The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression.

Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1, has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1 remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1. Enforced expression of Rac1 induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1 mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1 mutation.

A 23-year-old Japanese man presented with a history of sudden-onset right abdominal pain accompanied by nausea and vomiting. Contrast-enhanced CT showed a large cluster on the right side of the retroperitoneum, with most of the small bowel incarcerated. The patient was diagnosed with small bowel obstruction caused by a right paraduodenal hernia, and emergency laparoscopic surgery was performed. The large retroperitoneal cluster on the right side contained almost all segments of the small bowel, although the incarcerated bowel showed no evidence of volvulus or ischemia. The bowel was reduced, and the hernia orifice was closed. The patient made good progress and was discharged 7 days after surgery. We herein report an acute case of right paraduodenal hernia with small bowel obstruction that was successfully treated with emergency laparoscopic surgery. With an early preoperative diagnosis, laparoscopic surgery is appropriate for the treatment of right paraduodenal hernia.

Background/Aim: In order to overcome postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP), we have developed a new simple technique-Clip on Staple method. Patients and Methods: In Clip on Staple method, pancreatic parenchyma was divided using a stapling device with a steppedheight staple design to make linear compression line, and thereafter, the full length of the staple line was reinforced by multiple clips. Clinical outcomes were retrospectively compared between Clip on Staple group (n=23) and Non-Clip group (n=38). Results: The incidence of clinically relevant POPF (CR-POPF) was significantly lower in the Clip on Staple group than in the Non-Clip group (4.3 and 36.8%, p=0.005). Multivariate logistic regression analysis revealed that only Clip on Staple method was an independent predictive factor of a decrease in the occurrence of CR-POPF. Conclusion: The Clip on Staple method, a simple and easily applicable technique even in laparoscopic surgery, significantly reduced the occurrence of CR-POPF among patients undergoing DP.