that TRIM24 can be purified as at least two macromolecular complexes comprising either TRIM33 or TRIM33 and TRIM28. Somatic hepatocyte-specific inactivation of TRIM24, TRIM28, or TRIM33 all promote HCC in a cell-autonomous manner in mice. Moreover, HCC formation upon TRIM24 inactivation is strongly potentiated by further loss of TRIM33. These results demonstrate that the TIF1-related subfamily of TRIM proteins interact both physically and functionally to modulate HCC formation in mice.

The present retrospective study evaluates the diagnostic value of integrated ¹⁸F-Fluorocholine positron emission tomography/four-dimensional contrast-enhanced computed tomography (¹⁸F-FCH PET/4D-CT) as second-line imaging in preoperative work-up of primary hyperparathyroidism (pHPT), and compares ¹⁸F-FCH PET with 4D-CT. Patients with pHPT and negative/discordant first-line imaging addressed for integrated ¹⁸F-FCH PET/4D-CT were retrospectively selected. Sensitivity and detection rate (DR%) of ¹⁸F-FCH PET/CT, 4D-CT, and PET/4D-CT were calculated according to the per patient and per lesion analyses, and afterwards compared. Histology associated with a decrease more than 50% of perioperative parathyroid hormone (PTH) blood level was used as a gold standard. Persistent high serum PTH and calcium levels during a 6-month follow-up was considered as presence of pHPT in both operated and non-operated patients. 50 patients (55 glands) were included. 44/50 patients (88%) were surgically treated. On a per patient analysis, sensitivity was 93%, 80%, and 95%, and DR% was 82%, 68%, and 84%, respectively for PET/CT, 4D-CT, and PET/4D-CT. PET/CT was more sensitive than 4D-CT (p = 0.046). PET/4D-CT performed better than 4D-CT (p = 0.013) but was equivalent to PET/CT alone. On a per gland analysis, sensitivity PET/CT, 4D-CT, and PET/4D-CT was 88%, 66%, and 92%, and DR% was 79%, 57%, and 83%, respectively. PET/CT and PET/4D-CT were more sensitive than 4D-CT alone (p = 0.01, p < 0.001, respectively). However, PET/CT and PET/4D-CT performed similarly. In conclusion, ¹⁸F-FCH PET provides better identification of hyperfunctioning parathyroids than 4D-CT and the combination of both did not significantly improve diagnostic sensitivity. Further investigations involving larger populations are necessary to define the role of ¹⁸F-FCH PET/4D-CT as a “one-stop shop” second-line imaging in preoperative work-up of pHPT, especially considering the additional patient radiation exposure due to multi-phase CT.

Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1α (TIF1α), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1α is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1α resemble those seen in mice carrying an activating mutation of the calcium sensor receptor ( Casr ) gene and, in TIF1 α-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2 , Cyp24a1 , Trpv5 , Trpv6 , Calb1 , S100g , Pthlh , and Spp1 . Thus, our data indicate that TIF1α represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1 α deficiency. Interestingly, the calcifying arteriopathy of TIF1 α-null mutant mice shares features with the human age-related Mönckeberg's disease and, overall, the TIF1 α-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway.