Ischemic stroke outcome after promoting CD4+CD25+ Treg cell migration through CCR4 overexpression in a tMCAO animal model.

The importance of neuroinflammation during the ischemic stroke has been extensively studied. The role of CD4+CD25+ regulatory T (Treg) cells during the recovery phase have shown infarct size reduction and functional improvement, possibly through the mitigation of inflammatory immune responses. We aimed to investigate the molecular factors involved in microglia-Treg cell communication that result in Treg trafficking. First, we observed the migration patterns of CD8+ (cytotoxic) T cells and Treg cells and then searched for chemokines released by activated microglia in an oxygen-glucose deprivation (OGD) model. The transwell migration assay showed increased migration into OGD media for both cell types, in agreement with the increase in chemokines involved in immune cell trafficking from the mouse chemokine profiling array. MSCV retrovirus was transduced to overexpress CCR4 in Treg cells. CCR4-overexpressed Treg cells were injected into the mouse transient middle cerebral artery occlusion (tMCAO) model to evaluate the therapeutic potential via the tetrazolium chloride (TTC) assay and behavioral tests. A general improvement in the prognosis of animals after tMCAO was observed. Our results suggest the increased mobility of CCR4-overexpressed Treg cells in response to microglia-derived chemokines in vitro and the therapeutic potential of Treg cells with increased mobility in cellular therapy.

Clinical and Imaging Characteristics of SARS-CoV-2 Breakthrough Infection in Hospitalized Immunocompromised Patients.

OBJECTIVE: To evaluate the clinical and imaging characteristics of SARS-CoV-2 breakthrough infection in hospitalized immunocompromised patients in comparison with immunocompetent patients. MATERIALS AND METHODS: This retrospective study analyzed consecutive adult patients hospitalized for COVID-19 who received at least one dose of the SARS-CoV-2 vaccine at two academic medical centers between June 2021 and December 2022. Immunocompromised patients (with active solid organ cancer, active hematologic cancer, active immune-mediated inflammatory disease, status post solid organ transplantation, or acquired immune deficiency syndrome) were compared with immunocompetent patients. Multivariable logistic regression analysis was performed to evaluate the effect of immune status on severe clinical outcomes (in-hospital death, mechanical ventilation, or intensive care unit admission), severe radiologic pneumonia (≥ 25% of lung involvement), and typical CT pneumonia. RESULTS: Of 2218 patients (mean age, 69.5 ± 16.1 years), 274 (12.4%), and 1944 (87.6%) were immunocompromised an immunocompetent, respectively. Patients with active solid organ cancer and patients status post solid organ transplantation had significantly higher risks for severe clinical outcomes (adjusted odds ratio = 1.58 [95% confidence interval {CI}, 1.01-2.47], P = 0.042; and 3.12 [95% CI, 1.47-6.60], P = 0.003, respectively). Patient status post solid organ transplantation and patients with active hematologic cancer were associated with increased risks for severe pneumonia based on chest radiographs (2.96 [95% CI, 1.54-5.67], P = 0.001; and 2.87 [95% CI, 1.50-5.49], P = 0.001, respectively) and for typical CT pneumonia (9.03 [95% CI, 2.49-32.66], P < 0.001; and 4.18 [95% CI, 1.70-10.25], P = 0.002, respectively). CONCLUSION: Immunocompromised patients with COVID-19 breakthrough infection showed an increased risk of severe clinical outcome, severe pneumonia based on chest radiographs, and typical CT pneumonia. In particular, patients status post solid organ transplantation was specifically found to be associated with a higher risk of all three outcomes than hospitalized immunocompetent patients.

Blood transcriptome differentiates clinical clusters for asthma.

Background: In previous studies, several asthma phenotypes were identified using clinical and demographic parameters. Transcriptional phenotypes were mainly identified using sputum and bronchial cells. Objective: We aimed to investigate asthma phenotypes via clustering analysis using clinical variables and compare the transcription levels among clusters using gene expression profiling of the blood. Methods: Clustering analysis was performed using 6 parameters: age of asthma onset, body mass index, pack-years of smoking, forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity, and blood eosinophil counts. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and RNA was extracted from selected PBMCs. Transcriptional profiles were generated (Illumina NovaSeq 6000) and analyzed using the reference genome and gene annotation files (hg19.refGene.gft). Pathway enrichment analysis was conducted using GO, KEGG, and REACTOME databases. Results: In total, 355 patients with asthma were included in the analysis, of whom 72 (20.3%) had severe asthma. Clustering of the 6 parameters revealed 4 distinct subtypes. Cluster 1 (n = 63) had lower predicted FEV1 % and higher pack-years of smoking and neutrophils in sputum. Cluster 2 (n = 43) had a higher proportion and number of eosinophils in sputum and blood, and severe airflow limitation. Cluster 3 (n = 110) consisted of younger subjects with atopic features. Cluster 4 (n = 139) included features of late-onset mild asthma. Differentially expressed genes between clusters 1 and 2 were related to inflammatory responses and cell activation. Th17 cell differentiation and interferon gamma-mediated signaling pathways were related to neutrophilic inflammation in asthma. Conclusion: Four clinical clusters were differentiated based on clinical parameters and blood eosinophils in adult patients with asthma form the Cohort for Reality and Evolution of Adult Asthma in Korea (COREA) cohort. Gene expression profiling and molecular pathways are novel means of classifying asthma phenotypes.

A novel approach of kinship determination based on the physical length of genetically shared regions of chromosomes.

BACKGROUND: Determination of genetic relatedness between individuals plays a crucial role in resolving numerous civil cases involving familial relationships and in forensic investigation concerning missing persons. Short tandem repeats (STRs), known for their high degree of DNA polymorphism, have traditionally been the primary choice of DNA markers in genetic testing, but their application for kinships testing is limited to cases involving close kinship. SNPs have emerged as promising supplementary markers for kinship determination. Nevertheless, the challenging remains in discriminating between third-degree or more distant relatives, such as first cousins, using SNPs. OBJECTIVE: To investigate a kinship analysis method for distant degree of familial relationships using high-density SNP data. METHODS: A high-density SNP data from 337 individuals of Korean families using Affymetrix Axiom KORV1.0-96 Array was obtained for this study. SNPs were aligned by chromosomal positions, and identity-by-state (IBS) was determined, and then shared regions as consecutive SNPs with IBS of 1 or 2 were investigated. The physical lengths of these IBS segments were measured and summed them to create an Index, as a measure of kinship. RESULTS: The kinship was determined by the physical length of shared chromosomal regions that are distinguished by each kinship. Using this method, the relationship was able be distinguished up to the fourth degree of kinship, and non-relatives were clearly distinguished from true relatives. We also found a potential for this approach to be used universally, regardless of microarray platforms for SNP genotyping and populations. CONCLUSION: This method has a potential to determine the different degree of kinship between individuals and to distinguish non-relatives from true relatives, which can be of great help for practical applications in kinship determination.

Cardiac Magnetic Resonance Imaging Findings and Clinical Features of COVID-19 Vaccine-Associated Myocarditis, Compared With Those of Other Types of Myocarditis.

BACKGROUND: To compare the clinical and cardiac magnetic resonance (CMR) imaging findings of coronavirus disease 2019 (COVID-19) vaccine-associated myocarditis (VAM) with those of other types of myocarditis. METHODS: From January 2020 to March 2022, a total of 39 patients diagnosed with myocarditis via CMR according to the Modified Lake Louise criteria were included in the present study. The patients were classified into two groups based on their vaccination status: COVID-19 VAM and other types of myocarditis not associated with COVID-19 vaccination. Clinical outcomes, including the development of clinically significant arrhythmias, sudden cardiac arrest, and death, and CMR imaging features were compared between COVID-19 VAM and other types of myocarditis. RESULTS: Of the 39 included patients (mean age, 39 years ± 16.4 [standard deviation]; 23 men), 23 (59%) had COVID-19 VAM and 16 (41%) had other types of myocarditis. The occurrence of clinical adverse events did not differ significantly between the two groups. As per the CMR imaging findings, the presence and dominant pattern of late gadolinium enhancement did not differ significantly between the two groups. The presence of high native T1 or T2 values was not significantly different between the two groups. Although the native T1 and T2 values tended to be lower in COVID-19 VAM than in other types of myocarditis, there were no statistically significant differences between the native T1 and T2 values in the two groups. CONCLUSION: The present study demonstrated that the CMR imaging findings and clinical outcomes of COVID-19 VAM did not differ significantly from those of other types of myocarditis during hospitalization.

Identifying subgroups of eating behavior traits unrelated to obesity using functional connectivity and feature representation learning.

Eating behavior is highly heterogeneous across individuals and cannot be fully explained using only the degree of obesity. We utilized unsupervised machine learning and functional connectivity measures to explore the heterogeneity of eating behaviors measured by a self-assessment instrument using 424 healthy adults (mean ± standard deviation [SD] age = 47.07 ± 18.89 years; 67% female). We generated low-dimensional representations of functional connectivity using resting-state functional magnetic resonance imaging and estimated latent features using the feature representation capabilities of an autoencoder by nonlinearly compressing the functional connectivity information. The clustering approaches applied to latent features identified three distinct subgroups. The subgroups exhibited different levels of hunger traits, while their body mass indices were comparable. The results were replicated in an independent dataset consisting of 212 participants (mean ± SD age = 38.97 ± 19.80 years; 35% female). The model interpretation technique of integrated gradients revealed that the between-group differences in the integrated gradient maps were associated with functional reorganization in heteromodal association and limbic cortices and reward-related subcortical structures such as the accumbens, amygdala, and caudate. The cognitive decoding analysis revealed that these systems are associated with reward- and emotion-related systems. Our findings provide insights into the macroscopic brain organization of eating behavior-related subgroups independent of obesity.

Chronic Lung Injury after COVID-19 Pneumonia: Clinical, Radiologic, and Histopathologic Perspectives.

With the COVID-19 pandemic having lasted more than 3 years, concerns are growing about prolonged symptoms and respiratory complications in COVID-19 survivors, collectively termed post-COVID-19 condition (PCC). Up to 50% of patients have residual symptoms and physiologic impairment, particularly dyspnea and reduced diffusion capacity. Studies have also shown that 24%-54% of patients hospitalized during the 1st year of the pandemic exhibit radiologic abnormalities, such as ground-glass opacity, reticular opacity, bronchial dilatation, and air trapping, when imaged more than 1 year after infection. In patients with persistent respiratory symptoms but normal results at chest CT, dual-energy contrast-enhanced CT, xenon 129 MRI, and low-field-strength MRI were reported to show abnormal ventilation and/or perfusion, suggesting that some lung injury may not be detectable with standard CT. Histologic patterns in post-COVID-19 lung disease include fibrosis, organizing pneumonia, and vascular abnormality, indicating that different pathologic mechanisms may contribute to PCC. Therefore, a comprehensive imaging approach is necessary to evaluate and diagnose patients with persistent post-COVID-19 symptoms. This review will focus on the long-term findings of clinical and radiologic abnormalities and describe histopathologic perspectives. It also addresses advanced imaging techniques and deep learning approaches that can be applied to COVID-19 survivors. This field remains an active area of research, and further follow-up studies are warranted for a better understanding of the chronic stage of the disease and developing a multidisciplinary approach for patient management.

Effectiveness of COVID-19 Vaccines Over Time Against Clinical and Radiologic Outcomes Related to Severe SARS-CoV-2 Infection.

Background The impact of waning vaccine effectiveness on the severity of COVID-19-related findings discovered with radiologic examinations remains underexplored. Purpose To evaluate the effectiveness of vaccines over time against severe clinical and radiologic outcomes related to SARS-CoV-2 infections. Materials and Methods This multicenter retrospective study included patients in the Korean Imaging Cohort of COVID-19 database who were hospitalized for COVID-19 between June 2021 and December 2022. Patients who had received at least one dose of a SARS-CoV-2 vaccine were categorized based on the time elapsed between diagnosis and their last vaccination. Adjusted multivariable logistic regression analysis was used to estimate vaccine effectiveness against a composite of severe clinical outcomes (invasive ventilation, extracorporeal membrane oxygenation, or in-hospital death) and severe radiologic pneumonia (≥25% of lung involvement), and odds ratios (ORs) were compared between patients vaccinated within 90 days of diagnosis and those vaccinated more than 90 days before diagnosis. Results Of 4196 patients with COVID-19 (mean age, 66 years ± 17 [SD]; 2132 [51%] women, 2064 [49%] men), the ratio of severe pneumonia since their most recent vaccination was as follows: 90 days or less, 18% (277 of 1527); between 91 and 120 days, 22% (172 of 783); between 121 and 180 days, 27% (274 of 1032); between 181 and 240 days, 32% (159 of 496); and more than 240 days, 31% (110 of 358). Patients vaccinated more than 240 days before diagnosis showed increased odds of severe clinical outcomes compared with patients vaccinated within 90 days (OR = 1.94 [95% CI: 1.16, 3.24]; P = .01). Similarly, patients vaccinated more than 240 days before diagnosis showed increased odds of severe pneumonia on chest radiographs compared with patients vaccinated within 90 days (OR = 1.65 [95% CI: 1.13, 2.40]; P = .009). No difference in odds of severe clinical outcomes (P = .13 to P = .68) or severe pneumonia (P = .15 to P = .86) were observed between patients vaccinated 91-240 days before diagnosis and those vaccinated within 90 days of diagnosis. Conclusion Vaccine effectiveness against severe clinical outcomes and severe pneumonia related to SARS-CoV-2 infection gradually declined, with increased odds of both observed in patients vaccinated more than 240 days before diagnosis. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Wells in this issue.

Is wide excision really needed? Correlation between resection margin and recurrence in benign phyllodes tumors of the breast.

Purpose: Phyllodes tumors are similar to fibroadenomas in imaging and in pathological characteristics and are difficult to identify preoperatively. The purpose of this study was to analyze the recurrence rate after excision stratified by the surgical margin width and to propose and emphasize the "wait and watch" treatment strategy for benign phyllodes tumors. Methods: We performed a retrospective cohort study of patients diagnosed with benign phyllodes tumors by surgical excision between January 2000 and December 2022 at our institution. The medical and histopathological records were reviewed. Results: The results were obtained using the Cox proportional hazard regression and logistic regression. Resection margin status and recurrence were the independent variables. In each variable selection model, the resection margin was positive or less than 1 cm, and the recurrence rate was 3.7 and 1.04 times higher than the control group, but the difference was not statistically significant in 2 analyses. Conclusion: The surgical resection margin status of benign phyllodes tumors did not significantly affect locoregional recurrence. Therefore, follow-up imaging at short intervals without additional surgery is a feasible clinical option when the surgical resection margin is positive or less than 1 cm.

Tracking antigen-specific TCR clonotypes in SARS-CoV-2 infection reveals distinct severity trajectories.

Despite the importance of antigen-specific T cells in infectious disease, characterizing and tracking clonally amplified T cells during the progression of a patient's symptoms remain unclear. Here, we performed a longitudinal, in-depth single-cell multiomics analysis of samples from asymptomatic, mild, usual severe, and delayed severe patients of SARS-CoV-2 infection. Our in-depth analysis revealed that hyperactive or improper T-cell responses were more aggressive in delayed severe patients. Interestingly, tracking of antigen-specific T-cell receptor (TCR) clonotypes along the developmental trajectory indicated an attenuation in functional T cells upon severity. In addition, increased glycolysis and interleukin-6 signaling in the cytotoxic T cells were markedly distinct in delayed severe patients compared to usual severe patients, particularly in the middle and late stages of infection. Tracking B-cell receptor clonotypes also revealed distinct transitions and somatic hypermutations within B cells across different levels of disease severity. Our results suggest that single-cell TCR clonotype tracking can distinguish the severity of patients through immunological hallmarks, leading to a better understanding of the severity differences in and improving the management of infectious diseases by analyzing the dynamics of immune responses over time.

Death-associated protein kinase 1 phosphorylates MDM2 and inhibits its protein stability and function.

Breast cancer is one of the major malignancies in women, and most related deaths are due to recurrence, drug resistance, and metastasis. The expression of the mouse double minute 2 (MDM2) oncogene is upregulated in breast cancer; however, its regulatory mechanism has yet to be fully elucidated. Herein, we identified the tumor suppressor death-associated protein kinase 1 (DAPK1) as a novel MDM2 regulator by unbiased peptide library screening. DAPK1 is directly bound to MDM2 and phosphorylates it at Thr419. DAPK1-mediated MDM2 phosphorylation promoted its protein degradation via the ubiquitin-proteasome pathway, resulting in upregulated p53 expression. DAPK1 overexpression, but not its kinase activity-deficient form, decreased colony formation and increased doxorubicin-induced cell death; however, DAPK1 knockdown produced the opposite effects in human breast cancer cells. In a xenograft tumorigenesis assay, DAPK1 overexpression significantly reduced tumor formation, whereas inhibition of DAPK1 kinase activity reduced its antitumorigenic effect. Finally, DAPK1 expression was negatively correlated with MDM2 levels in human breast cancer tissues. Thus, these results suggest that DAPK1-mediated MDM2 phosphorylation and its protein degradation may contribute to its antitumorigenic function in breast cancer.

SGLT2 and DPP4 inhibitors improve Alzheimer's disease-like pathology and cognitive function through distinct mechanisms in a T2D-AD mouse model.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium-glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D-AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D-AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D-AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid ß (Aß) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1-7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Aß accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms.

Hyperpolarized [1-13C]pyruvate Magnetic Resonance Spectroscopy Shows That Agmatine Increased Lactate Production in the Brain of Type 2 Diabetic Mice.

PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with a 2-fold increased risk of developing Alzheimer's disease. In earlier research, agmatine has been demonstrated to alleviate diabetes symptoms and increase cognitive performance. However, it is unclear whether the improvement of cognitive function is attributable to the reduction of diabetic symptoms or its direct influence on brain metabolism. Using hyperpolarized (HP) [1-13C]pyruvate magnetic resonance spectroscopy (MRS), this study intends to evaluate the influence of agmatine on brain metabolism. MATERIALS AND METHODS: ICR mice were fed a high-fat diet and injected with streptozotocin to develop a T2DM animal model. During a 2-week period, T2DM mice were treated with normal saline or 100 mg/kg of agmatine, and brain HP [1-13C]pyruvate MRS was performed. The effect of agmatine on lactate generation and NADH/NAD+ redox state was investigated using C6 and neuro-2a (N2a) cells. RESULTS: As a perfusion marker, the total 13C signals in the brain of T2DM mice (p=0.07) and agmatine-treated mice (p<0.05) were reduced. The conversion constant (Kpl) from [1-13C]pyruvate to [1-13C]lactate was not distinguishable in the brains of T2DM mice but was significantly increased in the brains of agmatine-treated T2DM mice. Treating C6 and N2a cells with agmatine increased NADH/NAD+ratio and lactate generation. CONCLUSION: Agmatine influences the NADH/NAD+ redox state in the brains of T2DM mice, which may be connected with enhanced cognitive performance and increased conversion of HP [1-13C]pyruvate to HP [1-13C]lactate.

Correction: Deep Learning With Chest Radiographs for Making Prognoses in Patients With COVID-19: Retrospective Cohort Study.

[This corrects the article DOI: 10.2196/42717.].

Erratum: Correction of Affiliations in the Article "Establishment of a Nationwide Korean Imaging Cohort of Coronavirus Disease 2019".

This corrects the article on p. e413 in vol. 35, PMID: 33258333.

Comparison of Clinical Outcomes and Imaging Features in Hospitalized Patients with SARS-CoV-2 Omicron Subvariants.

Background Differences in the clinical and radiological characteristics of SARS-CoV-2 Omicron subvariants have not been well studied. Purpose To compare clinical disease severity and radiologically severe pneumonia in patients with COVID-19 hospitalized during a period of either Omicron BA.1/BA.2 or Omicron BA.5 subvariant predominance. Materials and Methods This multicenter retrospective study, included patients registered in the Korean Imaging Cohort of COVID-19 database who were hospitalized for COVID-19 between January and December 2022. Publicly available relative variant genome frequency data were used to determine the dominant periods of Omicron BA.1/BA.2 subvariants (January 17 to June 20, 2022) and the Omicron BA.5 subvariant (July 4 to December 5, 2022). Clinical outcomes and imaging pneumonia outcomes based on chest radiography and CT were compared among predominant subvariants using multivariable analyses adjusted for covariates. Results Of 1916 confirmed patients with COVID-19 (mean age, 72 years ± 16 [SD]; 1019 males), 1269 were registered during the Omicron BA.1/BA.2 subvariant dominant period and 647 during the Omicron BA.5 subvariant dominant period. Patients in the BA.5 group showed lower odds of high-flow O2 requirement (adjusted odds ratio [OR], 0.75 [95% CI: 0.57, 0.99]; P = .04), mechanical ventilation (adjusted OR, 0.49 [95% CI: 0.34, 0.72]; P < .001]), and death (adjusted OR, 0.47 [95% CI: 0.33, 0.68]; P <.001) than those in the BA.1/BA.2 group. Additionally, the BA.5 group had lower odds of severe pneumonia on chest radiographs (adjusted OR, 0.68 [95% CI: 0.53, 0.88]; P = .004) and higher odds of atypical pattern pneumonia on CT images (adjusted OR, 1.81 [95% CI: 1.26, 2.58]; P = .001) than the BA.1/BA.2 group. Conclusions Patients hospitalized during the period of Omicron BA.5 subvariant predominance had lower odds of clinical and pneumonia severity than those hospitalized during the period of Omicron BA.1/BA.2 predominance, even after adjusting for covariates. See also the editorial by Hammer in this issue.

Acute respiratory distress syndrome and severe pneumonitis after atezolizumab plus bevacizumab for hepatocellular carcinoma treatment: A case report.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a high mortality. However, the treatment options for advanced HCC are limited to tyrosine kinase inhibitors, such as sorafenib and lenvatinib. Since previous regimens have an insufficient efficacy, the combination therapy of atezolizumab and bevacizumab (Ate/Bev) has been investigated, which showed an improvement in progression-free and overall survival. However, the adverse events of this combination therapy in advanced HCC have not been established. Herein, we report a novel case of an unresectable HCC and acute respiratory distress syndrome (ARDS) after a combination therapy of Ate/Bev. CASE SUMMARY: An 82-year-old male visited our outpatient clinic for an incidentally detected liver mass. Liver magnetic resonance imaging and enhanced chest computed tomography (CT) were performed, which showed arterial hyperenhancement with washout in delayed phase suggesting HCC, and a well-defined metastatic solid nodule, respectively. F-18 fluorodeoxyglucose positron emission tomography (PET)-CT exhibited multiple hypermetabolic lesions in the iliac bone, lumbar vertebrae, and femur. Because of the high burden of the intrahepatic tumor, transarterial radioembolization was initially performed; after 37 d, a combination therapy of Ate/Bev was administered. The patient visited the emergency department three days after Ate/Bev treatment complaining of dyspnea. He was diagnosed with severe pneumonitis based on CT. Despite administering oxygen via a high-flow nasal cannula, the P/F ratio was only 74; therefore, the patient was diagnosed with ARDS based on the overall examination results. Low tidal volume with high positive end-expiratory pressure, sedative agents combined with a neuromuscular blocker, and a systemic steroid were promptly applied to manage the ARDS. However, the patient did not recover from the hypoxia and expired 31 h after being admitted. CONCLUSION: Clinicians should be aware of severe pneumonitis due to the immune-related adverse events of this combination therapy, and patients should be closely monitored after therapy.

Prediction of Residual Axillary Nodal Metastasis Following Neoadjuvant Chemotherapy for Breast Cancer: Radiomics Analysis Based on Chest Computed Tomography.

OBJECTIVE: To evaluate the diagnostic performance of chest computed tomography (CT)-based qualitative and radiomics models for predicting residual axillary nodal metastasis after neoadjuvant chemotherapy (NAC) for patients with clinically node-positive breast cancer. MATERIALS AND METHODS: This retrospective study included 226 women (mean age, 51.4 years) with clinically node-positive breast cancer treated with NAC followed by surgery between January 2015 and July 2021. Patients were randomly divided into the training and test sets (4:1 ratio). The following predictive models were built: a qualitative CT feature model using logistic regression based on qualitative imaging features of axillary nodes from the pooled data obtained using the visual interpretations of three radiologists; three radiomics models using radiomics features from three (intranodal, perinodal, and combined) different regions of interest (ROIs) delineated on pre-NAC CT and post-NAC CT using a gradient-boosting classifier; and fusion models integrating clinicopathologic factors with the qualitative CT feature model (referred to as clinical-qualitative CT feature models) or with the combined ROI radiomics model (referred to as clinical-radiomics models). The area under the curve (AUC) was used to assess and compare the model performance. RESULTS: Clinical N stage, biological subtype, and primary tumor response indicated by imaging were associated with residual nodal metastasis during the multivariable analysis (all P < 0.05). The AUCs of the qualitative CT feature model and radiomics models (intranodal, perinodal, and combined ROI models) according to post-NAC CT were 0.642, 0.812, 0.762, and 0.832, respectively. The AUCs of the clinical-qualitative CT feature model and clinical-radiomics model according to post-NAC CT were 0.740 and 0.866, respectively. CONCLUSION: CT-based predictive models showed good diagnostic performance for predicting residual nodal metastasis after NAC. Quantitative radiomics analysis may provide a higher level of performance than qualitative CT features models. Larger multicenter studies should be conducted to confirm their performance.

Agmatine-IRF2BP2 interaction induces M2 phenotype of microglia by increasing IRF2-KLF4 signaling.

BACKGROUND: Following central nervous system (CNS) injury, the investigation for neuroinflammation is vital because of its pleiotropic role in both acute injury and long-term recovery. Agmatine (Agm) is well known for its neuroprotective effects and anti-neuroinflammatory properties. However, Agm's mechanism for neuroprotection is still unclear. We screened target proteins that bind to Agm using a protein microarray; the results showed that Agm strongly binds to interferon regulatory factor 2 binding protein (IRF2BP2), which partakes in the inflammatory response. Based on these prior data, we attempted to elucidate the mechanism by which the combination of Agm and IRF2BP2 induces a neuroprotective phenotype of microglia. METHODS: To confirm the relationship between Agm and IRF2BP2 in neuroinflammation, we used microglia cell-line (BV2) and treated with lipopolysaccharide from Escherichia coli 0111:B4 (LPS; 20 ng/mL, 24 h) and interleukin (IL)-4 (20 ng/mL, 24 h). Although Agm bound to IRF2BP2, it failed to enhance IRF2BP2 expression in BV2. Therefore, we shifted our focus onto interferon regulatory factor 2 (IRF2), which is a transcription factor and interacts with IRF2BP2. RESULTS: IRF2 was highly expressed in BV2 after LPS treatment but not after IL-4 treatment. When Agm bound to IRF2BP2 following Agm treatment, the free IRF2 translocated to the nucleus of BV2. The translocated IRF2 activated the transcription of Kruppel-like factor 4 (KLF4), causing KLF4 to be induced in BV2. The expression of KLF4 increased the CD206-positive cells in BV2. CONCLUSIONS: Taken together, unbound IRF2, resulting from the competitive binding of Agm to IRF2BP2, may provide neuroprotection against neuroinflammation via an anti-inflammatory mechanism of microglia involving the expression of KLF4.