Publications by authors named "Jung Ho Kim"

459 Publications

Immune signature as a potential marker for predicting response to immunotherapy in obesity-associated colorectal cancer.

J Gastroenterol Hepatol 2022 Jun 9. Epub 2022 Jun 9.

Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea.

Background And Aim: It remains unclear whether immunotherapy, which is not generally considered for microsatellite stable (MSS) colorectal cancer (CRC), can be used to effectively treat select CRC patients. We investigated the feasibility of obesity-associated MSS CRC patients for immunotherapy based on genomic alterations.

Methods: We evaluated differences in genomic alteration types and immune signatures between obese and non-obese patients with MSS CRC. We performed genomic analyses using 434 CRC patients from The Cancer Genome Atlas (TCGA). Patients with MSS CRC were stratified into subgroups based on their BMI and numbers of nonsynonymous single nucleotide variants (nsSNVs) and frameshift insertions and deletions (fs INDELs) using machine learning.

Results: The obese subgroup showed higher incidences of single nucleotide variants (SNV) and insertions and deletions (INDELs) in comparison with healthy weight patients with MSS CRC. The subgroup, who had higher numbers of nsSNVs and fs INDLEs, exhibited increased immune signatures, increased number of SNV-derived neoantigens, and had up-regulated two immune checkpoint genes in comparison with healthy weight patients with MSS CRC, reflecting interactions between the cancer genome and immune system.

Conclusions: This study suggests that immunotherapy may be suitable for some obesity-associated CRC patients.
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http://dx.doi.org/10.1111/jgh.15909DOI Listing
June 2022

Prevalence and Risks of Depression and Substance Use Among Adults Living with HIV in the Asia-Pacific Region.

AIDS Behav 2022 Jun 6. Epub 2022 Jun 6.

The Kirby Institute, UNSW Sydney, Sydney, Australia.

Despite the mental health and substance use burden among people living with HIV (PLHIV) in the Asia-Pacific, data on their associations with HIV clinical outcomes are limited. This cross-sectional study of PLHIV at five sites assessed depression and substance use using PHQ-9 and ASSIST. Among 864 participants, 88% were male, median age was 39 years, 97% were on ART, 67% had an HIV viral load available and < 1000 copies/mL, 19% had moderate-to-severe depressive symptoms, and 80% had ever used at least one substance. Younger age, lower income, and suboptimal ART adherence were associated with moderate-to-severe depressive symptoms. Moderate-to-high risk substance use, found in 62% of users, was associated with younger age, being male, previous stressors, and suboptimal adherence. Our findings highlight the need for improved access to mental health and substance use services in HIV clinical settings.
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http://dx.doi.org/10.1007/s10461-022-03714-5DOI Listing
June 2022

Wasting condition as a marker for severe disease in pediatric Crohn's disease.

Medicine (Baltimore) 2022 May 20;101(20):e29296. Epub 2022 May 20.

CHA University Bundang Medical Center Digestive Disease Center, Seongnam, Korea.

Abstract: Several studies have shown an association between sarcopenia and clinical outcomes in patients with Crohn's disease (CD). However, studies have shown different results, and the association between prognosis and wasting conditions in pediatric patients with CD is uncertain. In this study, we evaluated the clinical significance of wasting in pediatric CD patients.We retrospectively analyzed data on wasting syndrome in patients diagnosed with CD at the Pediatric Department of Gachon University Gil Medical Center between January 1995 and January 2018.Of 105 patients diagnosed with CD, 39.0% were classified into the wasting group (weight-for-age z-score ≤-1) and 61.0% into the nonwasting group (weight-for-age z-score >-1). Height-for-age and body mass index-for-age z-scores at the time of diagnosis were significantly associated with wasting (P < .001 and P < .001, respectively). Additionally, wasting was significantly associated with low levels of hemoglobin (P < .001), high levels of inflammatory markers, including C-reactive protein (P = .005) and erythrocyte sedimentation rate (P = .04), and a smaller surface area of the gluteus maximus muscle (P < .001). Interestingly, since the site of CD involvement and other markers for nutrition did not correlate with wasting syndrome, wasting appears to be a marker for the severity of pediatric CD. Lastly, the wasting group tended to have a greater use of biologic therapy after first-line therapy failed to improve wasting syndrome.Wasting syndrome, including sarcopenia, can serve as a marker for the severity of pediatric CD.
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http://dx.doi.org/10.1097/MD.0000000000029296DOI Listing
May 2022

Resistive Water Level Sensors Based on AgNWs/PEDOT:PSS--PEGME Hybrid Film for Agricultural Monitoring Systems.

ACS Omega 2022 May 26;7(18):15459-15466. Epub 2022 Apr 26.

School of Advanced Materials Science & Engineering, Sungkyunkwan University, Suwon 440-745, Republic of Korea.

Recently, an agricultural monitoring system using the Internet of Things has been developed to realize smart farming. The high performance of various sensors in agricultural monitoring systems is essential for smart farming to automatically monitor and control agricultural environmental conditions such as temperature and water level. In this study, we propose resistive water level sensors based on an AgNWs/PEDOT:PSS--PEGME hybrid structure to improve the already high conductivity and water stability of PEDOT:PSS. After spin-coating the AgNWs/PEDOT:PSS--PEGME hybrid film, a laser treatment method successfully patterns the resistive water level sensor with areas of higher resistance. When water contacts the sensor, the variation in resistance caused by the water level changes the current flow of the sensor, allowing it to be used to detect the water level. Finally, we develop a water level sensor module as a component of the agricultural monitoring system by connecting the sensor to a microcontroller for water level monitoring in real time. The proposed water level sensors may be a new solution for detecting water levels in agricultural monitoring systems.
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http://dx.doi.org/10.1021/acsomega.2c00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9096971PMC
May 2022

A comprehensive evaluation of regression-based drug responsiveness prediction models, using cell viability inhibitory concentrations (IC50 values).

Bioinformatics 2022 05;38(10):2810-2817

Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Korea.

Motivation: Predicting drug response is critical for precision medicine. Diverse methods have predicted drug responsiveness, as measured by the half-maximal drug inhibitory concentration (IC50), in cultured cells. Although IC50s are continuous, traditional prediction models have dealt mainly with binary classification of responsiveness. However, since there are few regression-based IC50 predictions, comprehensive evaluations of regression-based IC50 prediction models, including machine learning (ML) and deep learning (DL), for diverse data types and dataset sizes, have not been addressed.

Results: Here, we constructed 11 input data settings, including multi-omics settings, with varying dataset sizes, then evaluated the performance of regression-based ML and DL models to predict IC50s. DL models considered two convolutional neural network architectures: CDRScan and residual neural network (ResNet). ResNet was introduced in regression-based DL models for predicting drug response for the first time. As a result, DL models performed better than ML models in all the settings. Also, ResNet performed better than or comparable to CDRScan and ML models in all settings.

Availability And Implementation: The data underlying this article are available in GitHub at https://github.com/labnams/IC50evaluation.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btac177DOI Listing
May 2022

Novel fabrication technique for high-resolution spherical crystal analyzers using a microporous aluminium base.

J Synchrotron Radiat 2022 May 1;29(Pt 3):749-754. Epub 2022 Apr 1.

Advanced Photon Source, Argonne National Laboratory, 9700 South Cass Avenue, Lemont, IL 60439, USA.

Modern inelastic X-ray spectrometers employ curved, bent and diced analyzers to capture sufficiently large solid angles of radially emitted scattered radiation emanating from the sample. Fabricating these intricate analyzers, especially when a high energy resolution of a few millielectronvolts is required, is very time-consuming, expensive and often a hit-or-miss affair. A novel fabrication technique is introduced, utilizing a concave-spherical, microporous aluminium base to hold an assembly of a thin glass substrate with a diced crystal wafer bonded to it. Under uniform vacuum forces, the glass substrate is drawn into the aluminium base, achieving the desired bending radius, while dicing of the diffracting crystal layer prevents bending strain from being imposed on the individual crystal pixels. This technique eliminates the need for permanently bonding the crystal assembly to the concave lens, offering the opportunity for correcting figure errors, avoiding long-term degradation of the permanent bond, and making both lens and crystal reusable. Process and material costs are thus substantially decreased. Two analyzers, Si(844) and Ge(337) with intrinsic resolutions of 14.6 meV and 36.5 meV, respectively, were produced in this fashion and characterized in resonant inelastic X-ray scattering (RIXS) measurements. The achieved overall energy resolutions for both analyzers were 29.4 meV for Si(844) and 56.6 meV for Ge(337). Although the RIXS technique is veru sensitive to analyzer imperfections, the analyzers were found to be equal, if not superior, in quality to their traditional, permanently bonded counterparts.
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http://dx.doi.org/10.1107/S1600577522001886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9070708PMC
May 2022

Impact of Valve Culture Positivity on Prognosis in Patients with Infective Endocarditis Who Underwent Valve Surgery.

Infect Dis Ther 2022 Jun 30;11(3):1253-1265. Epub 2022 Apr 30.

Division of Infectious Disease, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Introduction: Infective endocarditis (IE) is a severe and fatal infection with high in-hospital and overall mortality rates of approximately up to 30%. Valve culture positivity was associated with in-hospital mortality and postoperative complications; however, few studies have analyzed the relationship between valve cultures and overall mortality over a long observation period. This study aimed to compare the association of valve culture positivity with overall mortality in patients with IE who underwent valve surgery.

Methods: A total of 416 IE patients admitted to a tertiary hospital in South Korea from November 2005 to August 2017 were retrospectively reviewed. A total of 202 IE patients who underwent valve surgery and valve culture were enrolled. The primary endpoint was long-term overall mortality. Kaplan-Meier curve and Cox proportional hazards model were used for survival analysis.

Results: The median follow-up duration was 63 (interquartile range, 38-104) months. Valve cultures were positive in 22 (10.9%) patients. The overall mortality rate was 15.8% (32/202) and was significantly higher in valve culture-positive patients (36.4%, p = 0.011). Positive valve culture [hazard ratio (HR) 3.921, p = 0.002], Charlson Comorbidity Index (HR 1.181, p = 0.004), Coagulase-negative staphylococci (HR 4.233, p = 0.001), new-onset central nervous system complications (HR 3.689, p < 0.001), and new-onset heart failure (HR 4.331, p = 0.001) were significant risk factors for overall mortality.

Conclusions: Valve culture positivity is a significant risk factor for long-term overall mortality in IE patients who underwent valve surgery. The importance of valve culture positivity needs to be re-evaluated, as the valve culture positivity rate increases with increasing early surgical intervention.
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http://dx.doi.org/10.1007/s40121-022-00642-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124244PMC
June 2022

The impact of sarcopenia on short-term and long-term mortality in patients with septic shock.

J Cachexia Sarcopenia Muscle 2022 Apr 27. Epub 2022 Apr 27.

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

Background: Despite medical advances, septic shock remains one of the main causes of high mortality in critically ill patients. Although sarcopenia is considered a predictor of mortality in septic shock patients, most studies have only investigated short-term mortality, and those on long-term prognosis are limited. We investigated the impact of sarcopenia on long-term mortality in a large patient population with septic shock.

Methods: A retrospective cohort study comprising 905 patients with septic shock was conducted from 2008 to 2019. Sarcopenia was defined based on the measurement of the total abdominal muscle area, assessed using abdominal computed tomography scans. Thereafter, we stratified the patients into two groups-sarcopenia and non-sarcopenia groups-and compared the impact of sarcopenia on short-term (28 days) and long-term (1 year and overall) mortality using multivariable Cox proportional analysis.

Results: A total of 905 patients were included, and the mean age was 65.7 ± 15.1 years. Among them, 430 (47.5%) patients were male and 407 (45.0%) had sarcopenia. We found that the 28 day, 1 year, and overall mortality rates in the sarcopenia group were significantly higher than those in the non-sarcopenia group (13.8% vs. 6.4%, P < 0.001; 41.8% vs. 21.7%, P < 0.001; 62.2% vs. 35.7%, P < 0.001, respectively). Univariable Cox analysis showed that the sarcopenia group had a significant association with the increase in each mortalities compared with the non-sarcopenia group (28 day mortality, hazard ratio (HR) = 2.230, 95% confidence interval (CI) [1.444-3.442], P < 0.001; 1 year mortality, HR = 2.189, 95% CI [1.720, 2.787], P < 0.001; overall mortality, HR = 2.254, 95% CI [1.859, 2.734], P < 0.001). Multivariable Cox analysis showed that both the short-term and long-term mortality rates remained significantly higher in the sarcopenia group than in the non-sarcopenia group, even after adjusting for confounding variables (28 day mortality, HR = 2.116, 95% CI [1.312, 3.412], P = 0.002; 1 year mortality, HR = 1.679, 95% CI [1.291, 2.182], P < 0.001; overall mortality, HR = 1.704, 95% CI [1.381, 2.102], P < 0.001).

Conclusions: Sarcopenia was associated with both short-term and long-term mortality in patients with septic shock. In clinical settings, close attention should be paid to these patients for both short-term and long-term outcomes.
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http://dx.doi.org/10.1002/jcsm.12995DOI Listing
April 2022

Tauroursodeoxycholic Acid Inhibits Nuclear Factor Kappa B Signaling in Gastric Epithelial Cells and Ameliorates Gastric Mucosal Damage in Mice.

Korean J Gastroenterol 2022 04;79(4):161-169

Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea.

Background/aims: Previous studies have reported the protective effects of tauroursodeoxycholic acid (TUDCA) on gastric epithelial cells in some animal models, but the precise mechanisms are unclear. This study examined the effects of TUDCA on NF-κB signaling in gastric epithelial cells. Moreover, the protective effects of TUDCA in experimental gastritis models induced by ethanol and NSAID were evaluated and compared with ursodeoxycholic acid (UDCA).

Methods: After a pretreatment with TUDCA or UDCA, human gastric epithelial MKN-45 cells were stimulated with tumor necrosis factor (TNF)-α to activate NF-κB signaling. A real-time PCR (RT-PCR) for human interleukin (IL)-1 mRNA was performed. An electrophoretic mobility shift assay (EMSA) and immunoblot analyses were carried out. In murine models, after a pretreatment with TUDCA or UDCA, ethanol and indomethacin were administered via oral gavage. Macroscopic and microscopic assessments were performed to evaluate the preventive effects of TUDCA and UDCA on murine gastritis.

Results: A pretreatment with TUDCA downregulated the IL-1α mRNA levels in MKN-45 cells stimulated with TNF-α, as assessed by RT-PCR. As determined using EMSA, a pretreatment with TUDCA reduced the TNF-α-induced NF-κB DNA binding activity. A pretreatment with TUDCA inhibited IκBα phosphorylation induced by TNF-α, as assessed by immunoblot analysis. TUDCA attenuated the ethanol-induced and NSAID-induced gastritis in murine models, as determined macroscopically and microscopically.

Conclusions: TUDCA inhibited NF-κB signaling in gastric epithelial cells and ameliorated ethanol- and NSAID-induced gastritis in murine models. These results support the potential of TUDCA for the prevention of gastritis in humans.
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http://dx.doi.org/10.4166/kjg.2022.003DOI Listing
April 2022

Porous carbon architectures with different dimensionalities for lithium metal storage.

Sci Technol Adv Mater 2022 6;23(1):169-188. Epub 2022 Apr 6.

Institute for Superconducting & Electronic Materials (ISEM), Australian Institute of Innovative Materials (AIIM), University of Wollongong, Squires Way, North Wollongong, NSW 2500, Australia.

Lithium metal batteries have recently gained tremendous attention owing to their high energy capacity compared to other rechargeable batteries. Nevertheless, lithium (Li) dendritic growth causes low Coulombic efficiency, thermal runaway, and safety issues, all of which hinder the practical application of Li metal as an anodic material. In this review, the failure mechanisms of Li metal anode are described according to its infinite volume changes, unstable solid electrolyte interphase, and Li dendritic growth. The fundamental models that describe the Li deposition and dendritic growth, such as the thermodynamic, electrodeposition kinetics, and internal stress models are summarized. From these considerations, porous carbon-based frameworks have emerged as a promising strategy to resolve these issues. Thus, the main principles of utilizing these materials as a Li metal host are discussed. Finally, we also focus on the recent progress on utilizing one-, two-, and three-dimensional carbon-based frameworks and their composites to highlight the future outlook of these materials.
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http://dx.doi.org/10.1080/14686996.2022.2050297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004537PMC
April 2022

Increasing Fusobacterium infections with Fusobacterium varium, an emerging pathogen.

PLoS One 2022 14;17(4):e0266610. Epub 2022 Apr 14.

Division of Infectious Diseases, Department of Internal Medicine and AIDS Research Institute, Seoul, South Korea.

Infections caused by Fusobacterium species are rare; however serious infections with complications or mortality may occur occasionally. We conducted a retrospective study to investigate the clinical features of patients with Fusobacterium infections and the differences between infections caused by the species F. necrophorum, F. nucleatum, and F. varium. Additionally, we attempted to identify risk factors for Fusobacterium-associated mortality. This study included all patients at a large tertiary care teaching hospital in South Korea with Fusobacterium infections from January 2006 to April 2021. Demographic, clinical, laboratory, and outcome data were analyzed. Multiple logistic regression analysis was performed to assess the risk factors for in-hospital mortality associated with F. nucleatum and F. varium infections. We identified 272 patients with Fusobacterium infections during the study period. The number of Fusobacterium cases has increased recently, with F. varium infections markedly increasing since 2016 and causing a significant proportion of infections. Patients with F. varium infections were older and had a higher proportion of nosocomial infections than the other groups. The F. nucleatum and F. varium groups showed higher in-hospital mortality than the F. necrophorum group. Through logistic regression analysis, APACHE II score and serum albumin level were considered risk factors for in-hospital mortality. APACHE II score was positively correlated with age, red cell distribution width, and serum blood urea nitrogen, and negatively correlated with serum albumin level. Infections caused by Fusobacterium species are increasing. F. varium causes a significant proportion of severe infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0266610PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9009667PMC
April 2022

Loop-mediated isothermal amplification-based nucleic acid lateral flow assay for the specific and multiplex detection of genetic markers.

Anal Chim Acta 2022 May 28;1205:339781. Epub 2022 Mar 28.

Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea. Electronic address:

In this study, a loop-mediated isothermal amplification-based nucleic acid lateral flow assay (LAMP-NALFA) system was developed for the specific and multiplex detection of genetic markers at a low cost. In principle, the LAMP reaction was optimized to generate a single-stranded sequence in the LAMP product, which was designed to serve as a barcode sequence and to specifically bind to the DNA capture on a NALFA strip. As a target genetic marker, the Salmonella enterotoxin (stn) gene was chosen and determined down to 9 aM (∼5.44 copies/μL). Importantly, the proposed system clearly discriminated the specific target amplification products from non-specific amplification products resulting from primers or non-target nucleic acids, proving the high selectivity of the LAMP-NALFA system. Furthermore, the practical applicability of the system was demonstrated by detecting Salmonella bacteria in Luria-Bertani medium, drinking water, and eggshells, with a limit of detection of 1.6 CFU. Finally, two different bacteria (Salmonella and Staphylococcus) were simultaneously determined by the multiplex LAMP-NALFA system. It is expected that the LAMP-NALFA system could be used in a point-of-care setting for the detection of bacteria or viruses, consequently improving both individual and public health.
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http://dx.doi.org/10.1016/j.aca.2022.339781DOI Listing
May 2022

Prolonged viral shedding in severely ill patients infected with SARS-CoV-2 Delta variants: A retrospective cohort study.

J Infect 2022 Jul 5;85(1):90-122. Epub 2022 Apr 5.

Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2022.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8979836PMC
July 2022

Patterns and prognosis of holding regimens for people living with HIV in Asian countries.

PLoS One 2022 30;17(3):e0264157. Epub 2022 Mar 30.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.

The use of holding regimens for people living with HIV (PLWH) without effective antiretroviral options can have effects on outcomes and future treatment options. We aimed to investigate the use of holding regimens for PLWH in Asian countries. Data from adults enrolled in routine HIV care in IeDEA Asia-Pacific cohorts were included. Individuals were considered to be on holding regimen if they had been on combination antiretroviral therapy for at least 6 months, had two confirmed viral loads (VL) ≥1000 copies/mL, and had remained on the same medications for at least 6 months. Survival time was analyzed using Fine and Gray's competing risk regression. Factors associated with CD4 changes and VL <1000 copies/mL were analyzed using linear regression and logistic regression, respectively. A total of 425 PLWH (72.9% male; 45.2% high-income and 54.8% low-to-middle-income country) met criteria for being on a holding regimen. From high-income countries, 63.0% were on protease inhibitors (PIs); from low-to-middle-income countries, 58.4% were on non-nucleoside reverse transcriptase inhibitors (NNRTIs); overall, 4.5% were on integrase inhibitors. The combination of lamivudine, zidovudine, and efavirenz was the most commonly used single regimen (n = 46, 10.8%), followed by lamivudine, zidovudine, and nevirapine (n = 37, 8.7%). Forty-one PLWH (9.7%) died during follow-up (mortality rate 2.0 per 100 person-years). Age >50 years compared to age 31-40 years (sub-hazard ratio [SHR] 3.29, 95% CI 1.45-7.43, p = 0.004), and VL ≥1000 copies/ml compared to VL <1000 copies/mL (SHR, 2.14, 95% CI 1.08-4.25, p = 0.029) were associated with increased mortality, while higher CD4 counts were protective. In our Asia regional cohort, there was a diversity of holding regimens, and the patterns of PI vs. NNRTI use differed by country income levels. Considering the high mortality rate of PLWH with holding regimen, efforts to extend accessibility to additional antiretroviral options are needed in our region.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0264157PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967045PMC
March 2022

Prognostic Impact of Extramural Lymphatic, Vascular, and Perineural Invasion in Stage II Colon Cancer: A Comparison With Intramural Invasion.

Dis Colon Rectum 2022 Mar 23. Epub 2022 Mar 23.

Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.

Background: Lymphatic invasion, vascular invasion, and perineural invasion are prognostic factors for colon cancer. However, the prognostic significance of those factors according to the location of permeation (intramural and extramural invasion) in stage II colon cancer is still unclear.

Objective: This study aims to clarify whether the location of lymphatic invasion, vascular invasion, and perineural invasion could affect survival of stage II colon cancer patients.

Design: This was a retrospective cohort study.

Settings: This study took place at a university teaching hospital.

Patients: A total of 1130 patients with stage II colon cancers who underwent radical surgery at the Seoul National University Hospital between July 2003 and December 2015 were included.

Main Outcome Measures: Patients were classified according to the location of lymphatic invasion, vascular invasion, and perineural invasion. Survival outcomes were compared among those without invasion, and those with intramural and extramural invasion. Primary end point is overall survival and secondary end point is disease free survival.

Results: Disease-free survival and overall survival of patients with extramural invasion were worse than those of patients without invasion and those with intramural invasion. Multivariate analysis for survival outcomes confirmed that extramural invasion were significant independent prognostic factors. However, both disease free survival and overall survival were not significantly different between patients without invasion and those with intramural invasion.

Limitations: This study was limited by its retrospective design.

Conclusions: Extramural invasion was associated with worse prognosis in stage II colon cancer, but intramural invasion was not. Therefore, pathologic reports about the location of lymphatic invasion, vascular invasion, and perineural invasion might be helpful for predicting prognosis and for determining the need of adjuvant chemotherapy in stage II colon cancers. See Video Abstract at http://links.lww.com/DCR/B939.
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http://dx.doi.org/10.1097/DCR.0000000000002339DOI Listing
March 2022

A comprehensive evaluation of regression-based drug responsiveness prediction models, using cell viability inhibitory concentrations (IC50 values).

Bioinformatics 2022 Mar 23. Epub 2022 Mar 23.

Department of Health Sciences and Technology, Gachon Advanced Institute for Health Sciences and Technology (GAIHST), Gachon University, Korea Incheon, 21999.

Motivation: Predicting drug response is critical for precision medicine. Diverse methods have predicted drug responsiveness, as measured by the half-maximal drug inhibitory concentration (IC50), in cultured cells. Although IC50s are continuous, traditional prediction models have dealt mainly with binary classification of responsiveness. However, since there are few regression-based IC50 predictions, comprehensive evaluations of regression-based IC50 prediction models, including machine learning (ML) and deep learning (DL), for diverse data types and dataset sizes, have not been addressed.

Results: Here, we constructed eleven input data settings, including a multi-omics setting, with varying dataset sizes, then evaluated the performance of regression-based ML and DL models to predict IC50s. DL models considered two convolutional neural network (CNN) architectures: CDRScan and residual neural network (ResNet). ResNet was introduced in regression-based DL models for predicting drug response for the first time. As a result, DL models performed better than ML models in all the settings. Also, ResNet performed better than or comparable to CDRScan and ML models in all scenarios.

Availability: Freely available on the web at https://github.com/labnams/IC50evaluation.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btac177DOI Listing
March 2022

Acute esophageal obstruction after ingestion of psyllium seed husk powder: A case report.

World J Clin Cases 2022 Mar;10(7):2336-2340

Department of Emergency Medicine, Yeungnam University School of Medicine and College of Medicine, Daegu 42415, South Korea.

Background: Bezoar is a mass of hardened external material found in the gastrointestinal (GI) tract. It may form anywhere in the GI tract, but esophageal bezoar is rare because of the short esophageal transit time. Psyllium seed husk is an indigestible natural derivative that is widely used as an herbal laxative. Herein, we report a case of acute esophageal obstruction caused by a bezoar after ingestion of psyllium seed husk powder.

Case Summary: A 76-year-old male with Parkinson's disease visited the emergency department with swallowing difficulty approximately 10 h after ingesting psyllium seed husk powder. Symptoms began a few hours after ingestion and progressed to severe dysphagia. There were no abnormal findings on simple radiography. However, a computed tomography scan revealed an approximately 2.0 cm × 2.5 cm mass located near the gastro-esophageal junction. After grinding, the mass was removed using an endoscopic capture net. Esophageal bezoars may cause life-threatening complications. Patients with Parkinson's disease may have esophageal motility dysfunction, which may increase esophageal transit time. Since our patient had Parkinson's disease, this effect may have contributed to the formation of the bezoar.

Conclusion: Attention should be paid to using bulk-laxatives, and an appropriate specified regimen will be needed when marketed as a dietary supplement.
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http://dx.doi.org/10.12998/wjcc.v10.i7.2336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895160PMC
March 2022

K-selective percolation: A simple model leading to a rich repertoire of phase transitions.

Authors:
Jung-Ho Kim K-I Goh

Chaos 2022 Feb;32(2):023115

Department of Physics, Korea University, Seoul 02841, South Korea.

We propose a K-selective percolation process as a model for iterative removals of nodes with a specific intermediate degree in complex networks. In the model, a random node with degree K is deactivated one by one until no more nodes with degree K remain. The non-monotonic response of the giant component size on various synthetic and real-world networks implies a conclusion that a network can be more robust against such a selective attack by removing further edges. From a theoretical perspective, the K-selective percolation process exhibits a rich repertoire of phase transitions, including double transitions of hybrid and continuous, as well as reentrant transitions. Notably, we observe a tricritical-like point on Erdős-Rényi networks. We also examine a discontinuous transition with unusual order parameter fluctuation and distribution on simple cubic lattices, which does not appear in other percolation models with cascade processes. Finally, we perform finite-size scaling analysis to obtain critical exponents on various transition points, including those exotic ones.
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http://dx.doi.org/10.1063/5.0081253DOI Listing
February 2022

DNA barcode-based detection of exosomal microRNAs using nucleic acid lateral flow assays for the diagnosis of colorectal cancer.

Talanta 2022 May 16;242:123306. Epub 2022 Feb 16.

Department of Biological Engineering, College of Engineering, Konkuk University, Seoul, 05029, Republic of Korea. Electronic address:

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. The standard methods for diagnosing CRC, endoscopy and tissue biopsy, are invasive and time-consuming. Herein, we propose a novel method for the accurate and non-invasive diagnosis of CRC based on the analysis of exosomes that are circulating in biological fluids using a DNA barcode-based nucleic acid lateral flow assay (NALFA). Our technology combines reverse transcription using a stem-loop primer with DNA barcode-based NALFA. A colorimetric signal is generated only in the presence of the target exosomal miRNA, which can be determined even with the naked eye. The proposed system successfully detected miR-92a and miR-141, which are overexpressed in CRC exosomes. Moreover, when applied to plasma samples from CRC patients, our system simultaneously detected multiple markers in one strip. By combining these markers, we achieved high analytical performance with a sensitivity and a specificity of 95.24% and 100.0%, respectively, demonstrating that the proposed assay can be a simple diagnostic platform for the detection of exosomal miRNA.
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http://dx.doi.org/10.1016/j.talanta.2022.123306DOI Listing
May 2022

Surveillance of Close Contacts and Implications of Pediatric Patients with COVID-19-Experiences from a Single Residential Treatment Center.

Yonsei Med J 2022 Mar;63(3):292-295

Division of Infectious Disease, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.

Residential treatment centers (RTCs) are successful in isolating and closely monitoring adults confirmed with coronavirus disease 2019 (COVID-19), but there are concerns for children who need care. This study was conducted as a retrospective analysis of the surveillance of guardians who entered an RTC with infected pediatric patients to identify the secondary attack rate of COVID-19 to close contacts in a single RTC and to provide directions for developing guidelines for caregivers who co-isolate with infected children. When caregivers were admitted to this RTC, aside from negative confirmation before discharge, tests were additionally performed one or two times. There were 57 index children and adolescent patients who entered the RTC with their parents as caregivers. The secondary attack rate by pediatric patients to close contacts outside their households was 25% (95% confidence interval, 10.0 to 40.0) (8 out of 32 contacts). The transmissibility of SARS-CoV-2 in children was close to zero at 6 days after the confirmation tests. It is reasonable to test the close contacts of pediatric patients after 7 days of isolation to identify infections among caregivers.
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http://dx.doi.org/10.3349/ymj.2022.63.3.292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860931PMC
March 2022

Faecal microbiota transplantation reduces amounts of antibiotic resistance genes in patients with multidrug-resistant organisms.

Antimicrob Resist Infect Control 2022 01 29;11(1):20. Epub 2022 Jan 29.

Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Yonsei University Health System, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.

Background: Multidrug-resistant organisms (MDROs) such as vancomycin-resistant enterococci (VRE) and carbapenemase-producing Enterobacteriaceae (CPE) are associated with prolonged hospitalisation, increased medical costs, and severe infections. Faecal microbiota transplantation (FMT) has emerged as an important strategy for decolonisation. This study aimed to evaluate the genetic response of MDROs to FMT.

Methods: A single-centre prospective study was conducted on patients infected with VRE, CPE, or VRE/CPE who underwent FMT between May 2018 and April 2019. Genetic response was assessed as the change in the expression of the resistance genes VanA, bla, bla, and bla on days 1, 7, 14, and 28 by real-time reverse-transcription polymerase chain reaction.

Results: Twenty-nine patients received FMT, of which 26 (59.3%) were infected with VRE, 5 (11.1%) with CPE, and 8 (29.6%) with VRE/CPE. The mean duration of MDRO carriage before FMT was 71 days. Seventeen patients (63.0%) used antibiotics within a week of FMT. In a culture-dependent method, the expression of VanA and overall genes significantly decreased (p = 0.011 and p = 0.003 respectively). In a culture-independent method, VanA, bla, and overall gene expression significantly decreased over time after FMT (p = 0.047, p = 0.048, p = 0.002, respectively). Similar results were confirmed following comparison between each time point in both the culture-dependent and -independent methods. Regression analysis did not reveal important factors underlying the genetic response after FMT. No adverse events were observed.

Conclusion: FMT in patients infected with MDROs downregulates the expression of resistance genes, especially VanA, and facilitates MDRO decolonisation.
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http://dx.doi.org/10.1186/s13756-022-01064-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800327PMC
January 2022

Comprehensive clinicopathologic, molecular, and immunologic characterization of colorectal carcinomas with loss of three intestinal markers, CDX2, SATB2, and KRT20.

Virchows Arch 2022 Mar 14;480(3):543-555. Epub 2022 Jan 14.

Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Caudal-type homeobox 2 (CDX2), special AT-rich sequence-binding protein 2 (SATB2), and keratin 20 (KRT20) are frequently used as intestinal epithelium-specific markers in immunohistochemical studies. However, subsets of colorectal carcinomas (CRCs) show loss of these markers. We analyzed The Cancer Genome Atlas data to explore molecular correlates of CDX2, SATB2, and KRT20 genes in 390 CRCs. The decreased mRNA expression of each of the three genes commonly correlated with microsatellite instability-high (MSI-H), CpG island methylator phenotype-high (CIMP-H), BRAF/RNF43 mutations, consensus molecular subtype 1, and high tumor mutational burden. The downregulation of CDX2 or SATB2 was dependent on both MSI-H and CIMP-H, whereas that of KRT20 was more dependent on MSI-H than on CIMP-H. Next, we evaluated the immunohistochemical expression of CDX2, SATB2, and KRT20 in 436 primary CRCs. In contrast to RNA-level expression, decreased expression of CDX2 and SATB2 was more dependent on CIMP-H than on MSI-H. However, consistent with RNA-level expression, decreased expression of KRT20 was more dependent on MSI-H than on CIMP-H. CIMP-H and lymphatic invasion were consistently associated with both CDX2 loss and SATB2 loss in CRCs, regardless of MSI status. In microsatellite stable CRCs, CDX2 loss correlated with BRAF mutation, whereas SATB2 loss was associated with KRAS mutations and decreased T-cell infiltration. Cases with concurrent loss of all three markers were found exclusively in MLH1-methylated MSI-H/CIMP-H CRCs. In conclusion, MSI-H and/or CIMP-H are major common correlates of decreased CDX2/SATB2/KRT20 expression in CRCs, but the specific features associated with the loss of each marker are different in CRCs.
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http://dx.doi.org/10.1007/s00428-021-03260-wDOI Listing
March 2022

Combinatory statuses of tumor stromal percentage and tumor infiltrating lymphocytes as prognostic factors in stage III colorectal cancers.

J Gastroenterol Hepatol 2022 Mar 25;37(3):551-557. Epub 2022 Jan 25.

Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea.

Background And Aim: Tumor stroma and tumor-infiltrating lymphocytes (TILs) are major constituents of the tumor microenvironment, although they have different effects on the prognosis of patients with colorectal cancer (CRC). Combinatory statuses of tumor-stromal percentage (TSP) and TILs are expected to provide more powerful prognostic information but have never been studied in CRCs.

Methods: Stage III CRCs from patients (n = 487) treated with adjuvant chemotherapy were assessed for their TSP and CD3-TIL or CD8-TIL densities using computer-aided methodology. With cut-off values set at median values for intraepithelial TIL (iTIL) and stromal TIL (sTIL) densities, CRCs were sorted into low and high iTIL or sTIL groups. CRCs were classified into five quintile (Q1-Q5) groups according to their TSP and divided into high TSP (Q5) and low TSP (Q1-4) groups.

Results: The combination of CD8 iTIL density and TSP was found to be an independent prognostic parameter in multivariate survival analysis in terms of cancer-specific survival and recurrence-free survival. CRCs with low CD8 iTIL density and high TSP showed the worst survival. The combinatory status showed more prognostic power than CD8 iTIL density or TSP alone. Multivariate survival analysis in an independent cohort of stage III CRC validated the prognostic power of the combinatory statuses.

Conclusions: The findings suggest that the combinatory status might serve as a prognostic parameter in stage III CRCs. Further research in a large-scale cohort of patients with stage III CRC is needed to validate the prognostic power of the combinatory status.
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http://dx.doi.org/10.1111/jgh.15774DOI Listing
March 2022

SKI-G-801, an AXL kinase inhibitor, blocks metastasis through inducing anti-tumor immune responses and potentiates anti-PD-1 therapy in mouse cancer models.

Clin Transl Immunology 2022 29;11(1):e1364. Epub 2021 Dec 29.

Yonsei Cancer Center Yonsei University College of Medicine Seoul Korea.

Objectives: AXL-mediated activation of aberrant tyrosine kinase drives various oncogenic processes and facilitates an immunosuppressive microenvironment. We evaluated the anti-tumor and anti-metastatic activities of SKI-G-801, a small-molecule inhibitor of AXL, alone and in combination with anti-PD-1 therapy.

Methods: pAXL inhibition by SKI-G-801 was performed in both human and mouse cancer cell lines. Immunocompetent mouse models of tumor were established to measure anti-metastatic potential of SKI-G-801. Furthermore, SKI-G-801, anti-PD-1 or their combination was administered as an adjuvant or neoadjuvant in the 4T1 tumor model to assess their potential for clinical application.

Results: SKI-G-801 robustly inhibited pAXL expression in various cell lines. SKI-G-801 alone or in combination with anti-PD-1 potently inhibited metastasis in B16F10 melanoma, CT26 colon and 4T1 breast models. SKI-G-801 inhibited the growth of B16F10 and 4T1 tumor-bearing mice but not immune-deficient mice. An antibody depletion assay revealed that CD8 T cells significantly contributed to SKI-G-801-mediated survival. Anti-PD-1 and combination group were observed the increased CD8Ki67 and effector T cells and M1 macrophage and decreased M2 macrophage, and granulocytic myeloid-derived suppressor cell (G-MDSC) compared to the control group. The neoadjuvant combination of SKI-G-801 and anti-PD-1 therapy achieved superior survival benefits by inducing more profound T-cell responses in the 4T1 syngeneic mouse model.

Conclusion: SKI-G-801 significantly suppressed tumor metastasis and growth by enhancing anti-tumor immune responses. Our results suggest that SKI-G-801 has the potential to overcome anti-PD-1 therapy resistance and allow more patients to benefit from anti-PD-1 therapy.
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http://dx.doi.org/10.1002/cti2.1364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716998PMC
December 2021

Mutational Characterization of Colorectal Cancer from Korean Patients with Targeted Sequencing.

J Cancer 2021 28;12(24):7300-7310. Epub 2021 Oct 28.

Department of Surgery, Gachon University College of Medicine Gil Medical Center, Incheon, Republic of Korea.

Effective treatment of colorectal cancer could benefit from understanding molecular characteristics including mutation profiles of important genes. This study aimed to explore the molecular characteristics of colorectal cancer based on next generation sequencing. The mutational characteristics by targeted next generation sequencing in 172 colorectal tumor samples from Korean patients were evaluated to explore their associations with clinical features. Targeted sequencing of 375 genes was performed with an average target-depth of 800X. TP53 and APC showed higher mutation frequencies from the left-sided tumors, while CTNNB1 were more frequent from the right-sided tumors. The tumor suppressor NOTCH1 and the DNA strand break repair gene PALB2 were more frequently mutated in early onset tumors. KRAS and PTEN mutations were more frequent from patients with advanced cancers by cancer antigen markers. TP53 and BRAF mutations were more frequent from patients of T3 and T4 stages, where their variant allele fractions were generally higher in T4 tumors, implying that advanced tumors have higher fraction of cancer cells with TP53 and BRAF mutations. Mutational profiles of these patients were also assessed with other clinical features. Comparison of mutational characteristics with the Caucasian subjects from independent data showed that the identified mutational characteristics are largely Korean-specific except for a few key colorectal cancer genes. Next generation sequencing-based targeted sequencing can provide valuable information on molecular characterization of colorectal cancer patients, and its clinically relevant information can provide benefits to better understand colorectal cancer.
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http://dx.doi.org/10.7150/jca.61324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8734410PMC
October 2021

MgB Superconducting Joint Architecture with the Functionality to Screen External Magnetic Fields for MRI Magnet Applications.

ACS Appl Mater Interfaces 2022 Jan 5;14(2):3418-3426. Epub 2022 Jan 5.

School of Mechanical and Mining Engineering, The University of Queensland, St Lucia, Queensland 4072, Australia.

A superconducting joint architecture to join unreacted carbon-doped multifilament magnesium diboride (MgB) wires with the functionality to screen external magnetic fields for magnetic resonance imaging (MRI) magnet applications is proposed. The intrinsic diamagnetic property of a superconducting MgB bulk was exploited to produce a magnetic field screening effect around the current transfer path within the joint. Unprecedentedly, the joint fabricated using this novel architecture was able to screen magnetic fields up to 1.5 T at 20 K and up to 2 T at 15 K and thereby almost nullified the effect of the applied magnetic field by maintaining a constant critical current (). The joint showed an of 30.8 A in 1.5 T at 20 K and an ultralow resistance of about 3.32 × 10 Ω at 20 K in a self-field. The magnetic field screening effect shown by the MgB joint is expected to be extremely valuable for MRI magnet applications, where the of the joints is lower than the of the connected MgB wires in a given magnetic field and temperature.
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http://dx.doi.org/10.1021/acsami.1c19581DOI Listing
January 2022

Comparing Treatment Outcomes of Ampicillin-Sulbactam, Other β-Lactams, and Vancomycin in Blood Culture-Negative Infective Endocarditis.

Antibiotics (Basel) 2021 Dec 1;10(12). Epub 2021 Dec 1.

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

Selection of proper antibiotics for blood culture-negative infective endocarditis (BCNIE) is difficult due to limited data on antibiotic regimens for BCNIE in existing literature. The aim of this study was to compare ampicillin-sulbactam, other β-lactams antibiotics, and vancomycin among patients with BCNIE to determine the proper antibiotic regimens. This retrospective study included adult patients with BCNIE admitted to Severance Hospital from November 2005 to August 2017. Patients were classified into three groups as, treated with ampicillin-sulbactam, other β-lactams, and vancomycin. The primary outcome was 1-year all-cause mortality. A total of 74 cases with BCNIE were enrolled in this study. There were no statistically significant differences in clinical characteristics between the three groups. One-year mortality did not significantly differ between the study groups either. Further, in-hospital mortality, 28-day mortality and overall mortality showed no difference. However, Cox-regression analysis showed nosocomial infective endocarditis as an independent risk factor and a protective effect of surgery on 1-year mortality. This study showed no clear difference in the outcomes of BCNIE as per the antibiotic therapy but suggested the beneficial effect of surgical treatment. With increasing global concern of antimicrobial resistance, it might be reasonable to select ampicillin-sulbactam-based antibiotic therapy while actively considering surgical treatment in BCNIE.
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http://dx.doi.org/10.3390/antibiotics10121476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698808PMC
December 2021

Vegetation Size, Multiplicity, and Position in Patients With Infective Endocarditis.

Ann Thorac Surg 2021 Dec 18. Epub 2021 Dec 18.

Division of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea. Electronic address:

Background: Infective endocarditis is a life-threatening condition and is associated with embolic events. We aimed to evaluate the association of vegetation size, multiplicity, and position with cerebral embolism and late mortality in patients with infective endocarditis.

Methods: We retrospectively reviewed patients with infective endocarditis who were admitted to a single institution between November 2005 and August 2017. A total of 419 patients with infective endocarditis were included in the study, 273 of whom had undergone surgery. The primary endpoint was all-cause mortality, and the secondary endpoint was cerebral embolism. Multivariate Cox regression and logistic regression analyses were performed to identify independent risk factors for 30-day mortality, late mortality, and cerebral embolism.

Results: Age (hazard ratio [HR] 1.02; 95% confidence interval [CI], 1.00 to 1.04), renal failure (HR 4.21; 95% CI, 2.67 to 6.65), surgery (HR 0.31; 95% CI, 0.21 to 0.46), and Acute Physiology and Chronic Health Evaluation II score (HR 1.08; 95% CI, 1.01 to 1.15) were associated with late mortality. Vegetation size, multiplicity, and position were not significantly associated with late mortality, but a mitral vegetation size of greater than 10 mm (odds ratio 2.25; 95% CI, 1.32 to 3.84) was an independent risk factor for cerebral embolism.

Conclusions: A vegetation size of greater than 10 mm and the mitral position were found to be significant risk factors for cerebral embolism, and for this group, early surgery might be considered to prevent cerebral embolism.
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http://dx.doi.org/10.1016/j.athoracsur.2021.10.071DOI Listing
December 2021

Prehospital Notification Using a Mobile Application Can Improve Regional Stroke Care System in a Metropolitan Area.

J Korean Med Sci 2021 Dec 13;36(48):e327. Epub 2021 Dec 13.

Department of Emergency Medicine, Yeungnam University College of Medicine, Daegu, Korea.

Background: Acute ischemic stroke is a time-sensitive disease. Emergency medical service (EMS) prehospital notification of potential patients with stroke could play an important role in improving the in-hospital medical response and timely treatment of patients with acute ischemic stroke. We analyzed the effects of FASTroke, a mobile app that EMS can use to notify hospitals of patients with suspected acute ischemic stroke at the prehospital stage.

Methods: We conducted a retrospective observational study of patients diagnosed with acute ischemic stroke at 5 major hospitals in metropolitan Daegu City, Korea, from February 2020 to January 2021. The clinical conditions and time required for managing patients were compared according to whether the EMS employed FASTroke app and further compared the factors by dividing the patients into subgroups according to the preregistration received by the hospitals when using FASTroke app.

Results: Of the 563 patients diagnosed with acute ischemic stroke, FASTroke was activated for 200; of these, 93 were preregistered. The FASTroke prenotification showed faster door-to-computed-tomography times (19 minutes vs. 25 minutes, < 0.001), faster door-to-intravenous-thrombolysis times (37 minutes vs. 48 minutes, < 0.001), and faster door-to-endovascular-thrombectomy times (82 minutes vs. 119 minutes, < 0.001). The time was further shortened when the preregistration was conducted simultaneously by the receiving hospital.

Conclusion: The FASTroke app is an easy and useful tool for prenotification as a regional stroke care system in the metropolitan area, leading to reduced transport and acute ischemic stroke management time and more reperfusion treatment. The effect was more significant when the preregistration was performed jointly.
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http://dx.doi.org/10.3346/jkms.2021.36.e327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8668497PMC
December 2021

Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers.

J Immunother Cancer 2021 12;9(12)

Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea

Background: Colorectal cancers (CRCs) with microsatellite instability-high (MSI-H) are hypermutated tumors and are generally regarded as immunogenic. However, their heterogeneous immune responses and underlying molecular characteristics remain largely unexplained.

Methods: We conducted a retrospective analysis of 73 primary MSI-H CRC tissues to characterize heterogeneous immune subgroups. Based on combined tumor-infiltrating lymphocyte (TIL) immunoscore and tertiary lymphoid structure (TLS) activity, MSI-H CRCs were classified into immune-high, immune-intermediate, and immune-low subgroups. Of these, the immune-high and immune-low subgroups were further analyzed using whole-exome and transcriptome sequencing.

Results: We found considerable variations in immune parameters between MSI-H CRCs, and immune subgrouping of MSI-H CRCs was performed accordingly. The TIL densities and TLS activities of immune-low MSI-H CRCs were comparable to those of an immune-low or immune-intermediate subgroup of microsatellite-stable CRCs. There were remarkable differences between immune-high and immune-low MSI-H CRCs, including their pathological features (medullary vs mucinous), genomic alterations (tyrosine kinase fusions vs mutations), and activated signaling pathways (immune-related vs Wnt and Notch signaling), whereas no significant differences were found in tumor mutational burden (TMB) and neoantigen load. The immune-low MSI-H CRCs were subdivided by the consensus molecular subtype (CMS1 vs CMS3) with different gene expression signatures (mesenchymal/stem-like vs epithelial/goblet-like), suggesting distinct immune evasion mechanisms. Angiogenesis and CD200 were identified as potential therapeutic targets in immune-low CMS1 and CMS3 MSI-H CRCs, respectively.

Conclusions: MSI-H CRCs are immunologically heterogeneous, regardless of TMB. The unusual immune-low MSI-H CRCs are characterized by mucinous histology, mutations, and Wnt/Notch activation, and can be further divided into distinct gene expression subtypes, including CMS4-like CMS1 and CMS3. Our data provide novel insights into precise immunotherapeutic strategies for subtypes of MSI-H tumors.
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http://dx.doi.org/10.1136/jitc-2021-003414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672019PMC
December 2021
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