Publications by authors named "Dong Joon Kim"

433 Publications

Stent Opening Visualization During Mechanical Thrombectomy; Relationship with the Retrieved Clot and Procedural Success.

J Stroke Cerebrovasc Dis 2021 Oct 20;31(1):106168. Epub 2021 Oct 20.

Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Purpose: The angiographic visualization of the stent during mechanical thrombectomy (MT) may provide information regarding the characteristics of the underlying occluding clot, device-clot interaction, and recanalization. The purpose of this study was to evaluate the open stent sign in relation to the retrieved clot and recanalization.

Methodology: 78 patients treated with the stent retriever for acute stroke were retrospectively reviewed. The open stent sign was defined as full opening (>80% of normal vessel diameter) of the stent on DSA after deployment across the occlusion. The retrieved clot was visually classified as red or non-red clots. The relationship between the open stent sign and the patient characteristics, recanalization, retrieved clot, and clinical outcome were analyzed.

Results: Overall successful recanalization and good outcome was achieved in 68 (87.2%) and 35 (44.9%) patients, respectively. Open stent sign was seen in 52 patients (66.7%). Occlusions showing positive open stent sign was associated with significantly higher first pass effect (44.2% vs 19.2%, p=0.044) and successful recanalization rate (94.2% vs 73.1%, p=0.013) compared to negative open stent sign. The open stent sign was associated with higher incidence of red clot (75.0% vs 38.9%, p=0.008). On multivariate analysis, the open stent sign (OR 22.721, 95% CI 1.953-264.372, p=0.013) was a predictor of successful recanalization.

Conclusions: The visualization of the open stent during MT of acute ischemic stroke may provide added information in terms of clot characteristics and procedural success. The open stent sign is associated with red clots, higher first pass effect and successful recanalization.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106168DOI Listing
October 2021

Gut Microbiota-Related Cellular and Molecular Mechanisms in the Progression of Nonalcoholic Fatty Liver Disease.

Cells 2021 Oct 2;10(10). Epub 2021 Oct 2.

Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24253, Korea.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common and increasing liver diseases worldwide. NAFLD is a term that involves a variety of conditions such as fatty liver, steatohepatitis, or fibrosis. Gut microbiota and its products have been extensively studied because of a close relation between NAFLD and microbiota in pathogenesis. In the progression of NAFLD, various microbiota-related molecular and cellular mechanisms, including dysbiosis, leaky bowel, endotoxin, bile acids enterohepatic circulation, metabolites, or alcohol-producing microbiota, are involved. Currently, diagnosis and treatment techniques using these mechanisms are being developed. In this review, we will introduce the microbiota-related mechanisms in the progression of NAFLD and future directions will be discussed.
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http://dx.doi.org/10.3390/cells10102634DOI Listing
October 2021

Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients.

J Gastroenterol Hepatol 2021 Oct 15. Epub 2021 Oct 15.

Department of Precision Medicine, Sungkyunkwan University, School of Medicine, Suwon, Republic of Korea.

Background/aims: Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy.

Methods: This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed.

Results: A total of 46 CHB patients received liver biopsies (BSV, n = 29; TDF, n = 17). After 48 weeks of treatment, virological response rate was comparable between the groups (P = 0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% versus 36.4%, P = 0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48 weeks of BSV or TDF treatment (P <0.001) without intergroup differences (P = 0.349).

Conclusions: BSV therapy improves hepatic histology and decreases intrahepatic cccDNA in CHB patients.
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http://dx.doi.org/10.1111/jgh.15710DOI Listing
October 2021

'First week' is the crucial period for deciding living donor liver transplantation in patients with acute-on-chronic liver failure.

Hepatol Int 2021 Oct 4. Epub 2021 Oct 4.

Department of Hepatology, Cardinal Santos Medical Centre, Manila, Philippines.

Background And Aims: Acute-on-chronic liver failure (ACLF) is a rapidly progressive illness with high short-term mortality. Timely liver transplant (LT) may improve survival. We evaluated various indices for assessment of the severity of liver failure and their application for eligibility and timing of living donor LT (LDLT).

Methods: Altogether 1021 patients were analyzed for the severity and organ failure at admission to determine transplant eligibility and 28 day survival with or without transplant.

Results: The ACLF cohort [mean age 44 ± 12.2 years, males 81%) was of sick patients; 55% willing for LT at admission, though 63% of them were ineligible due to sepsis or organ failure. On day 4, recovery in sepsis and/or organ failure led to an improvement in transplant eligibility from 37% at baseline to 63.7%. Delay in LT up to 7 days led to a higher incidence of multiorgan failure (p < 0.01) contributing to 23% of the first week and 55% of all-cause 28-day mortality. In a matched cohort analysis, the actuarial survival with LT (n = 41) and conditional survival in the absence of transplant (n = 191) were comparable, when the condition, i.e., transplant was adjusted. The comparison curve showed differentiation in survival beyond 7 days (p < 0.01).

Conclusions: ACLF is a rapidly progressive disease and risk stratification within the first week of hospitalization is needed. 'Emergent LT' should be defined in the first week in the ACLF patients; the transplant window for improving survival in a live donor setting.
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http://dx.doi.org/10.1007/s12072-021-10206-6DOI Listing
October 2021

Sec-O-glucosylhamaudol mitigates inflammatory processes and autophagy via p38/JNK MAPK signaling in a rat neuropathic pain model.

Korean J Pain 2021 Oct;34(4):405-416

Department of Anesthesiology and Pain Medicine, Chosun University Hospital, Gwangju, Korea.

Background: This study investigated the effect of intrathecal Sec-O-glucosylhamaudol (SOG) on the p38/c-Jun N-terminal kinase (JNK) signaling pathways, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-related inflammatory responses, and autophagy in a spinal nerve ligation (SNL)-induced neuropathic pain model.

Methods: The continuous administration of intrathecal SOG via an osmotic pump was performed on male Sprague-Dawley rats (n = 50) with SNL-induced neuropathic pain. Rats were randomized into four groups after the 7th day following SNL and treated for 2 weeks as follows (each n = 10): Group S, sham-operated; Group D, 70% dimethylsulfoxide; Group SOG96, SOG at 96 μg/day; and Group SOG192, SOG at 192 μg/day. The paw withdrawal threshold (PWT) test was performed to assess neuropathic pain. Western blotting of the spinal cord (L5) was performed to measure changes in the expression of signaling pathway components, cytokines, and autophagy. Additional studies with naloxone challenge (n = 10) and cells were carried out to evaluate the potential mechanisms underlying the effects of SOG.

Results: Continuous intrathecal SOG administration increased the PWT with p38/JNK mitogen-activated protein kinase (MAPK) pathway and NF-κB signaling pathway inhibition, which induced a reduction in proinflammatory cytokines with the concomitant downregulation of autophagy.

Conclusions: SOG alleviates mechanical allodynia, and its mechanism is thought to be related to the regulation of p38/JNK MAPK and NF-κB signaling pathways, associated with autophagy during neuroinflammatory processes after SNL.
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http://dx.doi.org/10.3344/kjp.2021.34.4.405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494959PMC
October 2021

Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR.

Phytother Res 2021 Sep 20. Epub 2021 Sep 20.

The Pathophysiology Department, The School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

Harmaline is a naturally occurring β-carboline alkaloid that is isolated from Peganum harmala. It has shown efficacy in treating Parkinson's disease and has been reported to exhibit antimicrobial and anticancer properties. However, the molecular mechanism of harmaline in the context of esophageal squamous cell carcinoma (ESCC) has not been characterized. Here, we report that harmaline attenuates ESCC growth by directly targeting the mammalian target of rapamycin (mTOR). Harmaline strongly reduced cell proliferation and anchorage-independent cell growth. Additionally, harmaline treatment induced G2/M phase cell-cycle arrest through upregulation of p27. The results of in vitro and cell-based assays showed that harmaline directly inhibited the activity of mTOR kinase and the phosphorylation of its downstream pathway components. Depletion of mTOR using an shRNA-mediated strategy in ESCC cell lines indicated that reduced mTOR protein expression levels are correlated with decreased cell proliferation. Additionally, we observed that the inhibitory effect of harmaline was dependent upon mTOR expression. Notably, oral administration of harmaline suppressed ESCC patient-derived tumor growth in vivo. Taken together, harmaline is a potential mTOR inhibitor that might be used for therapeutically treating ESCC.
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http://dx.doi.org/10.1002/ptr.7289DOI Listing
September 2021

Outcome in Patients Treated with Intra-arterial thrombectomy: The optiMAL Blood Pressure control (OPTIMAL-BP) Trial.

Int J Stroke 2021 Aug 29:17474930211041213. Epub 2021 Aug 29.

Department of Neurology, Chosun University School of Medicine, Gwangju, Korea.

Rationale: Very early stage blood pressure (BP) levels may affect outcome in stroke patients who have successfully undergone recanalization following intra-arterial treatment, but the optimal target of BP management remains uncertain.

Aim: We hypothesized that the clinical outcome after intensive BP-lowering is superior to conventional BP control after successful recanalization by intra-arterial treatment.

Sample-size Estimates: We aim to randomize 668 patients (334 per arm), 1:1.

Methods And Design: We initiated a multicenter, prospective, randomized, open-label trial with a blinded end-point assessment (PROBE) design. After successful recanalization (thrombolysis in cerebral infarction score ≥ 2 b), patients with elevated systolic BP level, defined as the mean of two readings ≥ 140 mmHg, will be randomly assigned to the intensive BP-lowering (systolic BP < 140 mm Hg) group or the conventional BP-lowering (systolic BP, 140-180 mm Hg) group.

Study Outcomes: The primary efficacy outcomes are from dichotomized analysis of modified Rankin Scale (mRS) scores at three months (mRS scores: 0-2 vs. 3-6). The primary safety outcomes are symptomatic intracerebral hemorrhage and death within three months.

Discussion: The OPTIMAL-BP trial will provide evidence for the effectiveness of active BP control to achieve systolic BP < 140 mmHg during 24 h in patients with successful recanalization after intra-arterial treatment.

Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04205305.
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http://dx.doi.org/10.1177/17474930211041213DOI Listing
August 2021

The Gut Microbiota-Derived Immune Response in Chronic Liver Disease.

Int J Mol Sci 2021 08 2;22(15). Epub 2021 Aug 2.

Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon 24253, Korea.

In chronic liver disease, the causative factor is important; however, recently, the intestinal microbiome has been associated with the progression of chronic liver disease and the occurrence of side effects. The immune system is affected by the metabolites of the microbiome, and diet is the primary regulator of the microbiota composition and function in the gut-liver axis. These metabolites can be used as therapeutic material, and postbiotics, in the future, can increase or decrease human immunity by modulating inflammation and immune reactions. Therefore, the excessive intake of nutrients and the lack of nutrition have important effects on immunity and inflammation. Evidence has been published indicating that microbiome-induced chronic inflammation and the consequent immune dysregulation affect the development of chronic liver disease. In this research paper, we discuss the overall trend of microbiome-derived substances related to immunity and the future research directions.
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http://dx.doi.org/10.3390/ijms22158309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347749PMC
August 2021

Identification of Video Game Addiction Using Heart-Rate Variability Parameters.

Sensors (Basel) 2021 Jul 8;21(14). Epub 2021 Jul 8.

Department of Clothing and Textiles, Kyung Hee University, Seoul 02447, Korea.

The purpose of this study is to determine heart rate variability (HRV) parameters that can quantitatively characterize game addiction by using electrocardiograms (ECGs). 23 subjects were classified into two groups prior to the experiment, 11 game-addicted subjects, and 12 non-addicted subjects, using questionnaires (CIUS and IAT). Various HRV parameters were tested to identify the addicted subject. The subjects played the game for 30-40 min. The experimenter measured ECG during the game at various window sizes and specific events. Moreover, correlation and factor analyses were used to find the most effective parameters. A logistic regression equation was formed to calculate the accuracy in diagnosing addicted and non-addicted subjects. The most accurate set of parameters was found to be pNNI20, RMSSD, and LF in the 30 s after the "being killed" event. The logistic regression analysis provided an accuracy of 69.3% to 70.3%. AUC values in this study ranged from 0.654 to 0.677. This study can be noted as an exploratory step in the quantification of game addiction based on the stress response that could be used as an objective diagnostic method in the future.
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http://dx.doi.org/10.3390/s21144683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309595PMC
July 2021

Combination of Rescue Stenting and Antiplatelet Infusion Improved Outcomes for Acute Intracranial Atherosclerosis-Related Large-Vessel Occlusion.

Front Neurol 2021 5;12:608270. Epub 2021 Jul 5.

Department of Radiology, Seoul National University Bundang Hospital, Seongnam, South Korea.

Intracranial atherosclerosis-related large-vessel occlusion caused by thrombo-occlusion (ICAS-LVO) has been regarded an important reason for refractoriness to mechanical thrombectomy (MT). To achieve better outcomes for ICAS-LVO, different endovascular strategies should be explored. We aimed to investigate an optimal endovascular strategy for ICAS-LVO. We retrospectively reviewed three prospective registries of acute stroke underwent endovascular treatment. Among them, patients with ICAS-LVO were assigned to four groups based on their endovascular strategy: (1) , (2) rescue intracranial stenting after MT failure (), (3) glycoprotein IIb/IIIa inhibitor infusion after MT failure (), and (4) a combination of MT-RS and MT-GPI (+). Baseline characteristics and outcomes were compared among the groups. To evaluate whether the endovascular strategy resulted in favorable outcome, multivariable analysis was also performed. A total of 184 patients with ICAS-LVO were included. Twenty-four patients (13.0%) were treated with MT alone, 25 (13.6%) with MT-RS, 84 (45.7%) with MT-GPI, and 51 (27.7%) with MT-RS+GPI. The MT-RS+GPI group showed the highest recanalization efficiency (98.0%). Frequency of patent arteries on follow-up (98.0%, < 0.001) and favorable outcome (84.3%, < 0.001) were higher in the MT-RS+GPI group than other groups. The MT-RS+GPI strategy remained an independent factor for favorable outcome (odds ratio, 20.4; 95% confidence interval, 1.97-211.4; = 0.012). Endovascular strategy was significantly associated with procedural and clinical outcomes in acute stroke by ICAS-LVO. A combination of RS and GPI infusion might be an optimal rescue modality when frontline MT fails.
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http://dx.doi.org/10.3389/fneur.2021.608270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287123PMC
July 2021

Dynamic assessments of hepatic encephalopathy and ammonia levels predict mortality in acute-on-chronic liver failure.

Hepatol Int 2021 Aug 18;15(4):970-982. Epub 2021 Jul 18.

Department of Medicine, Ankara University School of Medicine, Ankara, Turkey.

Background: We evaluated the dynamics of hepatic encephalopathy (HE) and ammonia estimation in acute-on-chronic liver failure (ACLF) patients due to a paucity of evidence.

Methods: ACLF patients recruited from the APASL-ACLF Research Consortium (AARC) were followed up till 30 days, death or transplantation, whichever earlier. Clinical details, including dynamic grades of HE and laboratory data, including ammonia levels, were serially noted.

Results: Of the 3009 ACLF patients, 1315 (43.7%) had HE at presentation; grades I-II in 981 (74.6%) and grades III-IV in 334 (25.4%) patients. The independent predictors of HE at baseline were higher age, systemic inflammatory response, elevated ammonia levels, serum protein, sepsis and MELD score (p < 0.05; each). The progressive course of HE was noted in 10.0% of patients without HE and 8.2% of patients with HE at baseline, respectively. Independent predictors of progressive course of HE were AARC score (≥ 9) and ammonia levels (≥ 85 μmol/L) (p < 0.05; each) at baseline. A final grade of HE was achieved within 7 days in 70% of patients and those with final grades III-IV had the worst survival (8.9%). Ammonia levels were a significant predictor of HE occurrence, higher HE grades and 30-day mortality (p < 0.05; each). The dynamic increase in the ammonia levels over 7 days could predict nonsurvivors and progression of HE (p < 0.05; each). Ammonia, HE grade, SIRS, bilirubin, INR, creatinine, lactate and age were the independent predictors of 30-day mortality in ACLF patients.

Conclusions: HE in ACLF is common and is associated with systemic inflammation, poor liver functions and high disease severity. Ammonia levels are associated with the presence, severity, progression of HE and mortality in ACLF patients.
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http://dx.doi.org/10.1007/s12072-021-10221-7DOI Listing
August 2021

740-watt level optical tap coupler using side-polished large-mode-area double clad fibers for a high power fiber laser.

Opt Express 2021 Jun;29(13):19525-19530

We fabricated a fiber-optic directional coupler based on evanescent field coupling between side-polished large mode area (LMA) double clad fibers (DCFs) for a high power fiber laser. The tapping ratio of the fabricated coupler was measured to be - 32 dB. The fundamental mode coupled in a core of the lower side-polished fiber (SPF) was transferred to the upper SPF without clad-mode coupling. Two SPFs were directly faced to increase an optical handling power up to 740 W. The tapping ratio of the coupler was constantly maintained at the applied laser output. The beam quality of the laser including the fabricated coupler was maintained to be 1.22, without mode distortion by the coupler.
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http://dx.doi.org/10.1364/OE.430284DOI Listing
June 2021

CDK15 promotes colorectal cancer progression via phosphorylating PAK4 and regulating β-catenin/ MEK-ERK signaling pathway.

Cell Death Differ 2021 Jul 14. Epub 2021 Jul 14.

Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.

Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths. However, there are few effective therapeutic targets for CRC patients. Here, we found that CDK15 was highly expressed in human CRC and negatively correlated with patient prognosis and overall survival in tissue microarray. Knockdown of CDK15 suppressed cell proliferation and anchorage-independent growth of CRC cells and inhibited tumor growth in cell line-derived xenograft (CDX) model. Importantly, knockout of CDK15 in mice retarded AOM/DSS-induced tumorigenesis and CDK15 silencing by lentivirus significantly suppressed tumor progression in patient-derived xenograft (PDX) model. Mechanistically, CDK15 could bind PAK4 and phosphorylate PAK4 at S291 site. Phosphorylation of PAK4 at the S291 residue promoted cell proliferation and anchorage-independent growth through β-catenin/c-Myc, MEK/ERK signaling pathway in CRC. Moreover, inhibition of PAK4 reversed the tumorigenic function of CDK15 in CRC cells and pharmacological targeting PAK4 suppressed tumor growth in PDX models. Thus, our data reveal the pivotal role of CDK15 in CRC progression and demonstrate CDK15 promotes CRC tumorigenesis by phosphorylating PAK4. Hence, the CDK15-PAK4 axis may serve as a novel therapeutic target for CRC.
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http://dx.doi.org/10.1038/s41418-021-00828-6DOI Listing
July 2021

Diet-Regulating Microbiota and Host Immune System in Liver Disease.

Int J Mol Sci 2021 Jun 13;22(12). Epub 2021 Jun 13.

Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon 24253, Korea.

The gut microbiota has been known to modulate the immune responses in chronic liver diseases. Recent evidence suggests that effects of dietary foods on health care and human diseases are related to both the immune reaction and the microbiome. The gut-microbiome and intestinal immune system play a central role in the control of bacterial translocation-induced liver disease. Dysbiosis, small intestinal bacterial overgrowth, translocation, endotoxemia, and the direct effects of metabolites are the main events in the gut-liver axis, and immune responses act on every pathways of chronic liver disease. Microbiome-derived metabolites or bacteria themselves regulate immune cell functions such as recognition or activation of receptors, the control of gene expression by epigenetic change, activation of immune cells, and the integration of cellular metabolism. Here, we reviewed recent reports about the immunologic role of gut microbiotas in liver disease, highlighting the role of diet in chronic liver disease.
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http://dx.doi.org/10.3390/ijms22126326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231888PMC
June 2021

Ipriflavone Suppresses Growth of Esophageal Squamous Cell Carcinoma Through Inhibiting mTOR and .

Front Oncol 2021 10;11:648809. Epub 2021 Jun 10.

China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.

Ipriflavone, a synthetic isoflavone that inhibits osteoclastic bone resorption, has been used clinically for the treatment of osteoporosis. However, the anticancer activity of Ipriflavone and its molecular mechanisms in the context of esophageal squamous cell carcinoma (ESCC) have not been investigated. In this study, we report that Ipriflavone is a novel mammalian target of rapamycin (mTOR) inhibitor that suppresses cell proliferation and induces cell apoptosis in ESCC cells. Ipriflavone inhibited anchorage-dependent and -independent growth of ESCC cells. Ipriflavone induced G1 phase cell cycle arrest and intrinsic cell apoptosis by activating caspase 3 and increasing the expression of cytochrome c. Based on the results of screening and cell-based assays, Ipriflavone inhibited mTOR signaling pathway through directly targeting mTOR. Knockdown of mTOR strongly inhibited the growth of ESCC cells, and the cell growth inhibitory effect exerted by Ipriflavone was found to be dependent upon mTOR signaling pathway. Remarkably, Ipriflavone strongly inhibited ESCC patient-derived xenograft tumor growth in an mouse model. Our findings suggest that Ipriflavone is an mTOR inhibitor that could be potentially useful for treating ESCC.
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http://dx.doi.org/10.3389/fonc.2021.648809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222593PMC
June 2021

Comparative accuracy of prognostic models for short-term mortality in acute-on-chronic liver failure patients: CAP-ACLF.

Hepatol Int 2021 Jun 25;15(3):753-765. Epub 2021 Jun 25.

Department of Medicine, Ankara University School of Medicine, Ankara, Turkey.

Background: Multiple predictive models of mortality exist for acute-on-chronic liver failure (ACLF) patients that often create confusion during decision-making. We studied the natural history and evaluated the performance of prognostic models in ACLF patients.

Methods: Prospectively collected data of ACLF patients from APASL-ACLF Research Consortium (AARC) was analyzed for 30-day outcomes. The models evaluated at days 0, 4, and 7 of presentation for 30-day mortality were: AARC (model and score), CLIF-C (ACLF score, and OF score), NACSELD-ACLF (model and binary), SOFA, APACHE-II, MELD, MELD-Lactate, and CTP. Evaluation parameters were discrimination (c-indices), calibration [accuracy, sensitivity, specificity, and positive/negative predictive values (PPV/NPV)], Akaike/Bayesian Information Criteria (AIC/BIC), Nagelkerke-R, relative prediction errors, and odds ratios.

Results: Thirty-day survival of the cohort (n = 2864) was 64.9% and was lowest for final-AARC-grade-III (32.8%) ACLF. Performance parameters of all models were best at day 7 than at day 4 or day 0 (p < 0.05 for C-indices of all models except NACSELD-ACLF). On comparison, day-7 AARC model had the numerically highest c-index 0.872, best accuracy 84.0%, PPV 87.8%, R 0.609 and lower prediction errors by 10-50%. Day-7 NACSELD-ACLF-binary was the simple model (minimum AIC/BIC 12/17) with the highest odds (8.859) and sensitivity (100%) but with a lower PPV (70%) for mortality. Patients with day-7 AARC score > 12 had the lowest 30-day survival (5.7%).

Conclusions: APASL-ACLF is often a progressive disease, and models assessed up to day 7 of presentation reliably predict 30-day mortality. Day-7 AARC model is a statistically robust tool for classifying risk of death and accurately predicting 30-day outcomes with relatively lower prediction errors. Day-7 AARC score > 12 may be used as a futility criterion in APASL-ACLF patients.
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http://dx.doi.org/10.1007/s12072-021-10175-wDOI Listing
June 2021

Recurrence and risk factors of posterior communicating artery aneurysms after endovascular treatment.

Acta Neurochir (Wien) 2021 08 18;163(8):2319-2326. Epub 2021 Jun 18.

Department of Neurosurgery, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Gyeonggi-do, Republic of Korea.

Background: Endovascular treatment (EVT) of posterior communicating artery aneurysms (PcomA) is challenging because of posterior communicating artery (Pcom) architecture. Additionally, these aneurysms have a high risk of recanalization compared with those located elsewhere.

Methods: The radiographic findings of 171 patients treated with EVT at two institutions were retrospectively reviewed. Univariate and multivariate analyses were performed, and subgroup analyses were performed based on Pcom characteristics.

Results: Recanalization of PcomAs occurred in 53 patients (30.9%). Seven patients (4.0%) were retreated (six endovascularly and one with microsurgical clipping). The mean follow-up duration was 27.7 months (range: 3.5-78.6). The maximum diameter (odds ratio [OR] 1.23, P = .006, 95% CI 1.07-1.44), a Raymond-Roy classification of grade II or III (OR 2.26, P = .03, 95% CI 1.08-4.82), and the presence of reinforcement (balloon or/and stent, OR 0.44, P = .03, 95% CI 0.20-0.91) were associated with recanalization using multivariate logistic regression. Significant differences were found in maximum aneurysm diameter (P = .03) between normal- and fetal-type Pcoms on analysis of variance.

Conclusions: The recanalization rate of PcomAs after EVT was 30.9%; the retreatment rate was 4.0%. Maximum diameter, Raymond-Roy classification, and presence of reinforcement were significantly associated with recanalization but not associated with fetal-type Pcom. Aneurysm size was larger in patients with a fetal-type Pcom than in those with a normal Pcom. Pcom size was not related to recanalization rate.
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http://dx.doi.org/10.1007/s00701-021-04881-5DOI Listing
August 2021

Prediction of Early Recanalization after Intravenous Thrombolysis in Patients with Large-Vessel Occlusion.

J Stroke 2021 May 31;23(2):244-252. Epub 2021 May 31.

Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.

Background And Purpose: We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion.

Methods: Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization.

Results: Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032).

Conclusions: The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.
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http://dx.doi.org/10.5853/jos.2020.03622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189851PMC
May 2021

Heterogeneity Analysis of Esophageal Squamous Cell Carcinoma in Cell Lines, Tumor Tissues and Patient-Derived Xenografts.

J Cancer 2021 10;12(13):3930-3944. Epub 2021 May 10.

Department of Pathophysiology, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, China.

Esophageal Squamous Cell Carcinoma (ESCC) is the predominant type of Esophageal Cancer (EC), accounting for nearly 88% of EC incidents worldwide. Importantly, it is also a life-threatening cancer for patients diagnosed in advanced stages, with only a 20% 5-year survival rate due to a limited number of actionable targets and therapeutic options. Increasing evidence has shown that inter-tumor and intra-tumor heterogeneity are widely distributed across ESCC tumor tissues. In our work, multi-omics data from ESCC cell lines, tumor tissue, normal tissue and Patient-Derived Xenograft (PDX) tissues were analyzed to investigate the heterogeneity among ESCC samples at the DNA, RNA, and protein level. We identified enrichment of ECM-receptor interaction and Focal adhesion pathways from the subset of protein-coding genes with non-silent mutations in ESCC patients. We also found that , , , , , and are the most frequently mutated genes in ESCC patient samples. Out of the identified genes, is the most frequently mutated, with 84 distinct non-silent mutation variants. We observed that p.R248Q, p.R175G/H, and p.R273C/H are the most common mutation variants. The diversity of mutations reveal its importance in ESCC progression and may also provide promising targets for precision therapeutics. Additionally, we identified the Olfactory transduction as the top signaling pathway, enriched from genes uniquely expressed in The Cancer Genome Atlas (TCGA)-ESCC patient tumor tissues, which may provide implications for the exact roles of the corresponding genes in ESCC. Cyclic nucleotide-gated channel subunit beta 1(CNGB1), a gene belonging to the Olfactory transduction pathway, was found exclusively overexpressed in ESCC. Expression of CNGB1 could serve as a marker, indicating potential diagnostic or therapeutic value. Finally, we investigated heterogeneity in the context of the ESCC PDX model, which is an emerging tool used to predict drug response and recapitulate tumor behavior . We observed trans-species heterogeneity in as high as 75% of the identified proteins, indicating that the ambiguity of proteins should be addressed by specific strategies to avoid drawing false conclusions. The identification and characterization of gene mutation and expression heterogeneity across different ESCC datasets, including various novel mutations, ECM-receptor interaction, Focal adhesion, and Olfactory transduction pathways (), provide researchers with evidence and implications for accurate research and precision therapeutic development.
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http://dx.doi.org/10.7150/jca.52286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176252PMC
May 2021

Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B.

Hepatology 2021 Oct 25;74(4):1795-1808. Epub 2021 Aug 25.

Roche Innovation Centre, Welwyn Garden City, United Kingdom.

Background And Aims: RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed.

Approach And Results: Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1-4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3-5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self-limiting injection site reactions and influenza-like illness. Supradose-proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose-dependent and time-dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log  IU/mL) independent of HBeAg status.

Conclusions: RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose-proportional exposure at doses of 3.0-4.0 mg/kg was indicative of partial saturation of the ASGPR-mediated liver uptake system. Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931.
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http://dx.doi.org/10.1002/hep.31920DOI Listing
October 2021

Low Hypoperfusion Intensity Ratio Is Associated with a Favorable Outcome Even in Large Ischemic Core and Delayed Recanalization Time.

J Clin Med 2021 Apr 26;10(9). Epub 2021 Apr 26.

Department of Neurology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.

In ischemic brain tissue, hypoperfusion severity can be assessed using the hypoperfusion intensity ratio (HIR). We evaluated the link between HIR and clinical outcomes after successful recanalization by endovascular treatment. We retrospectively reviewed 162 consecutive patients who underwent endovascular treatment for intracranial large vessel occlusion. The HIR was calculated using an automated software program, with initial computed tomography perfusion images. The HIR was compared between patients with and without favorable outcomes. To observe the modifying effect of the HIR on the well-known major outcome determinants, regression analyses were performed in the low and high HIR groups. The median HIR value was significantly lower in patients with a favorable outcome, with an optimal cut-off point of 0.54. The HIR was an independent factor for a favorable outcome in a specific multivariable model and was significantly correlated with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). In contrast to the high HIR group, the low HIR group showed that ASPECTS and onset-to-recanalization time were not independently associated with a favorable outcome. Finally, the low HIR group had a more favorable outcome even in cases with an unfavorable ASPECTS and onset-to-recanalization time. The HIR could be useful in predicting outcomes after successful recanalization.
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http://dx.doi.org/10.3390/jcm10091869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123392PMC
April 2021

The longitudinal outcomes of applying non-selective beta-blockers in portal hypertension: real-world multicenter study.

Hepatol Int 2021 Apr 16;15(2):424-436. Epub 2021 Apr 16.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20, Ilsan-ro, Wonju, 26426, Korea.

Background/aim: We investigated the effect of non-selective β-blockers (NSBB) in real-world situations and whether low-dose NSBB is beneficial compared to maximally tolerated doses.

Methods: We performed a retrospective study of 740 patients with cirrhosis requiring prophylactic treatment of esophageal varices: 473 primary prophylaxis (PP: NSBB = 349, non-NSBB = 124) and 267 secondary prophylaxis (SP: NSBB = 200, non-NSBB = 67). The NSBB group was divided into low-dose (≤ 80 mg/day) and high-dose (> 80 mg/day).

Results: In the PP group, NSBB treatment reduced mortality and showed the most pronounced effect in patients with moderate/severe ascites (hazard ratio [HR], 0.46; p < 0.01), HVPG ≥ 16 mmHg (HR, 0.53; p = 0.04), or CTP class B/C (HR, 0.46; p < 0.01) but not in those with no/mild ascites, HVPG < 16 mmHg, or CTP class A. Low-dose NSBB group showed a significant reduction in mortality compared with non-NSBB (moderate/severe ascites: HR, 0.61; p = 0.02 and CTP class B/C: HR, 0.41; p < 0.01) and the effect size was stronger than the high-dose NSBB. NSBB was associated with a reduced risk of infection (HR, 0.36; p = 0.01). In the SP group, NSBB prolonged survival in patients with moderate/severe ascites (HR, 0.56; p = 0.02), HVPG ≥ 16 mmHg (HR, 0.42; p < 0.01), or CTP class B/C (HR, 0.52; p < 0.01). Low-dose NSBB was more beneficial with 56% risk reduction (p < 0.01) of mortality compared with 33% risk reduction in the high-dose NSBB (p = 0.05).

Conclusion: NSBB therapy was associated with longer survival in PP and SP groups who had an advanced stage of cirrhosis. Moreover, low-dose NSBB exhibited a better benefit than a standard-titrated high-dose NSBB with better tolerability.
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http://dx.doi.org/10.1007/s12072-021-10160-3DOI Listing
April 2021

Increased Expression of S100B and RAGE in a Mouse Model of Bile Duct Ligation-induced Liver Fibrosis.

J Korean Med Sci 2021 Apr 12;36(14):e90. Epub 2021 Apr 12.

Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Korea.

Background: Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL).

Methods: BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis.

Results: Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B.

Conclusion: These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.
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http://dx.doi.org/10.3346/jkms.2021.36.e90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042478PMC
April 2021

Effect of Korea red ginseng on nonalcoholic fatty liver disease: an association of gut microbiota with liver function.

J Ginseng Res 2021 Mar 16;45(2):316-324. Epub 2020 Jul 16.

Department of Life Science, Multidisciplinary Genome Institute, Hallym University, Chuncheon, Republic of Korea.

Background: Korea Red Ginseng (KRG) has been used as remedies with hepato-protective effects in liver-related condition. Microbiota related gut-liver axis plays key roles in the pathogenesis of chronic liver disease. We evaluated the effect of KRG on gut-liver axis in patients with nonalcoholic statohepatitis by the modulation of gut-microbiota.

Methods: A total of 94 patients (KRG: 45 and placebo: 49) were prospectively randomized to receive KRG (2,000 mg/day, ginsenoside Rg1+Rb1+Rg3 4.5mg/g) or placebo during 30 days. Liver function test, cytokeraton 18, and fatigue score were measured. Gut microbiota was analyzed by MiSeq systems based on 16S rRNA genes.

Results: In KRG group, the mean levels (before vs. after) of aspartate aminotransferase (53 ± 19 vs. 45 ± 23 IU/L), alanine aminotransferase (75 ± 40 vs. 64 ± 39 IU/L) and fatigue score (33 ± 13 vs. 26 ± 13) were improved ( < 0.05). In placebo group, only fatigue score (34 ± 13 vs. 31 ± 15) was ameliorated ( < 0.05). The changes of phyla were not statistically significant on both groups. In KRG group, increased abundance of was related with improved alanine aminotransferase level and increased abundance of and was associated with no improvement after KRG supplementation. In placebo group, increased abundance of could be related with aggravation of liver enzyme ( < 0.05).

Conclusion: KRG effectively improved liver enzymes and fatigue score by modulating gut-microbiota in patients with fatty liver disease. Further studies are needed to understand the mechanism of improvement of nonalcoholic steatohepatitis.

Clnicaltrialsgov: NCT03945123 (www.ClinicalTrials.gov).
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http://dx.doi.org/10.1016/j.jgr.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020261PMC
March 2021

An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia.

Int J Mol Sci 2021 Mar 5;22(5). Epub 2021 Mar 5.

Department of Internal Medicine, Hallym University College of Medicine, Gangwon-do, Chuncheon 24252, Korea.

The prevalence of osteoporosis and sarcopenia is significantly higher in patients with liver disease than in those without liver disease and osteoporosis and sarcopenia negatively influence morbidity and mortality in liver disease, yet these musculoskeletal disorders are frequently overlooked in clinical practice for patients with chronic liver disease. The objective of this review is to provide a comprehensive understanding of the molecular mechanisms of musculoskeletal disorders accompanying the pathogenesis of liver disease. The increased bone resorption through the receptor activator of nuclear factor kappa (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) system and upregulation of inflammatory cytokines and decreased bone formation through increased bilirubin and sclerostin and lower insulin-like growth factor-1 are important mechanisms for osteoporosis in patients with liver disease. Sarcopenia is associated with insulin resistance and obesity in non-alcoholic fatty liver disease, whereas hyperammonemia, low amount of branched chain amino acids, and hypogonadism contributes to sarcopenia in liver cirrhosis. The bidirectional crosstalk between muscle and bone through myostatin, irisin, β-aminoisobutyric acid (BAIBA), osteocalcin, as well as the activation of the RANK and the Wnt/β-catenin pathways are associated with osteosarcopenia. The increased understandings for these musculoskeletal disorders would be contributes to the development of effective therapies targeting the pathophysiological mechanism involved.
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http://dx.doi.org/10.3390/ijms22052604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961345PMC
March 2021

EPRS/GluRS promotes gastric cancer development via WNT/GSK-3β/β-catenin signaling pathway.

Gastric Cancer 2021 09 19;24(5):1021-1036. Epub 2021 Mar 19.

Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, 450001, Henan, China.

Background: Glutamyl-prolyl-tRNA synthetase (EPRS/GluRS) is primarily part of the multi-synthetase complex that may play a key role in cancer development. However, the biological function, molecular mechanism, and inhibitor of EPRS have not been investigated in gastric cancer (GC).

Methods: Immunohistochemistry was performed to detect the expression of EPRS in human gastric tumor tissues. Knocking down of EPRS, cell-derived xenograft mouse model, and patient-derived xenograft mouse model was used to identify the biological function of EPRS. Immunoprecipitation was applied to elucidate the interaction between EPRS and SCYL2. Computer docking model and multiple in vitro and in vivo experiments were conducted to discover EPRS inhibitors.

Results: Here, we report that EPRS is frequently overexpressed in GC tissues compared to that adjacent controls and its overexpression predicts poor prognosis in GC patients. Functionally, high expression of EPRS positively co-relates with GC development both in vitro and in vivo. Mechanistically, EPRS directly binds with SCYL2 to enhance the activation of WNT/GSK-3β/β-catenin signaling pathway and the accumulation of β-catenin in the nuclear, leading to GC cell proliferation and tumor growth. Moreover, we identified that xanthoangelol (XA) and 4-hydroxyderricin (4-HD) can directly bind to EPRS to block WNT/GSK-3β/β-catenin signaling pathway. More importantly, XA and 4-HD restrain gastric cancer patient-derived xenograft tumor growth and Helicobacter pylori combined with alcohol-induced atrophic gastritis and gastric tumorigenesis.

Conclusion: These findings unveil a promising strategy for GC prevention and therapy by targeting EPRS-mediated WNT/GSK-3β/β-catenin cascades. Moreover, XA and 4-HD may be effective reagents used for GC prevention and therapy.
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http://dx.doi.org/10.1007/s10120-021-01180-xDOI Listing
September 2021

Comorbidity index for predicting mortality at 6 months after reperfusion therapy.

Sci Rep 2021 Mar 16;11(1):5963. Epub 2021 Mar 16.

Department of Neurology, Pusan National University School of Medicine, Busan, Korea.

The eligibility of reperfusion therapy has been expanded to increase the number of patients. However, it remains unclear the reperfusion therapy will be beneficial in stroke patients with various comorbidities. We developed a reperfusion comorbidity index for predicting 6-month mortality in patients with acute stroke receiving reperfusion therapy. The 19 comorbidities included in the Charlson comorbidity index were adopted and modified. We developed a statistical model and it was validated using data from a prospective cohort. Among 1026 patients in the retrospective nationwide reperfusion therapy registry, 845 (82.3%) had at least one comorbidity. As the number of comorbidities increased, the likelihood of mortality within 6 months also increased (p < 0.001). Six out of the 19 comorbidities were included for developing the reperfusion comorbidity index on the basis of the odds ratios in the multivariate logistic regression analysis. This index showed good prediction of 6-month mortality in the retrospective cohort (area under the curve [AUC], 0.747; 95% CI, 0.704-0.790) and in 333 patients in the prospective cohort (AUC, 0.784; 95% CI, 0.709-0.859). Consideration of comorbidities might be helpful for the prediction of the 6-month mortality in patients with acute ischemic stroke who receive reperfusion therapy.
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http://dx.doi.org/10.1038/s41598-021-85390-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966783PMC
March 2021

Intracranial Stenting; the Current Landscape.

Authors:
Dong Joon Kim

Neurointervention 2021 Mar 24;16(1):2-5. Epub 2021 Feb 24.

Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.5469/neuroint.2021.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946550PMC
March 2021

2,6-DMBQ suppresses cell proliferation and migration via inhibiting mTOR/AKT and p38 MAPK signaling pathways in NSCLC cells.

J Pharmacol Sci 2021 Mar 7;145(3):279-288. Epub 2021 Jan 7.

Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, College of Medicine, Zhengzhou University, Zhengzhou, Henan, 450008, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, 450008, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan, 450008, China. Electronic address:

2,6-Dimethoxy-1,4-benzoquinone (2,6-DMBQ) is the major bioactive compound found in fermented wheat germ extract. Although fermented wheat germ extract has been reported to show anti-proliferative and anti-metabolic effects in various cancers, the anticancer potential and molecular mechanisms exerted by 2,6-DMBQ have not been investigated in non-small cell lung cancer (NSCLC) cells. Here, we report that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibiting activation of AKT and p38 MAPK. 2,6-DMBQ significantly suppressed anchorage-dependent and independent cell growth. Additionally, 2,6-DMBQ induced G2 phase cell cycle arrest through inhibiting the expression and phosphorylation of cyclin B1 and CDC2, respectively. Furthermore, 2,6-DMBQ strongly suppressed NSCLC cell migration through induction of E-cadherin expression. To determine the molecular mechanism(s) exerted by 2,6-DMBQ upon NSCLC cell lines, various signaling kinases were screened; the results indicate that 2,6-DMBQ strongly inhibits the phosphorylation of AKT and p38 MAPK. Additionally, the growth kinetics of cells treated with an AKT or p38 MAPK inhibitor in combination with 2,6-DMBQ indicate that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibition of AKT and p38 MAPK. Taken together, our results suggest that 2,6-DMBQ is a potential anticancer reagent against NSCLC cells and could be useful for treating lung cancer patients.
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http://dx.doi.org/10.1016/j.jphs.2021.01.003DOI Listing
March 2021
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