CCAR1/CoCoA pair-mediated recruitment of the Mediator defines a novel pathway for GATA1 function.

The MED1 subunit of the Mediator transcriptional coregulator complex coactivates GATA1 and induces erythropoiesis. Here, we show the dual mechanism of GATA1- and MED1-mediated transcription. MED1 expression levels in K562 erythroleukemia cells paralleled the levels of GATA1-targeted gene transcription and erythroid differentiation. An N-terminal fragment of MED1, MED1(1-602), which is incapable of interacting with GATA1, enhanced GATA1-targeted gene transcription and erythroid differentiation, and introduction of MED1(1-602) into Med1(-/-) mouse embryonic fibroblasts (MEFs) partially rescued GATA1-mediated transcription. The C-terminal zinc-finger domain of GATA1 interacts with the MED1(1-602)-interacting coactivator CCAR1, CoCoA and MED1(681-715). CCAR1 and CoCoA synergistically enhanced GATA1-mediated transcription from the γ-globin promoter in MEFs. Recombinant GATA1, CCAR1, CoCoA and MED1(1-602) formed a complex in vitro, and GATA1, CCAR1, CoCoA and MED1 were recruited to the γ-globin promoter in K562 cells during erythroid differentiation. Therefore, in addition to the direct interaction between GATA1 and MED1, CoCoA and CCAR1 appear to relay the GATA1 signal to MED1, and multiple modes of the GATA1-MED1 axis may help to fine-tune GATA1 function during GATA1-mediated homeostasis events.

Prospective study on planned biliary stent placement to treat small common bile duct stones.

Aims: Small common bile duct stones are known to occasionally clear spontaneously. This study aimed to prospectively assess the role of biliary stent placement in promoting the spontaneous clearance of small common bile duct stones. Methods and Results: We analyzed patients presenting with common bile duct stones of ≤5 mm diameter between June 2020 and May 2022. The exclusion criteria included asymptomatic patients, biliary pancreatitis, altered gastrointestinal anatomy, bile duct strictures (malignant or benign), and a history of EST. The biliary stents were inserted without stone removal. Stone clearance was assessed using endoscopic ultrasonography or endoscopic retrograde cholangiopancreatography after 3 months. Our primary endpoint was the clearance rate of common bile duct stones over 6 months, targeting a lower limit for the 95% confidence interval (CI) exceeding 25%. Of the 32 enrolled patients, 18 (56.3%; 95% CI: 37.7-73.6%) exhibited stone clearance. Early complications occurred in 11 patients (34.4%), totaling 12 incidents: acute cholecystitis in four, acute pancreatitis in three, biliary pain in three, and cholangitis in two patients. No severe complications occurred. Six (18.8%) patients experienced asymptomatic stent migration. Following stone clearance, four (12.5%) patients experienced stone recurrence, with an average duration of 256 ± 164 days. Conclusion: Biliary stenting appeared to effectively promote the clearance of small common bile duct stones in approximately half of the patients. However, the potential complications and risks of stone recurrence warrant close monitoring.This trial was registered in the Japan Registry of Clinical Trials (jRCT1042200020).

PML-RARα induces all-trans retinoic acid-dependent transcriptional activation through interaction with MED1.

Transcriptional activation by PML-RARα, an acute promyelocytic leukemia-related oncofusion protein, requires pharmacological concentrations of all-trans retinoic acid (ATRA). However, the mechanism by which the liganded PML-RARα complex leads to the formation of the preinitiation complex has been unidentified. Here we demonstrate that the Mediator subunit MED1 plays an important role in the ATRA-dependent activation of the PML-RARα-bound promoter. Luciferase reporter assays showed that PML-RARα induced significant transcription at pharmacological doses (1 µM) of ATRA; however, this was submaximal and equivalent to the level of transcription driven by intact RARα at physiological doses (1 nM) of ATRA. Transcription depended upon the interaction of PML-RARα with the two LxxLL nuclear receptor recognition motifs of MED1, and LxxLL→LxxAA mutations led to minimal transcription. Mechanistically, MED1 interacted ATRA-dependently with the RARα portion of PML-RARα through the two LxxLL motifs of MED1. These results suggest that PML-RARα initiates ATRA-induced transcription through its interaction with MED1.

A case of pancreatic cancer with severe vomiting treated by endoscopic ultrasound-guided celiac ganglia neurolysis.

A 50-year-old man with advanced pancreatic cancer was admitted for intractable severe vomiting 5-6 times a day, continuing over a week. He had been treated for advanced pancreatic cancer with chemotherapy for 6 months, and had undergone self-expandable metalic stent placement for obstructive jaundice due to the pancreatic cancer 4 months before admission. No abnormal findings suggesting gastrointestinal obstruction or brain metastasis were revealed on diagnostic imaging. We performed endoscopic ultrasound-guided celiac ganglia neurolysis twice by injecting ethanol into the celiac ganglion. After the treatments, the vomiting disappeared, and his eating habits gradually returned to normal. The patient died 7 months after treatment due to the advanced pancreatic cancer without recurrence of the vomiting.