Background/Aims: Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression. Methods: We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo. Results: Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice. Conclusions KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.

Clearance of a difficult biliary stone can be obtained using various interventional techniques such as endoscopic sphincterotomy followed by endoscopic papillary large balloon dilation, mechanical lithotripsy, peroral cholangioscopy-assisted intraductal electrohydraulic/laser lithotripsy, temporary plastic stent insertion, percutaneous transhepatic cholangioscopy-guided lithotripsy, and extracorporeal shock wave lithotripsy. We hereby describe the successful endoscopic treatment using various currently available interventional techniques in a case with multiple difficult common bile duct stones. Furthermore, we discuss the countermeasures to overcome the hurdles of each procedure.

Purpose: K-MASTER project is a Korean national precision medicine platform that screened actionable mutations by analyzing next-generation sequencing (NGS) of solid tumor patients. We compared gene analyses between NGS panel from the K-MASTER project and orthogonal methods. Materials and Methods: Colorectal, breast, non–small cell lung, and gastric cancer patients were included. We compared NGS results from K-MASTER projects with those of non-NGS orthogonal methods (KRAS, NRAS, and BRAF mutations in colorectal cancer [CRC]; epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] fusion, and reactive oxygen species 1 [ROS1] fusion in non–small cell lung cancer [NSCLC], and Erb-B2 receptor tyrosine kinase 2 (ERBB2) positivity in breast and gastric cancers). Results: In the CRC cohort (n=225), the sensitivity and specificity of NGS were 87.4% and 79.3% (KRAS); 88.9% and 98.9% (NRAS); and 77.8% and 100.0% (BRAF), respectively. In the NSCLC cohort (n=109), the sensitivity and specificity of NGS for EGFR were 86.2% and 97.5%, respectively. The concordance rate for ALK fusion was 100%, but ROS1 fusion was positive in only one of three cases that were positive in orthogonal tests. In the breast cancer cohort (n=260), ERBB2 amplification was detected in 45 by NGS. Compared with orthogonal methods that integrated immunohistochemistry and in situ hybridization, sensitivity and specificity were 53.7% and 99.4%, respectively. In the gastric cancer cohort (n=64), ERBB2 amplification was detected in six by NGS. Compared with orthogonal methods, sensitivity and specificity were 62.5% and 98.2%, respectively. Conclusion The results of the K-MASTER NGS panel and orthogonal methods showed a different degree of agreement for each genetic alteration, but generally showed a high agreement rate.

Background: Microcirculatory disturbances are typically most severe during cardiopulmonary bypass (CPB), which occurs during cardiac surgeries. If microvascular reactivity compensates for microcirculatory disturbances during CPB, tissue hypoxemia can be minimized. The primary aim of this study was to assess whether microvascular reactivity during CPB could predict major adverse events (MAE) after cardiac surgery. Methods: This prospective observational study included 115 patients who underwent elective on-pump cardiac surgeries. A vascular occlusion test (VOT) with near-infrared spectroscopy was performed five times for each patient: before the induction of general anesthesia, 30 min after the induction of general anesthesia, 30 min after applying CPB, 10 min after protamine injection, and post-sternal closure. The postoperative MAE was recorded. The area under the receiver operating characteristic (AUROC) curve analysis was performed for the prediction of MAE using the recovery slope. Results: Of the 109 patients, MAE occurred in 32 (29.4%). The AUROC curve for the recovery slope during CPB was 0.701 (P < 0.001; 95% CI [0.606, 0.785]). If the recovery slope during CPB was < 1.08%/s, MAE were predicted with a sensitivity of 62.5% and specificity of 72.7%. Conclusions Our study demonstrated that the recovery slope of the VOT during CPB could predict MAE after cardiac surgery. These results support the idea that disturbances in microcirculation induced by CPB can predict the development of poor clinical outcomes, thereby demonstrating the potential role of microvascular reactivity as an early predictor of MAE after cardiac surgery.

Background: Diabetic nephropathy (DN) is characterized by albuminuria and accumulation of extracellular matrix (ECM) in kidney. Transforming growth factor-β (TGF-β) plays a central role in promoting ECM accumulation. We aimed to examine the effects of EW-7197, an inhibitor of TGF-β type 1 receptor kinase (ALK5), in retarding the progression of DN, both in vivo, using a diabetic mouse model (db/db mice), and in vitro, in podocytes and mesangial cells. Methods: In vivo study: 8-week-old db/db mice were orally administered EW-7197 at a dose of 5 or 20 mg/kg/day for 10 weeks. Metabolic parameters and renal function were monitored. Glomerular histomorphology and renal protein expression were evaluated by histochemical staining and Western blot analyses, respectively. In vitro study: DN was induced by high glucose (30 mM) in podocytes and TGF-β (2 ng/mL) in mesangial cells. Cells were treated with EW-7197 (500 nM) for 24 hours and the mechanism associated with the attenuation of DN was investigated. Results: Enhanced albuminuria and glomerular morphohistological changes were observed in db/db compared to that of the nondiabetic (db/m) mice. These alterations were associated with the activation of the TGF-β signaling pathway. Treatment with EW-7197 significantly inhibited TGF-β signaling, inflammation, apoptosis, reactive oxygen species, and endoplasmic reticulum stress in diabetic mice and renal cells. Conclusion EW-7197 exhibits renoprotective effect in DN. EW-7197 alleviates renal fibrosis and inflammation in diabetes by inhibiting downstream TGF-β signaling, thereby retarding the progression of DN. Our study supports EW-7197 as a therapeutically beneficial compound to treat DN.

To explore the potential function of interleukin-13 (IL-13), lipopolysaccharide (LPS) or PBS as a control was unilaterally microinjected into striatum of rat brain. Seven days after LPS injection, there was a significant loss of neurons and microglial activation in the striatum, visualized by immunohistochemical staining against neuronal nuclei (NeuN) and the OX-42 (complement receptor type 3, CR3), respectively. In parallel, IL-13 immunoreactivity was increased as early as 3 days and sustained up to 7 days post LPS injection, compared to PBS-injected control and detected exclusively within microglia. Moreover, GFAP immunostaining and blood brain barrier (BBB) permeability evaluation showed the loss of astrocytes and disruption of BBB, respectively. By contrast, treatment with IL-13 neutralizing antibody (IL-13NA) protects NeuN + neurons against LPSinduced neurotoxicity in vivo . Accompanying neuroprotection, IL-13NA reduced loss of GFAP + astrocytes and damage of BBB in LPS-injected striatum. Intriguingly, treatment with IL-13NA produced neurotrophic factors (NTFs) on survived astrocytes in LPS-injected rat striatum. Taken together, the present study suggests that LPS induces expression of IL-13 on microglia, which contributes to neurodegeneration via damage on astrocytes and BBB disruption in the striatum in vivo.

Purpose: Next-generation sequencing (NGS) can facilitate precision medicine approaches in metastatic colorectal cancer (mCRC) patients. We investigated the molecular profiling of Korean mCRC patients under the K-MASTER project which was initiated in June 2017 as a nationwide precision medicine oncology clinical trial platform which used NGS assay to screen actionable mutations. Materials and Methods: As of 22 January 2020, total of 994 mCRC patients were registered in K-MASTER project. Targeted sequencing was performed using three platforms which were composed of the K-MASTER cancer panel v1.1 and the SNUH FIRST Cancer Panel v3.01. If tumor tissue was not available, cell-free DNA was extracted and the targeted sequencing was performed by Axen Cancer Panel as a liquid biopsy. Results: In 994 mCRC patients, we found 1,564 clinically meaningful pathogenic variants which mutated in 71 genes. Anti-EGFR therapy candidates were 467 patients (47.0%) and BRAF V600E mutation (n=47, 4.7%), deficient mismatch repair/microsatellite instability–high (n=15, 1.5%), HER2 amplifications (n=10, 1.0%) could be incorporated with recently approved drugs. The patients with high tumor mutation burden (n=101, 12.7%) and DNA damaging response and repair defect pathway alteration (n=42, 4.2%) could be enrolled clinical trials with immune checkpoint inhibitors. There were more colorectal cancer molecular alterations such as PIK3CA, KRAS G12C, atypical BRAF, and HER2 mutations and even rarer but actionable genes that approved or ongoing clinical trials in other solid tumors. Conclusion K-MASTER project provides an intriguing background to investigate new clinical trials with biomarkers and give therapeutic opportunity for mCRC patients.

The Chiari network is an embryonic remnant of the sinus venosus valve, which is characterized by a fenestrated, netlike structure in the right atrium and has the potential to be misdiagnosed as another right atrial pathology. Additionally, the Chiari network has been frequently reported to entrap intracardiac devices during surgical procedures. In this case report, we present two patients with a Chiari network confirmed by three-dimensional transesophageal echocardiography, which assisted in preventing device entrapment during intracardiac procedures.

The Chiari network is an embryonic remnant of the sinus venosus valve, which is characterized by a fenestrated, netlike structure in the right atrium and has the potential to be misdiagnosed as another right atrial pathology. Additionally, the Chiari network has been frequently reported to entrap intracardiac devices during surgical procedures. In this case report, we present two patients with a Chiari network confirmed by three-dimensional transesophageal echocardiography, which assisted in preventing device entrapment during intracardiac procedures.

Thromboelastography or rotational thromboelastometry, is being increasingly utilized in cardiac surgery of late. However, it is an indirect test and is not available in all centers. Low fibrinogen levels before and after cardiopulmonary bypass (CPB) have been described to be associated with postoperative bleeding in cardiac surgery. This study explored the usefulness of reduction ratio of the fibrinogen levels before CPB (preCPB) and after CPB (postCPB) in predicting postoperative hemorrhage. A retrospective, observational study of adult patients who underwent cardiac surgery with CPB between February 2014 and January 2016 was conducted, which included a total of 264 patients. The fibrinogen levels were measured twice, preCPB and postCPB, and the fibrinogen reduction ratio was acquired [(preCPB − postCPB)/preCPB]. Postoperative blood loss, which was defined as the blood collected from the chest drain for 12 hours following arrival at the intensive care unit, was considered severe if it was more than 1,000 mL. A multivariate analysis showed that fibrinogen reduction ratio, sex, and postCPB platelet count were significantly associated with severe postoperative bleeding. However, the pre- and postCPB fibrinogen levels were not significantly associated with severe bleeding. Furthermore, a fibrinogen reduction ratio of > 41.3% was independently associated with postoperative severe bleeding, with an odds ratio of 3.472 (1.483–8.162). These results suggest that the reduction ratio of pre- and postCPB fibrinogen levels may be utilized in predicting postoperative bleeding.