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.
The outcomes of emergency surgery for acute abdomen were significantly worse for dialysis patients than for non-dialysis patients. Prompt diagnosis, initiation of the most suitable surgical procedure, and meticulous postoperative cares are imperative to improving the surgical outcomes of dialysis patients.
Background Intraductal papillary neoplasm of the bile duct (IPNB) is characterized by an intraluminal, growing papillary tumor covered by neoplastic biliary epithelial cells with a fine fibrovascular core. IPNB was introduced as a precancerous and early neoplastic lesion in the 2010 World Health Organization classification of tumors of the digestive system. IPNB eventually invades the bile duct wall and progresses to invasive cholangiocarcinoma. IPNB resembles intraductal papillary mucinous neoplasm of the pancreas (IPMN), particularly the main pancreatic duct type. IPNB cases, possibly corresponding to branch-type IPMN, have been recently reported, and these cases involved the peribiliary glands significantly and showed gross cystic dilatation. Small branch-type intrahepatic IPNB often mimics simple liver cysts, making the diagnosis of IPNB difficult. Some literature recommended surgical resection for treatment. Laparoscopic resection is a good treatment option for small tumor. We herein present the case of branch-type IPNB that was treated with laparoscopic anatomical liver resection 5 years after being detected. Case presentation A 64-year-old woman was undergoing follow-up for primary aldosteronism. In 2012, follow-up computed tomography (CT) incidentally revealed a 7-mm cystic lesion in segment 8 of the liver. From 2012 to 2017, the cystic lesion kept increasing in size, reaching 17 mm. In 2017, CT also revealed a 13-mm mural nodule in the cyst wall. Therefore, the patient was referred to our department for possible malignancy. We suspected a branch-type IPNB; however, the mass was small and diagnosis could not be made without performing biopsy. Accordingly, surgical resection was performed for diagnosis and treatment. Because branch-type IPNB might show horizontal spread through the intrahepatic bile duct, we believed that anatomical resection of the liver was appropriate considering the malignant potential of the lesion. Therefore, laparoscopic anatomical resection of segment 8 of the liver was performed. The resected tumor measured 17 mm and was histologically diagnosed as a high-grade IPNB. Conclusion Branch-type IPNBs are rare but can potentially lead to malignant tumors. Surgical resection is the treatment of choice, with laparoscopic anatomical resection being a good treatment option for this small tumor.
We herein present the case of a 77-year-old man who had fever and right hypochondriac pain. He visited his doctor and underwent contrast computed tomography (CT), and he was suspected to have a liver abscess. He received an antibiotic treatment and his symptoms soon disappeared, but the tumor did not get smaller and its density on contrast CT image got stronger. He underwent biopsy and moderately differentiated hepatocellular carcinoma (HCC) was found. Extended left hepatic and caudate lobectomy was performed. Histological examination showed moderately differentiated HCC with narrowing and occlusion both in the arteries and portal veins associated with mild chronic inflammation. The mechanisms of spontaneous regression of HCC, such as immunological reactions and tumor hypoxia, have been proposed. In our case, histological examination showed the same findings. However, the mechanism is complex, and therefore further investigations are essential to elucidate it.
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