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Purpose: Regulatory T cells (Tregs) exert immunosuppressive functions and hamper antitumor immune responses in the tumor microenvironment. Understanding the heterogeneity of intratumoral Tregs, and how it changes with tumor progression, will provide clues regarding novel target molecules of Treg-directed therapies. Experimental Design: From 42 patients with renal cell carcinoma and 5 patients with ovarian cancer, immune cells from tumor and peripheral blood were isolated. We performed multicolor flow cytometry and RNA-sequencing to characterize the phenotypes and heterogeneity of intratumoral Tregs. In vitro functional assays were performed to evaluate suppressive capacity of Tregs and effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-mediated depletion. The CT26 tumor model was used to evaluate the association between intratumoral Tregs and tumor growth, and examine the in vivo role of CEACAM1+ intratumoral Tregs on antitumor immunity. Results: We found that CEACAM1 was selectively expressed on intratumoral Tregs, whereas its expression on peripheral Tregs or other immune cells was low. The CEACAM1+ intratumoral Tregs accumulated with tumor progression, whereas the CEACAM1− subset did not. Notably, we found that CEACAM1 marked intratumoral Tregs that exhibited highly suppressive and activated phenotypes with substantial clonal expansion. Depletion of CEACAM1-expressing cells from tumor-infiltrating leukocytes led to increased effector functions of tumor-infiltrating T cells. Moreover, CEACAM1+ cell depletion further enhanced anti-PD-1–mediated reinvigoration of exhausted CD8+ T cells. Conclusions: CEACAM1 marks highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs. These results may inform future studies on CEACAM1-mediated depletion in patients with cancer.

The impact of 1-month dual antiplatelet therapy (DAPT) followed by aspirin monotherapy according to clinical presentation has not been elucidated.This study aimed to compare the impact of 1-month DAPT followed by aspirin monotherapy after polymer-free drug-coated stent (PF-DCS) implantation (1-month DAPT after PF-DCS) vs 6-12-month DAPT followed by aspirin monotherapy after biodegradable polymer drug-eluting stent (BP-DES) implantation (6-12-month DAPT after BP-DES) according to clinical presentation.This is a post hoc analysis of the One-Month DAPT trial. The primary outcome was the composite of major adverse cardiac and cerebrovascular events (MACCE; a composite of cardiac death, non-fatal myocardial infarction, target vessel revascularisation, and stroke) and major bleeding.Among 1,828 patients with stable coronary artery disease (CAD), 1-month DAPT after PF-DCS resulted in lower rates of the primary outcome than 6-12-month DAPT after BP-DES (3.9% vs 6.5%; hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.39-0.90; p=0.012). However, among 1,192 patients with acute coronary syndrome (ACS), the rates of the primary outcome were not significantly different between the two therapy groups (5.6% vs 3.6%; HR 1.57, 95% CI: 0.91-2.70; p=0.102) and a significant interaction was observed between therapy and clinical presentation regarding the primary outcome (PIn patients undergoing drug-eluting stent implantation for non-complex lesions, the benefits of 1-month DAPT followed by aspirin monotherapy for a composite of ischaemic and bleeding outcomes were found in patients with stable CAD, but not in those with ACS.gov: NCT02513810.

Background: We sought to explore the sex differences in clinical outcomes among patients with acute coronary syndrome treated with ticagrelor monotherapy after ticagrelor-based 3-month versus 12-month dual-antiplatelet therapy. Methods: This was a post hoc analysis of the TICO trial (Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-Eluting Stent for Acute Coronary Syndrome; n=3056)—a randomized controlled trial for patients with acute coronary syndrome treated with drug-eluting stent. The primary outcome was a net adverse clinical event (composite of major bleeding, death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization) 1 year after drug-eluting stent implantation. Secondary outcomes included major bleeding and major adverse cardiac and cerebrovascular events. Results: There were 27.3% (n=628) women in the TICO trial; they were older with lower body mass index and higher prevalence of hypertension, diabetes, or chronic kidney disease than men. Compared with men, women had higher risk of net adverse clinical events (hazard ratio [HR], 1.89 [95% CI, 1.34–2.67]), major adverse cardiac and cerebrovascular events (HR, 1.69 [95% CI, 1.07–2.68]), and major bleeding (HR, 2.04 [95% CI, 1.25–3.35]). Among the groups stratified by sex and dual-antiplatelet therapy strategy, the incidences of primary and secondary outcomes were significantly different and the highest in women with ticagrelor-based 12-month dual-antiplatelet therapy ( P P =0.02) and comparable in men (HR, 0.77 [95% CI, 0.52–1.14]; P =0.19) without significant interaction ( P for interaction, 0.18). Conclusions: After percutaneous coronary intervention for acute coronary syndrome, women demonstrated worse clinical outcomes than men. Ticagrelor monotherapy after 3-month dual-antiplatelet therapy was associated with significantly lower risk of net adverse clinical events in women without sex interaction.

Purpose:Regulatory T cells (Tregs) exert immunosuppressive functions and hamper antitumor immune responses in the tumor microenvironment. Understanding the heterogeneity of intratumoral Tregs, and how it changes with tumor progression, will provide clues regarding novel target molecules of Treg-directed therapies.Experimental Design:From 42 patients with renal cell carcinoma and 5 patients with ovarian cancer, immune cells from tumor and peripheral blood were isolated. We performed multicolor flow cytometry and RNA-sequencing to characterize the phenotypes and heterogeneity of intratumoral Tregs. In vitro functional assays were performed to evaluate suppressive capacity of Tregs and effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-mediated depletion. The CT26 tumor model was used to evaluate the association between intratumoral Tregs and tumor growth, and examine the in vivo role of CEACAM1+ intratumoral Tregs on antitumor immunity.Results:We found that CEACAM1 was selectively expressed on intratumoral Tregs, whereas its expression on peripheral Tregs or other immune cells was low. The CEACAM1+ intratumoral Tregs accumulated with tumor progression, whereas the CEACAM1− subset did not. Notably, we found that CEACAM1 marked intratumoral Tregs that exhibited highly suppressive and activated phenotypes with substantial clonal expansion. Depletion of CEACAM1-expressing cells from tumor-infiltrating leukocytes led to increased effector functions of tumor-infiltrating T cells. Moreover, CEACAM1+ cell depletion further enhanced anti-PD-1–mediated reinvigoration of exhausted CD8+ T cells.Conclusions:CEACAM1 marks highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs. These results may inform future studies on CEACAM1-mediated depletion in patients with cancer.

Drug combinations rather than increasing doses of one drug can achieve greater efficacy and lower risks. Thus, as an alternative to high-intensity statin monotherapy, moderate-intensity statin with ezetimibe combination therapy can lower LDL cholesterol concentrations effectively while reducing adverse effects. However, evidence from randomised trials to compare long-term clinical outcomes is needed.In this randomised, open-label, non-inferiority trial, patients with atherosclerotic cardiovascular disease (ASCVD) at 26 clinical centres in South Korea were randomly assigned (1:1) to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke, in the intention-to-treat population with a non-inferiority margin of 2·0%. This trial is registered with ClinicalTrials.gov, NCT03044665 and is complete.Between Feb 14, 2017, and Dec 18, 2018, 3780 patients were enrolled: 1894 patients to the combination therapy group and 1886 to the high-intensity statin monotherapy group. The primary endpoint occurred in 172 patients (9·1%) in the combination therapy group and 186 patients (9·9%) in the high-intensity statin monotherapy group (absolute difference -0·78%; 90% CI -2·39 to 0·83). LDL cholesterol concentrations of less than 70 mg/dL at 1, 2, and 3 years were observed in 73%, 75%, and 72% of patients in the combination therapy group, and 55%, 60%, and 58% of patients in the high-intensity statin monotherapy group (all p0·0001). Discontinuation or dose reduction of the study drug by intolerance was observed in 88 patients (4·8%) and 150 patients (8·2%), respectively (p0·0001).Among patients with ASCVD, moderate-intensity statin with ezetimibe combination therapy was non-inferior to high-intensity statin monotherapy for the 3-year composite outcomes with a higher proportion of patients with LDL cholesterol concentrations of less than 70 mg/dL and lower intolerance-related drug discontinuation or dose reduction.Hanmi Pharmaceutical.

BACKGROUND: Moderate-intensity statin role with ezetimibe combination therapy following percutaneous coronary intervention (PCI) has not been thoroughly investigated, particularly compared to high-intensity statin monotherapy. We aimed to investigate the effect of ezetimibe combination with moderate-intensity statin in patients with atherosclerotic cardiovascular disease following PCI. METHODS: This was a post-hoc analysis of a subset of patients who underwent PCI in the RACING trial. At 26 centres in South Korea, patients with atherosclerotic cardiovascular disease (ASCVD) were randomly assigned to receive either moderate-intensity statin with ezetimibe combination therapy (rosuvastatin 10 mg with ezetimibe 10 mg) or high-intensity statin monotherapy (rosuvastatin 20 mg). The prespecified endpoints of the RACING trial were used. The primary endpoint was the 3-year composite of cardiovascular death, major cardiovascular events, and nonfatal stroke. Event rates between the two groups were compared using log-rank tests, and hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox regression analysis. Consistent with the RACING trial, the primary and secondary efficacy endpoints were evaluated using an intention-to-treatment approach, and the safety endpoints were assessed in the safety population. The RACING trial was registered at ClinicalTrials.gov (NCT03044665). FINDINGS: Between Feb 14, 2017, and Dec 18, 2018, 3780 participants were enrolled in the RACING trial. Prior history of PCI was found in 2497 patients (67%, median 64 years, 79% male), and was associated with higher rates of the primary endpoint (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.06–1.69; p = 0.014). Among patients with prior PCI, moderate-intensity statin therapy with ezetimibe combination versus high-intensity statin therapy did not increase the risk of the primary endpoint (HR, 0.95; 95% CI, 0.74–1.24; p = 0.781). The proportion of patients with low-density lipoprotein cholesterol (LDL-C)

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BackgroundAlthough ticagrelor monotherapy after 3-month dual antiplatelet therapy (DAPT) results in a significantly greater net clinical benefit over that with ticagrelor-based 12-month DAPT in patients with acute coronary syndrome (ACS), it remains uncertain whether this effect is dependent on body mass index (BMI). We aimed to evaluate the BMI-dependent effect of these treatment strategies on clinical outcomes.MethodsThis was a pre-specified subgroup analysis from the TICO trial (Ticagrelor Monotherapy After 3 Months in Patients Treated With New Generation Sirolimus-eluting Stent for Acute Coronary Syndrome), evaluating the interaction between BMI and treatment strategies for the primary outcome [composite of major bleeding and adverse cardiac and cerebrovascular events (MACCE): death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization]. The secondary outcomes were major bleeding and MACCE.ResultsBased on a pre-specified BMI threshold of 25 kg/m2, 3,056 patients were stratified. Patients with BMI 2 had a higher risk of primary and secondary outcomes than those with BMI ≥25 kg/m2. Regardless of the BMI subgroup, the effects of ticagrelor monotherapy after 3-month DAPT on the primary outcome (pint = 0.61), major bleeding (pint = 0.76), and MACCE (pint = 0.80) were consistent without significant interaction compared with ticagrelor-based 12-month DAPT. The treatment effects according to the BMI quartiles and age, sex, and diabetic status were also consistent without significant interaction.ConclusionThe BMI-dependent impact of ticagrelor monotherapy after 3-month DAPT compared with 12-month DAPT on clinical outcomes was not heterogeneous in patients with ACS.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT02494895].

Regarding stent expansion indices, previous optical coherence tomography (OCT) studies have shown minimal stent area (MSA) to be most predictive of adverse events. We sought to evaluate the impact of various stent expansion and apposition indices by post-stent OCT on clinical outcomes and find OCT-defined optimal stent implantation criteria. A total of 1071 patients with 1123 native coronary artery lesions treated with new-generation drug-eluting stents with OCT guidance and final post-stent OCT analysis were included. Several stent expansion indices (MSA, MSA/average reference lumen area, MSA/distal reference lumen area, mean stent expansion, and stent expansion by linear model [stent volume/adaptive reference lumen volume]) were evaluated for their association with device-oriented clinical endpoints (DoCE) including cardiac death, target vessel-related myocardial infarction (MI) or stent thrombosis, and target lesion revascularization. MSA was negatively correlated with the risk of DoCE (hazard ratio [HR] 0.80 [0.68‒0.94]). However, stent expansion by linear model representing the overall volumetric stent expansion was associated with greater risk of DoCE (HR 1.02 [1.00‒1.04]). As categorical criteria, MSA 2 (HR 3.90 [1.99‒7.65]), MSA/distal reference lumen area

Objectives This study sought to evaluate the impact of post-stent optical coherence tomography (OCT) findings, including severe malapposition, on long-term clinical outcomes. Background Suboptimal OCT findings following percutaneous coronary intervention (PCI) are highly prevalent; however, their clinical implications remain controversial. Methods Of the patients registered in the Yonsei OCT registry, a total of 1,290 patients with 1,348 lesions, who underwent OCT immediately post-stenting, were consecutively enrolled for this study. All patients underwent implantation of drug-eluting stents. Post-stent OCT findings were assessed to identify predictors of device-oriented clinical endpoints (DoCE), including cardiac death, target vessel-related myocardial infarction (MI) or stent thrombosis, and target lesion revascularization (TLR). Significant malapposition criteria associated with major safety events (MSE) were also investigated, such as cardiac death, target vessel-related MI, or stent thrombosis. Results The median follow-up period was 43.0 months (interquartile range [IQR] 21.4 to 56.0 months). The incidence rates of stent edge dissection, tissue prolapse, thrombus, and malapposition after intervention were not associated with occurrence of DoCE. However, patients with significant malapposition (total malapposition volume [TMV] ≥7.0 mm3] exhibited more frequent MSE. A smaller minimal stent area (MSA) was identified as an independent predictor for DoCE (hazard ratio [HR]: 1.20 [95% confidence interval [CI]: 1.00 to 1.43]; p = 0.045). Malapposition with TMV ≥7.0 mm3 was found to be an independent predictor of MSE (HR: 6.12 [95% CI: 1.88 to 19.95]; p = 0.003). Follow-up OCT at 3, 6, or 9 months after PCI showed that post-stent TMV ≥7.0 mm3 was related to a greater occurrence of late malapposition and uncovered struts. Conclusions Although most suboptimal OCT findings were not associated with clinical outcomes, a smaller MSA was associated with DoCE, driven mainly by TLR, and significant malapposition with TMV ≥7.0 mm3 was associated with more MSE after PCI. (Yonsei OCT [Optical Coherence Tomography] Registry for Evaluation of Efficacy and Safety of Coronary Stenting; Yonsei OCT registry; NCT02099162 )

The immune system comprises a complex group of processes that provide defense against diverse pathogens. These defenses can be divided into innate and adaptive immunity, in which specific immune components converge to limit infections. In addition to genetic factors, aging, lifestyle, and environmental factors can influence immune function, potentially affecting the susceptibility of the host to disease-causing agents. Chemical compounds in certain foods have been shown to regulate signal transduction and cell phenotypes, ultimately impacting pathophysiology. Research has shown that the consumption of specific functional foods can stimulate the activity of immune cells, providing protection against cancer, viruses, and bacteria. Here, we review a number of functional foods reported to strengthen immunity, including ginseng, mushrooms, chlorella, and probiotics (Lactobacillus plantarum). We also discuss the molecular mechanisms involved in regulating the activity of various types of immune cells. Identifying immune-enhancing functional foods and understanding their mechanisms of action will support new approaches to maintain proper health and combat immunological diseases., Functional foods: Beneficial effects on the immune system Evidence is building to support the idea that specific ‘functional foods’ can stimulate the activity of cells and signaling systems of the immune system to provide protection against cancer, viruses and bacteria. Sanguine Byun and colleagues at Yonsei University in Seoul, South Korea, review research into a range of functional foods, foods thought to have health benefits beyond their nutritional value. These include ginseng, mushrooms, the green algae called Chlorella and the probiotic bacteria Lactobacillus plantarum. They also consider individual components of foods such as poly-gamma-glutamate, a natural polymer made by bacteria. A wide body of research is revealing diverse molecular mechanisms through which biochemicals in functional foods can modulate different aspects of the immune system. These include effects on both non-specific innate immunity and adaptive immunity, which targets specific invading pathogens and diseased cells.

ObjectivesThis study aimed to evaluate and compare the diagnostic accuracy of machine learning (ML)- fractional flow reserve (FFR) based on optical coherence tomography (OCT) with wire-based FFR irrespective of the coronary territory.BackgroundML techniques for assessing hemodynamics features including FFR in coronary artery disease have been developed based on various imaging modalities. However, there is no study using OCT-based ML models for all coronary artery territories.MethodsOCT and FFR data were obtained for 356 individual coronary lesions in 130 patients. The training and testing groups were divided in a ratio of 4:1. The ML-FFR was derived for the testing group and compared with the wire-based FFR in terms of the diagnosis of ischemia (FFR ≤ 0.80).ResultsThe mean age of the subjects was 62.6 years. The numbers of the left anterior descending, left circumflex, and right coronary arteries were 130 (36.5%), 110 (30.9%), and 116 (32.6%), respectively. Using seven major features, the ML-FFR showed strong correlation (r = 0.8782, P < 0.001) with the wire-based FFR. The ML-FFR predicted wire-based FFR ≤ 0.80 in the test set with sensitivity of 98.3%, specificity of 61.5%, and overall accuracy of 91.7% (area under the curve: 0.948). External validation showed good correlation (r = 0.7884, P < 0.001) and accuracy of 83.2% (area under the curve: 0.912).ConclusionOCT-based ML-FFR showed good diagnostic performance in predicting FFR irrespective of the coronary territory. Because the study was a small-size study, the results should be warranted the performance in further large-scale research.

BackgroundTumour-unrelated, virus-specific bystander CD8+T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet.MethodsWe studied the characteristics of bystander CD8+TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy.ResultsWe show that bystander CD8+TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment.ConclusionThus, the study demonstrates that bystander CD8+TILs can be repurposed by IL-15 for tumour immunotherapy.

BackgroundThe efficacy of spot stenting using drug-eluting stents (DES) for the treatment of long femoropopliteal (FP) lesion is unknown. This study aimed to compare clinical outcomes of long full coverage vs. spot coverage with DES for long FP artery disease.MethodsThis multicenter randomized trial compared long DES vs. spot DES for FP lesions longer than 150 mm. All lesions were treated with paclitaxel-eluting stents (Zilver PTX). The primary endpoint was primary patency at 12 months.ResultsThe study was terminated early after an interim analysis. A total of 103 patients (55 in the long DES group; 48 in the spot DES group) were eligible for analysis. There were no significant differences in baseline and lesion characteristics between groups. Total stent length was longer in the long DES group than in the spot DES group (225.6 ± 67.2 vs. 131.3 ± 48.7 mm, p < 0.001). Technical success was achieved in all patients. There was a trend toward a higher primary patency rate at 12 months in the long DES group than in the spot DES group (87.5% vs. 67.5%, p = 0.120). The rate of survival free from target lesion revascularization was significantly higher in the long DES group than in the spot DES group (91.7% vs. 72.0%, p = 0.044). In multivariate Cox regression analysis, spot DES [hazard ratio (HR) 2.42, 95% confidence interval (CI) 1.14–5.12, p = 0.021] and postdilation (HR 0.27, 95% CI 0.09–0.79, p = 0.018) were identified as independent predictors for loss of patency at 12 months post-procedure.ConclusionsLong DES were more effective than spot DES for treating long FP lesions.Clinical trial registrationClinicaltrials.gov, identifier: NCT02701881.

Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8

Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8 + T cells in tumors, metastatic lymph nodes (mLNs), and peripheral blood from patients with early breast cancer ( n = 131). Among tissue-resident memory CD8 + T (T RM ) cells, including virus- and tumor-specific CD8 + T cells, CD39 expression was observed in a tumor-specific and exhausted subpopulation in both tumors and mLNs. CD39 + T RM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39 + T RM cells clonally overlapped with CD39 − T RM and non-T RM cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39 + T RM clonotypes were frequently detected among effector memory CD8 + T cells in peripheral blood, suggesting a systemic clonal overlap. CD39 + T RM cell enrichment was heterogeneous among molecular subtypes of breast cancer, which is associated with the different role of antitumor immune responses in each subtype. In vitro blockade of PD-1 and/or CTLA-4 effectively restored proliferation of CD39 + T RM cells and enhanced cytokine production by CD8 + T cells from tumors or mLNs, particularly in the presence of CD39 + T RM enrichment. This suggests that CD39 + T RM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39 + T RM cells with a clonal overlap across compartments are key players in antitumor immunity in breast cancer.

Aims This study evaluated the effect of moderate-intensity statin with ezetimibe combination therapy vs. high-intensity statin monotherapy among patients with diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD). Methods and results This was a pre-specified, stratified subgroup analysis of the DM cohort in the RACING trial. The primary outcome was a 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke. Among total patients, 1398 (37.0%) had DM at baseline. The incidence of the primary outcome was 10.0% and 11.3% among patients with DM randomized to ezetimibe combination therapy vs. high-intensity statin monotherapy (hazard ratio: 0.89; 95% confidence interval: 0.64–1.22; P = 0.460). Intolerance-related discontinuation or dose reduction of the study drug was observed in 5.2% and 8.7% of patients in each group, respectively (P = 0.014). LDL cholesterol levels Conclusion Ezetimibe combination therapy effects observed in the RACING trial population are preserved among patients with DM. This study supports moderate-intensity statin with ezetimibe combination therapy as a suitable alternative to high-intensity statins if the latter cannot be tolerated, or further reduction in LDL cholesterol is required among patients with DM and ASCVD. Clinical Trial Registration ClinicalTrials.gov, Identifier:NCT03044665.

The Kanbara reactor (KR) process is a mechanical stirring method that reacts hot metal with desulfurization flux; it is a widely implemented desulfurization method in contemporary steel production. This study aimed to develop a new impeller profile for improving the desulfurization efficiency of the KR process. We implemented operational data analysis, a computational fluid dynamics simulation based on the operational data and performed testing and analysis with impeller models on-site a production facility. Operational data from the production facility was gathered over a 3-year period. Seven impeller models with varying impeller blade width (top and bottom), height, inclination, and curvature (curved, straight, and combination) were simulated. The results were analyzed to determine the optimal conditions. A new impeller design was selected for on-site operational testing to investigate the in situ desulfurization efficiency over 350 charges, and the results corroborated the predictions by the numerical simulations. It is expected that the proposed process modification can be successfully used for improving industrial desulfurization efficiency.

Immune checkpoint inhibitors are effective for advanced hepatocellular carcinoma (HCC), but there remains a need for peripheral blood biomarkers to predict the clinical response. Here, we analyzed the peripheral blood of 45 patients with advanced HCC who underwent nivolumab. During treatment, frequency of classical monocytes (CD14

BACKGROUND The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8+ T cells (CD8+ TILs) from ICC patients. METHODS From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing. RESULTS When compared to peripheral CD8+ T cells, the CD8+ TILs included significantly higher proportions of the CD69+ CD103- and CD69+ CD103+ TRM-like subsets (P

In recent years, there has been an increase in the number of phishing attacks targeting people in the fields of defense, security, and diplomacy around the world. In particular, hacking attack group Kimsuky has been conducting phishing attacks to collect key information from public institutions since 2013. The main feature of the attack techniques used by the Kimsuky attack group are to conceal malicious code in phishing e-mails disguised as normal e-mails to spread a document file that is vulnerable to security, such as a Hangul file, or to induce interest through a social engineering attack technique to collect account information. This study classified the types of phishing e-mail attacks into spoofed e-mails, e-mail body vulnerability use, and attached file spoofing, and detailed analyses of their attack methods, such as commonality and characteristic analyses, were performed to analyze the profile of this phishing e-mail attack group. Based on the results, the purpose of the attacking group was determined to be intelligence gathering because it focused on phishing attacks targeting Korean diplomatic and defense public institutions and related foreign institutions. Finally, a countermeasure that can be used by mail service providers and mail users to respond to phishing e-mails is suggested.

BackgroundThe clinical implication of new-onset left bundle branch block (LBBB) after transcatheter aortic valve replacement (TAVR) remains controversial. We investigated the impact of new-onset persistent LBBB on reverse cardiac remodeling and clinical outcomes after TAVR.MethodsAmong 478 patients who had undergone TAVR for symptomatic severe aortic stenosis from 2011 to 2021, we analyzed 364 patients after excluding patients with pre-existing intraventricular conduction disturbance or a pacing rhythm before or during the indexed hospitalization for TAVR. Echocardiographic variables of cardiac remodeling at baseline and 1 year after TAVR were comprehensively analyzed. The primary outcome was a composite of cardiovascular death and hospitalization for heart failure. Secondary outcomes were all-cause death and individual components of the primary outcome.ResultNew-onset persistent LBBB occurred in 41 (11.3%) patients after TAVR. The no LBBB group showed a significant increase in the left ventricular (LV) ejection fraction and decreases in LV dimensions, the left atrial volume index, and LV mass index 1 year after TAVR (all p < 0.001). However, the new LBBB group showed no significant changes in these parameters. During a median follow-up of 18.1 months, the new LBBB group experienced a higher incidence of primary outcomes [hazard ratio (HR): 5.03; 95% confidence interval (CI): 2.60–9.73; p < 0.001] and all-cause death (HR: 2.80; 95% CI: 1.38–5.69; p = 0.003). The data were similar after multivariable regression analysis.ConclusionNew-onset persistent LBBB after TAVR is associated with insufficient reverse cardiac remodeling and increased adverse clinical events.

Background & Aims Human liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. Methods Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. Results Human liver CD69+CD103-CD8+ T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103- cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103+ cells exhibited only hepatotropic virus specificity. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with acute hepatitis A or cirrhosis. Conclusions Liver CD69+CD103-CD8+ T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology. Lay summary The immunologic characteristics and the role of CD69+CD103-CD8+ T cells, which are a major population of human liver CD8+ T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.