Search

Abstract The bioartificial liver (BAL) system can potentially rescue acute liver failure (ALF) patients by providing partial liver function until a suitable donor liver can be found or the native liver has self-regenerated. In this study, we established a suitable cryopreservation process for the development of an off-the-shelf BAL system. The viability of hepatocyte spheroids cryopreserved in liquid nitrogen was comparable to that of fresh primary hepatocyte spheroids. When hepatocyte spheroids were subjected to cryopreservation in a deep freezer, no statistically significant differences were observed in ammonia removal rate or urea secretion rate based on the cryopreservation period. However, the functional activity of the liver post-cryopreservation in a deep freezer was significantly lower than that observed following liquid nitrogen cryopreservation. Moreover, cryopreserving spheroid hydrogel beads in a deep freezer resulted in a significant decrease (approximately 30%) in both ammonia removal and urea secretion rates compared to the group cryopreserved in liquid nitrogen. The viabilities of spheroid hydrogel beads filled into the bioreactor of a BAL system were similar across all four groups. However, upon operating the BAL system for 24 h, the liver function activity was significantly higher in the group comprising hydrogel beads generated after thawing hepatocyte spheroids cryopreserved in liquid nitrogen. Consequently, the manufacturing of beads after the cryopreservation of hepatocyte spheroids is deemed the most suitable method, considering efficiency, economic feasibility, and liver function activity, for producing a BAL system.

Abstract 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.

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.

Abstract Antimicrobial resistant pathogens are a global health threat driven by the indiscriminate use of antimicrobials. Antimicrobial resistance can be acquired by resistance genes encoded by mobile genetic elements. In this study, we identified a strain of Salmonella enterica serovar Gallinarum (SG4021) from an infected chicken in Korea and characterized the presence of resistance genes in its plasmid by whole genome sequencing. The sequence was then compared with that of a plasmid (P2) from strain SG_07Q015, the only other strain of S. Gallinarum isolated in Korea for which a genome sequence is available. The results revealed that both strains harbored nearly identical DNA carrying antibiotic resistance gene cassettes inserted into integron In2 of the transposable element Tn21, namely an aadA1 resistance gene conferring resistance to aminoglycosides and a sul1 resistance gene conferring resistance to sulfonamide. Interestingly, despite the presence of sul1 in SG4021, an antibiotic sensitivity test revealed that it was sensitive to sulfonamides. Further analysis revealed that this disparity was due to the insertion of a ~ 5 kb ISCR16 sequence downstream of the promoter driving sul1 expression in SG4021. Using various mutants, we showed that the insertion of ISCR16 blocked the expression of the sul1 gene from the upstream promoter. Therefore, the functionality of antimicrobial resistance genes determines phenotypic antimicrobial resistance.

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 β (Aβ) 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 Aβ 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.

Purpose To assess the clinicoradiological features of pulmonary cryptococcosis in immunocompetent patients. Materials and Methods This retrospective study included immunocompetent patients who had been diagnosed with pulmonary cryptococcosis on the histopathologic exam and underwent chest CT between January 2008 and November 2019. Imaging features were divided into major imaging patterns, distributions, and ancillary imaging findings. Univariable analysis was performed to evaluate clinicoradiological features according to the presence of serum cryptococcal antigen. Results Thirty-one patients were evaluated (mean age: 60 years, range: 19–78 years). A single nodular lesion confined to a single lobe was the most common imaging pattern (14/31, 45.2%). Serum cryptococcal antigen tests were performed in 19 patients (19/31, 61.3%). The presence of serum cryptococcal antigen was observed in six patients (6/19, 31.6%), all of whom showed a consolidation-dominant pattern. The presence of serum cryptococcal antigen was significantly associated with the consolidationdominant pattern compared to those associated with a nodule-dominant pattern (p = 0.011). Conclusion A combination of CT findings of consolidation and a positive serum cryptococcal antigen test may be helpful for diagnosing pulmonary cryptococcosis in immunocompetent patients.

Appendiceal mucocele is a rare mucin-producing neoplasm of appendiceal origin. Due to its location and imaging findings, appendiceal mucocele is easily confused with tumors of the right adnexa. We present a rare case of a patient initially misdiagnosed with an ovarian tumor intraoperatively diagnosed as an appendiceal mucocele and successfully treated. A 66-year-old postmenopausal woman was admitted to the gynecology department for an asymptomatic pelvic mass. Preoperative pelvic imaging showed an 8-cm cystic mass. Exploratory laparoscopy for the suspected epithelial borderline tumor from the right ovary revealed a cystic mass in the right pelvic area and normal uterus, fallopian tubes, and ovaries. Intraoperative consultation with the general surgery department confirmed the appendiceal origin. Laparoscopic appendectomy was performed. Histopathological examination confirmed a low-grade mucinous neoplasm of appendiceal origin. The patient was discharged on a postoperative day 5 without complications. The outpatient follow-up performed 1 month later showed no evidence of disease progression. Despite the use of advanced diagnostic tools, appendiceal mucocele may be confused for ovarian malignancies. Because the clinical features of appendiceal mucocele are nonspecific, clinicians and radiologists know the specific imaging findings. A multidisciplinary approach including general surgery, gynecology, and radiology is required for preoperative diagnosis and treatment.

The mediastinum is the most prevalent site of extragonadal teratomas. Patients with mediastinal mature teratomas are usually young adults, and the condition does not show significant sexual differences. Mediastinal teratomas are mostly located in the anterior mediastinum. Patients are usually asymptomatic, although they can have several complications when the teratomas become large or rupture. Most mediastinal teratomas can be diagnosed using CT. Diagnosing ruptured or malignant teratomas is challenging because of their atypical clinical and radiological presentations. In this article, we describe various manifestations of mediastinal teratomas, with an emphasis on radiologic features.

Abstract Background Interstitial lung abnormality (ILA) is closely related to lung cancer. This study aimed to assess whether the presence of ILA is associated with the clinicoradiological features of elderly patients (≥70 years) with early‐stage non‐small cell lung cancer (NSCLC). Methods Elderly patients who underwent surgical resection for stage I or II NSCLC with preserved lung function between 2012 and 2019 were retrospectively identified. ILA was evaluated using a three‐point scale. Univariate analyses were performed for clinicoradiological features based on the presence of ILA. Logistic and linear regression analyses were performed for cancer staging and tumor size, respectively. Results A total of 254 patients were evaluated. The presence of ILA (score = 2) was significantly associated with male sex, current or former smoker status, higher pack‐years of smoking, low forced expiratory volume in one second/forced vital capacity ratios and diffusing capacity of the lung for carbon monoxide, and presence of emphysema (≥5%). Tumor characteristics, such as lower lobe and outer one‐third location, squamous cell carcinoma, and higher cancer stage (stage II) were significantly associated with ILA. The presence of ILA independently predicted a higher cancer stage (adjusted odds ratio, 1.81; 95% confidence interval, 1.10–2.96; p = 0.02) and a larger tumor size in linear regression analysis (p = 0.04). Conclusions Patients with ILA showed clinicoradiological features similar to those of idiopathic pulmonary fibrosis in elderly patients with early‐stage NSCLC. Identifying the clinical implications of ILA in early‐stage lung cancer will guide clinicians in providing appropriate management for these patients.

BackgroundAn artificial intelligence (AI) model using chest radiography (CXR) may provide good performance in making prognoses for COVID-19. ObjectiveWe aimed to develop and validate a prediction model using CXR based on an AI model and clinical variables to predict clinical outcomes in patients with COVID-19. MethodsThis retrospective longitudinal study included patients hospitalized for COVID-19 at multiple COVID-19 medical centers between February 2020 and October 2020. Patients at Boramae Medical Center were randomly classified into training, validation, and internal testing sets (at a ratio of 8:1:1, respectively). An AI model using initial CXR images as input, a logistic regression model using clinical information, and a combined model using the output of the AI model (as CXR score) and clinical information were developed and trained to predict hospital length of stay (LOS) ≤2 weeks, need for oxygen supplementation, and acute respiratory distress syndrome (ARDS). The models were externally validated in the Korean Imaging Cohort of COVID-19 data set for discrimination and calibration. ResultsThe AI model using CXR and the logistic regression model using clinical variables were suboptimal to predict hospital LOS ≤2 weeks or the need for oxygen supplementation but performed acceptably in the prediction of ARDS (AI model area under the curve [AUC] 0.782, 95% CI 0.720-0.845; logistic regression model AUC 0.878, 95% CI 0.838-0.919). The combined model performed better in predicting the need for oxygen supplementation (AUC 0.704, 95% CI 0.646-0.762) and ARDS (AUC 0.890, 95% CI 0.853-0.928) compared to the CXR score alone. Both the AI and combined models showed good calibration for predicting ARDS (P=.079 and P=.859). ConclusionsThe combined prediction model, comprising the CXR score and clinical information, was externally validated as having acceptable performance in predicting severe illness and excellent performance in predicting ARDS in patients with COVID-19.

The clinical concept of coronary artery disease (CAD) has seen a paradigm shift over the last decade. CAD is mostly a progressive disease, and patients with CAD can develop acute coronary syndromes at any point in disease progression. In this clinical context, a new term, “chronic coronary syndrome,” was published in the 2019 European Society of Cardiology guidelines, reflecting the importance of early diagnosis and active management. Recent advances have been made in the evaluation of CAD using coronary CT angiography (CCTA). The clinical usefulness of CCTA in patients with stable angina or chronic coronary syndrome begins with the detection of early asymptomatic CAD. The characterization of atherosclerotic plaque and its role in determining treatment strategies for CAD have been demonstrated for all stages of the disease. This review describes the pathophysiology of stable angina to aid in the understanding of the clinical applications of CCTA.

Purpose To compare the per-patient diagnostic performance of simulated abbreviated MRI (AMRI) to that of conventional MRI (CMRI) with full-sequence dynamic gadoxetic acid (GA) enhancement for early-stage hepatocellular carcinoma (HCC) screening in high-risk patients. Materials and Methods A total of 201 consecutive patients at high-risk for HCC, who underwent 3T liver MRI, were included in this retrospective study. The AMRI protocol comprised T2-weighted imaging, hepatobiliary phase imaging after GA injection, and diffusion-weighted imaging. For each patient, two AMRI and CMRI image sets were independently reviewed by two radiologists. Inter-reader agreement was assessed using Cohen’s kappa value. A composite reference standard was used to determine the diagnostic performance of each image set for each reader. Results A total of 93 HCCs were detected in 79 patients. The inter-reader agreement was almost perfect for both image sets (κ = 0.839, 0.948). In AMRI, the per-patient sensitivity and negative predictive values (NPV) were 94.9% and 96.4%, respectively. In CMRI, the per-patient sensitivity and NPV were 96.2% and 97.5%, respectively. Conclusion AMRI, using only three sequences, had a comparable diagnostic performance to CMRI in screening early-stage HCC. AMRI could be an alternative HCC screening tool for highrisk HCC patients.

Percutaneous transthoracic needle biopsy (PTNB) is a minimally-invasive procedure that is an indispensable tool for evaluating pulmonary lesions. Though extremely rare, tumor seeding of the pleura and chest wall can occur as a complication. Given that the breast is located anterior to the thorax, needle tracking through the breast is inevitable when PTNB is performed using the anterior approach. We describe tumor seeding of metastatic pulmonary ameloblastoma in the pectoralis muscle layer of the breast along the needle track of PTNB in a 51-year-old female presenting with a palpable lump in the right breast.

Microglia, resident macrophages in the brain, play major roles in neuroinflammation after an acute many neurological diseases, including stroke. Our recent animal stroke model showed that interleukin (IL)-4 and IL-13 released by microglia are converted into monocyte-derived macrophages. However, the correlation with the migration mechanism of these cells is still unclear. This study aimed to clarify the effect of these cells on their migration and to identify potential targets that influence neuroinflammatory conditions. Inflammatory conditions were induced by lipopolysaccharide (LPS) treatment in in vitro and in vivo models. Cell migration was observed using transwell assay, and target chemokines were screened using the proteome profiler array in the in vitro model. Intravital, IVIS, and CLARITY imaging were used in the in vivo model. After LPS (1 ng/ml) treatment in BV2 (microglia cell line) and J774 (monocyte/macrophage cell line) cells, BV2 migration was approximately two-fold more enhanced compared to J774 migration. Overall, six types of chemokine C-C motif ligands (CCLs) were detected from the BV2 conditioned medium with LPS. These CCLs were related to C-C motif receptor (CCR)4 and CCR5. In the in vivo model, CCR4 and CCR5 antagonist significantly inhibited the migration of monocyte-derived macrophages to brain tissue following LPS (5 µg) treatment. In conclusion, the chemokines released by microglia may influence migration of monocyte-derived macrophages in necroinflammation conditions inducted by microglial activation. CCR4 and CCR5 expressed on monocyte-derived macrophages interacted with these chemokines and induced migration. Therefore, CCR4 and CCR5 may be explored as new therapeutic targets for neuroinflammation.

Abstract Background This study aimed to evaluate the computed tomography (CT) features of solitary pulmonary nodule (SPN), which can be a non-invasive diagnostic tool to differentiate between primary lung cancer (LC) and solitary lung metastasis (LM) in patients with colorectal cancer (CRC). Methods This retrospective study included SPNs resected in CRC patients between January 2011 and December 2019. The diagnosis of primary LC or solitary LM was based on histopathologic report by thoracoscopic wedge resection. Chest CT images were assessed by two thoracic radiologists, and CT features were identified by consensus. Predictive parameters for the discrimination of primary LC from solitary LM were evaluated using multivariate logistic regression analysis. Results We analyzed CT data of 199 patients (mean age, 65.95 years; 131 men and 68 women). The clinical characteristic of SPNs suggestive of primary LC rather than solitary LM was clinical stages I–II CRC (P < 0.001, odds ratio [OR] 21.70). The CT features of SPNs indicative of primary LC rather than solitary LM were spiculated margin (quantitative) (P = 0.020, OR 8.34), sub-solid density (quantitative) (P < 0.001, OR 115.56), and presence of an air bronchogram (quantitative) (P = 0.032, OR 5.32). Conclusions Quantitative CT features and clinical characteristics of SPNs in patients with CRC could help differentiate between primary LC and solitary LM.

Purpose High incidence of osteoporosis has been reported in breast cancer patients due to early menopause triggered by adjuvant treatment and temporary ovarian function suppression. In this study, we sought to determine whether long-term breast cancer survivors had an elevated risk of low bone density compared to the general population. Methods Long-term breast cancer survivors who had been treated for more than 5 years were selected for this study. Data were obtained from medical records and using a questionnaire from the Korea National Health and Nutrition Examination Survey (KNHANES). An age-matched non-cancer control group was selected from the KNHANES records. Incidence of fracture and bone mineral density (BMD) were compared between the two groups. Results In total, 74 long-term breast cancer survivors and 296 non-cancer controls were evaluated. The incidence of fracture did not differ between the two groups (P=0.130). No differences were detected in lumbar BMD (P=0.051) following adjustment for body mass index, while hip BMD was significantly lower in breast cancer survivors (P=0.028). Chemotherapy and endocrine treatment were not related to low BMD in breast cancer survivors. In more than half of the survivors, the 10-year risk of osteoporotic fracture was less than 1%. Conclusion Long-term breast cancer survivors had low bone density but a comparable risk of fracture compared to non-cancer age-matched controls. Further studies on the factors related to low bone density in long-term breast cancer survivors are required.

Abstract Background The objective of this study was to investigate the prognostic value of 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake of bone marrow (BM) and metabolic parameters of primary tumor on positron emission tomography/computed tomography (PET/CT) for predicting distant recurrence in patients with breast cancer. Methods Pretreatment [18F]FDG PET/CT images of 345 breast cancer patients were retrospectively evaluated. Maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of primary breast cancer and bone marrow-to-liver uptake ratio (BLR) on PET/CT were measured. A Cox proportional hazard regression model was used to evaluate the prognostic potential of parameters for predicting recurrence-free survival (RFS) and distant RFS. For Kaplan-Meier analysis, the specific cutoff values pf BLR and TLG were determined by the maximal chi-square method. Results The median follow-up duration of the enrolled patients was 48.7 months, and during follow-up, 36 patients (10.4%) experienced the cancer recurrence. BLR was significantly correlated with T stage, serum inflammatory markers, and recurrence pattern (p < 0.05). Patients with high BLR and TLG showed worse RFS and distant RFS than those with low BLR and TLG. On multivariate analysis, BLR was significantly associated with both RFS and distant RFS after adjusting for T stage, estrogen receptor status, and TLG (p = 0.001 for both). Only 0.5% of patients with TLG < 9.64 g and BLR < 0.91 experienced distant recurrence. However, patients with TLG ≥ 9.64 g and BLR ≥ 0.91 had a distant recurrence rate of 40.7%. Conclusions BLR on pretreatment [18F]FDG PET/CT were significant predictors for RFS and distant RFS in patients with breast cancer. By combining [18F]FDG uptake of BM and volumetric PET/CT index of breast cancer, the risk of distant recurrence could be stratified.

Oxidative stress is a key player in both chronic and acute brain disease due to the higher metabolic demand of the brain. Among the producers of free radicals, NADPH-oxidase (NOX) is a major contributor to oxidative stress in neurological disorders. In the brain, the superoxide produced by NOX is mainly found in leukocytes. However, recent studies have reported that it can be found in several other cell types. NOX has been reported to regulate neuronal signaling, memory processing, and central cardiovascular homeostasis. However, overproduction of NOX can contribute to neurotoxicity, CNS degeneration, and cardiovascular disorders. Regarding the above functions, NOX has been shown to play a crucial role in chronic CNS diseases like Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and in acute CNS disorders such as stroke, spinal cord injury, traumatic brain injury (TBI), and related cerebrovascular diseases. NOX is a multi-subunit complex consisting of two membrane-associated and four cytosolic subunits. Thus, in recent years, inhibition of NOX activity has drawn a great deal of attention from researchers in the field of treating chronic and acute CNS disorders and preventing secondary complications. Mounting evidence has shown that NOX inhibition is neuroprotective and that inhibiting NOX in circulating immune cells can improve neurological disease conditions. This review summarizes recent studies on the therapeutic effects and pharmacological strategies regarding NOX inhibitors in chronic and acute brain diseases and focuses on the hurdles that should be overcome before their clinical implementation. Keywords: Ischemic stroke, NADPH oxidase, Superoxide, NOX inhibition

Abstract Increasing evidence suggests there is a relationship between cognitive impairment and metabolic dysfunction. Diabetes is a chronic disease, and metabolic factors affecting brain metabolisms, such as serum glucose, insulin, and glucagon, are altered according to disease progression. In our previous study, we applied hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy in prediabetic mice after feeding them a 60% high-fat diet (HFD) for 6 months. Ultimately, we detected significantly increased [1-13C]lactate conversion in the whole brain and an almost five-fold increased [1-13C]lactate/pyruvate ratio in the hippocampal region. In the present study, we induced diabetes in mice by injecting streptozotocin and feeding them an HFD for 6 months. Unlike in prediabetic mice, [1-13C]lactate conversion in the diabetic mice did not differ from that in the control group, but [1-13C]lactate/total 13C ratio showed an almost 1.4-fold increase in the hippocampal region. We measured the amount of the lactate and mRNA levels of glucose transporters from isolated hippocampus and cortex samples. In the hippocampus, significantly decreased GLUT1 mRNA levels and increased lactate were detected, suggesting an inconsistency between glucose and pyruvate metabolism. Pyruvate can be produced from oxaloacetate as well as glucose. We investigated ATP citrate lyase (ACLY) because it cleaves citrate into oxaloacetate and acetyl CoA. Phosphorylated ACLY (Ser455), the active form, was increased in both hippocampus and cortex samples of mice injected with streptozotocin and fed an HFD. Also, phosphorylated ACLY/total ACLY showed a positive correlation with lactate amount in the hippocampus. Our results suggest that the brain has different responses to diabetic progression, but, in the hippocampus, maintains metabolic alteration toward increasing lactate production from the prediabetic to the diabetic stage. We suggest that ACLY-mediated pyruvate be used to support lactate levels in the hippocampus in cases of limited glucose availability.

ObjectiveThis study was conducted in order to investigate the feasibility of using radiomics analysis (RA) with machine learning algorithms based on breast magnetic resonance (MR) images for discriminating malignant from benign MR-detected additional lesions in patients with primary breast cancer.Materials and MethodsOne hundred seventy-four MR-detected additional lesions (benign, n = 86; malignancy, n = 88) from 158 patients with ipsilateral primary breast cancer from a tertiary medical center were included in this retrospective study. The entire data were randomly split to training (80%) and independent test sets (20%). In addition, 25 patients (benign, n = 21; malignancy, n = 15) from another tertiary medical center were included for the external test. Radiomics features that were extracted from three regions-of-interest (ROIs; intratumor, peritumor, combined) using fat-saturated T1-weighted images obtained by subtracting pre- from postcontrast images (SUB) and T2-weighted image (T2) were utilized to train the support vector machine for the binary classification. A decision tree method was utilized to build a classifier model using clinical imaging interpretation (CII) features assessed by radiologists. Area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, and specificity were used to compare the diagnostic performance.ResultsThe RA models trained using radiomics features from the intratumor-ROI showed comparable performance to the CII model (accuracy, AUROC: 73.3%, 69.6% for the SUB RA model; 70.0%, 75.1% for the T2 RA model; 73.3%, 72.0% for the CII model). The diagnostic performance increased when the radiomics and CII features were combined to build a fusion model. The fusion model that combines the CII features and radiomics features from multiparametric MRI data demonstrated the highest performance with an accuracy of 86.7% and an AUROC of 91.1%. The external test showed a similar pattern where the fusion models demonstrated higher levels of performance compared with the RA- or CII-only models. The accuracy and AUROC of the SUB+T2 RA+CII model in the external test were 80.6% and 91.4%, respectively.ConclusionOur study demonstrated the feasibility of using RA with machine learning approach based on multiparametric MRI for quantitatively characterizing MR-detected additional lesions. The fusion model demonstrated an improved diagnostic performance over the models trained with either RA or CII alone.

Recently, myocarditis following messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccination has become an important social issue worldwide. According to the reports so far, myocarditis related to mRNA COVID-19 vaccination is rare and usually associated with a benign clinical course without intensive care or any sequelae of fulminant myocarditis. Here, we report a case of acute fulminant myocarditis and cardiogenic shock after the mRNA COVID-19 vaccination, requiring extracorporeal cardiopulmonary resuscitation. Clinicians should keep in mind the possibility of progression to fulminant myocarditis in patients who presented with suggestive symptoms or signs of myocarditis after the COVID-19 vaccination.

Current therapeutic strategies for spinal cord injury (SCI) cannot fully facilitate neural regeneration or improve function. Arginine decarboxylase (ADC) synthesizes agmatine, an endogenous primary amine with neuroprotective effects. Transfection of human ADC (hADC) gene exerts protective effects after injury in murine brain-derived neural precursor cells (mNPCs). Following from these findings, we investigated the effects of hADC-mNPC transplantation in SCI model mice. Mice with experimentally damaged spinal cords were divided into three groups, separately transplanted with fluorescently labeled (1) control mNPCs, (2) retroviral vector (pLXSN)-infected mNPCs (pLXSN-mNPCs), and (3) hADC-mNPCs. Behavioral comparisons between groups were conducted weekly up to 6 weeks after SCI, and urine volume was measured up to 2 weeks after SCI. A subset of animals was euthanized each week after cell transplantation for molecular and histological analyses. The transplantation groups experienced significantly improved behavioral function, with the best recovery occurring in hADC-mNPC mice. Transplanting hADC-mNPCs improved neurological outcomes, induced oligodendrocyte differentiation and remyelination, increased neural lineage differentiation, and decreased glial scar formation. Moreover, locomotor and bladder function were both rehabilitated. These beneficial effects are likely related to differential BMP-2/4/7 expression in neuronal cells, providing an empirical basis for gene therapy as a curative SCI treatment option.

Purpose: This study utilized a radiomics approach combined with a machine learning algorithm to distinguish primary lung cancer (LC) from solitary lung metastasis (LM) in colorectal cancer (CRC) patients with a solitary pulmonary nodule (SPN). Materials and Methods: In a retrospective study, 239 patients who underwent chest computerized tomography (CT) at three different institutions between 2011 and 2019 and were diagnosed as primary LC or solitary LM were included. The data from the first institution were divided into training and internal testing datasets. The data from the second and third institutions were used as an external testing dataset. Radiomic features were extracted from the intra and perinodular regions of interest (ROI). After a feature selection process, Support vector machine (SVM) was used to train models for classifying between LC and LM. The performances of the SVM classifiers were evaluated with both the internal and external testing datasets. The performances of the model were compared to those of two radiologists who reviewed the CT images of the testing datasets for the binary prediction of LC versus LM. Results: The SVM classifier trained with the radiomic features from the intranodular ROI and achieved the sensitivity/specificity of 0.545/0.828 in the internal test dataset, and 0.833/0.964 in the external test dataset, respectively. The SVM classifier trained with the combined radiomic features from the intra- and perinodular ROIs achieved the sensitivity/specificity of 0.545/0.966 in the internal test dataset, and 0.833/1.000 in the external test data set, respectively. Two radiologists demonstrated the sensitivity/specificity of 0.545/0.966 and 0.636/0.828 in the internal test dataset, and 0.917/0.929 and 0.833/0.929 in the external test dataset, which were comparable to the performance of the model trained with the combined radiomics features. Conclusion: Our results suggested that the machine learning classifiers trained using radiomics features of SPN in CRC patients can be used to distinguish the primary LC and the solitary LM with a similar level of performance to radiologists.

Alzheimer’s disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.

The ability to accurately predict the prognosis and intervention requirements for treating highly infectious diseases, such as COVID-19, can greatly support the effective management of patients, especially in resource-limited settings. The aim of the study is to develop and validate a multimodal artificial intelligence (AI) system using clinical findings, laboratory data and AI-interpreted features of chest X-rays (CXRs), and to predict the prognosis and the required interventions for patients diagnosed with COVID-19, using multi-center data. In total, 2282 real-time reverse transcriptase polymerase chain reaction-confirmed COVID-19 patients’ initial clinical findings, laboratory data and CXRs were retrospectively collected from 13 medical centers in South Korea, between January 2020 and June 2021. The prognostic outcomes collected included intensive care unit (ICU) admission and in-hospital mortality. Intervention outcomes included the use of oxygen (O2) supplementation, mechanical ventilation and extracorporeal membrane oxygenation (ECMO). A deep learning algorithm detecting 10 common CXR abnormalities (DLAD-10) was used to infer the initial CXR taken. A random forest model with a quantile classifier was used to predict the prognostic and intervention outcomes, using multimodal data. The area under the receiver operating curve (AUROC) values for the single-modal model, using clinical findings, laboratory data and the outputs from DLAD-10, were 0.742 (95% confidence interval [CI], 0.696–0.788), 0.794 (0.745–0.843) and 0.770 (0.724–0.815), respectively. The AUROC of the combined model, using clinical findings, laboratory data and DLAD-10 outputs, was significantly higher at 0.854 (0.820–0.889) than that of all other models (p < 0.001, using DeLong’s test). In the order of importance, age, dyspnea, consolidation and fever were significant clinical variables for prediction. The most predictive DLAD-10 output was consolidation. We have shown that a multimodal AI model can improve the performance of predicting both the prognosis and intervention in COVID-19 patients, and this could assist in effective treatment and subsequent resource management. Further, image feature extraction using an established AI engine with well-defined clinical outputs, and combining them with different modes of clinical data, could be a useful way of creating an understandable multimodal prediction model.

Abstract Background Poorly differentiated neuroendocrine carcinomas (NECs) originating from the gastrointestinal (GI) tract are rare and very highly malignant disease with a poor prognosis. Poorly differentiated NECs most commonly arise in the esophagus and the large bowel; however, they may occur within virtually any portion of the GI tract. It is known, however, that they do not typically occur in the small intestine. Case report A 21-year-old woman visited an emergency room with acute abdominal pain that commenced 2 days prior to her presentation. Thereafter, a computed tomography (CT) scan was notable for a small-intestine perforation, and huge masses were observed in the small intestine and the mesentery. The mass that was located at the ileum site is approximately 100 cm above the ileocecal (IC) valve, and while it is located on the anti-mesenteric border and it seems that luminal narrowing had occurred, an obstruction is absent. Also, a same-nature mass is on the mesentery. The pathologic reports confirmed a small-cell-type NEC with a mass size of 7.5 × 6.5 cm. The mitotic count is up to 24/10 high-power fields (HPFs), the results of the immunohistochemical stain are positive for CD56 and synaptophysin, and the Ki-67 level is 50%. %. After the operation, she was treated with Etoposide-Cisplatin (EP) chemotheraphy. Stable disease was seen during Etoposide-Cisplatin chemotheraphy. Liver metastasis was also confirmed after chemotheraphy. Additionally, Irinotecan and cisplatin were used for 3 cycles, but progression of disease, neutropenic fever, thrombocytopenia, general weakness persisted. Eventually, she died 1 year and 6 months after surgery. Conclusion Ileum-located NECs are diagnosed very rarely. The most common locations for these tumors along the GI tract are the esophagus and the large intestine, but they can arise anywhere. The prognosis for NECs is poor due to the metastatic disease of most patients at the time of diagnosis. The role of adjuvant treatment requires further evaluation for the attainment of a better understanding of the overall treatment effect.

The roles of miRNAs in lung cancer have not yet been explored systematically at the genome scale despite their important regulatory functions. Here, we report an integrative analysis of miRNA and mRNA sequencing data for matched tumor–normal samples from 109 Korean female patients with non‐small‐cell lung adenocarcinoma (LUAD). We produced miRNA sequencing (miRNA‐Seq) and RNA‐Seq data for 48 patients and RNA‐Seq data for 61 additional patients. Subsequent differential expression analysis with stringent criteria yielded 44 miRNAs and 2322 genes. Integrative gene set analysis of the differentially expressed miRNAs and genes using miRNA–target information revealed several regulatory processes related to the cell cycle that were targeted by tumor suppressor miRNAs (TSmiR). We performed colony formation assays in A549 and NCI‐H460 cell lines to test the tumor‐suppressive activity of downregulated miRNAs in cancer and identified 7 novel TSmiRs (miR‐144‐5p, miR‐218‐1‐3p, miR‐223‐3p, miR‐27a‐5p, miR‐30a‐3p, miR‐30c‐2‐3p, miR‐338‐5p). Two miRNAs, miR‐30a‐3p and miR‐30c‐2‐3p, showed differential survival characteristics in the Tumor Cancer Genome Atlas (TCGA) LUAD patient cohort indicating their prognostic value. Finally, we identified a network cluster of miRNAs and target genes that could be responsible for cell cycle regulation. Our study not only provides a dataset of miRNA as well as mRNA sequencing from the matched tumor–normal samples, but also reports several novel TSmiRs that could potentially be developed into prognostic biomarkers or therapeutic RNA drugs.

Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

Abstract Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer’s disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6 months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p

The circulatory neutrophil and brain tissue-resident microglia are two important immune cells involved in neuroinflammation. Since neutrophils that infiltrate through the brain vascular vessel may affect the immune function of microglia in the brain, close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and immunological aftermaths that follow. This study aimed to observe how morphology and function of both neutrophils and microglia are converted in the inflamed brain. To directly investigate cellular responses of neutrophils and microglia, LysMGFP/+ and CX3CR1GFP/+ mice were used for the observation of neutrophils and microglia, respectively. In addition, low-dose lipopolysaccharide (LPS) was utilized to induce acute inflammation in the central nervous system (CNS) of mice. Real-time observation on mice brain undergoing neuroinflammation via two-photon intravital microscopy revealed various changes in neutrophils and microglia; namely, neutrophil infiltration and movement within the brain tissue increased, while microglia displayed morphological changes suggesting an activated state. Furthermore, neutrophils seemed to not only actively interact with microglial processes but also exhibit reverse transendothelial migration (rTEM) back to the bloodstream. Thus, it may be postulated that, through crosstalk with neutrophils, macrophages are primed to initiate a neuroinflammatory immune response; also, during pathogenic events in the brain, neutrophils that engage in rTEM may deliver proinflammatory signals to peripheral organs outside the brain. Taken together, these results both show that neuroinflammation results in significant alterations in neutrophils and microglia and lay the pavement for further studies on the molecular mechanisms behind such changes.

Fusarium is a large genus of filamentous fungi that are rarely associated with disease in humans. In the clinical setting, Fusarium species are often difficult to distinguish from other fungal organisms, particularly Aspergillus species. Invasive fungal pneumonia caused by Fusarium species has rarely been reported, especially in immunocompetent patients. In this study, we reported a case of invasive Fusarium pneumonia in a previously healthy 68-year-old woman. The disease was initially misdiagnosed as invasive Aspergillus pneumonia because of the similarity in radiologic and histopathologic findings between these conditions. After Fusarium was identified via microbiological analysis, the antifungal agent was changed, and the patient recovered fully.

The immune response following neuroinflammation is a vital element of ischemic stroke pathophysiology. After the onset of ischemic stroke, a specialized vasculature system that effectively protects central nervous system tissues from the invasion of blood cells and other macromolecules is broken down within minutes, thereby triggering the inflammation cascade, including the infiltration of peripheral blood leukocytes. In this series of processes, blood-derived monocytes have a significant effect on the outcome of ischemic stroke through neuroinflammatory responses. As neuroinflammation is a necessary and pivotal component of the reparative process after ischemic stroke, understanding the role of infiltrating monocytes in the modulation of inflammatory responses may offer a great opportunity to explore new therapies for ischemic stroke. In this review, we discuss and highlight the function and involvement of monocytes in the brain after ischemic injury, as well as their impact on tissue damage and repair.

Summary: Exome and transcriptome analyses of clinically homogeneous early-stage never-smoker female patients with lung adenocarcinoma were performed to understand tumor-T cell interactions and immune escape points. Using our novel gene panels of eight functional categories in the cancer-immunity cycle, three distinct subgroups were identified in this immune checkpoint blockade-refractory cohort by defective gene expression in two major domains, i.e., type I interferon production/signaling pathway and antigen-presenting machinery. Our approach could play a critical role in understanding immune evasion mechanisms, developing a method for effective selection of rare immune checkpoint blockade responders, and finding new treatment strategies.

Background: Although international guidelines recommend bone screening for premenopausal breast cancer patients taking adjuvant tamoxifen, the effects of tamoxifen on osteoporosis and related risks remain controversial. The objective of this study was to investigate the incidence of and risk factors for osteoporosis and osteoporotic fractures in younger breast cancer patients.Methods: A nationwide retrospective cohort study was conducted using South Korea Health Insurance Review and Assessment Service claims data. The rates of osteoporosis and osteoporotic fracture were calculated as incident cases per person-year and disease-free probability rates were analyzed with the Kaplan-Meier method. To identify risk factors for osteoporosis and osteoporotic fracture, a multivariable Cox proportional hazard regression model was applied.Results: From January 2009 to December 2014, a total of 47,649 breast cancer patients were included. The incidence rates of osteoporosis and osteoporotic fracture were 23.59 and 2.40 per 1,000 person-years, respectively. In the overall population, tamoxifen was significantly associated with a decreased risk of osteoporosis and osteoporotic fractures 0.76). However, tamoxifen was not associated with the risk of osteoporosis (HR 1.24, CI 0.85–1.82) and osteoporotic fracture (HR 8.15, CI 0.36–186.70) in patients under age 40. In the 40–49 years subgroup, tamoxifen significantly decreased the risk of osteoporosis (HR 0.74, CI 0.65–0.84) and osteoporotic fracture (HR 0.49, CI 0.31–0.76).Conclusions: Tamoxifen is not associated with an increased risk of osteoporosis and osteoporotic fracture in premenopausal breast cancer patients. Tailored screening strategies for breast cancer survivors with different osteoporosis risks are needed.Precis: Tamoxifen is not associated with an increased risk of osteoporosis and osteoporotic fracture in premenopausal breast cancer patients. Tailored screening strategies for breast cancer survivors who are at different risks of developing osteoporosis are needed.

We investigated whether textural parameters of peritumoral breast adipose tissue (AT) based on F-18 fluorodeoxyglucose (FDG) PET/CT could predict axillary lymph node metastasis in patients with breast cancer. A total of 326 breast cancer patients with preoperative FDG PET/CT were retrospectively enrolled. PET/CT images were visually assessed and the maximum FDG uptake of axillary lymph nodes (LN SUVmax) was measured. From peritumoral breast AT, 38 textural features of PET imaging were extracted. The diagnostic ability of PET based on visual analysis, LN SUVmax, and textural features of peritumoral breast AT for predicting axillary lymph node metastasis were assessed using the area under the receiver operating characteristic curve (AUC) values. Among the 38 peritumoral breast AT textural features, grey-level co-occurrence matrix (GLCM) entropy showed the highest AUC value (0.830) for predicting axillary lymph node metastasis. The value of GLCM entropy was higher than that of visual analysis (0.739; p < 0.05) and the AUC value was comparable to that of LN SUVmax (0.793; p > 0.05). In the subgroup analysis of patients with negative findings on visual analysis, GLCM entropy still showed a high diagnostic ability (AUC: 0.759) in predicting lymph node metastasis. The findings suggest a potential diagnostic role of PET/CT imaging features of peritumoral breast AT in predicting axillary lymph node metastasis in patients with breast cancer.

Abstract Reliable and reproducible assessment of animal learning and behavior is a central aim of basic and translational neuroscience research. Recent developments in automated operant chamber technology have led to the possibility of universal standard protocols, in addition to increased translational potential, reliability and accuracy. However, the impact of regional and national differences in the supplies of available reinforcers in this system on behavioural performance and inter-laboratory variability is an unknown and at present uncontrolled variable. Therefore, we aimed to identify which constituent(s) of the reward determines reinforcer strength to enable improved standardization of this parameter across laboratories. Male C57BL/6 mice were examined in the touchscreen-based fixed ratio (FR) and progressive ratio (PR) schedules, reinforced with different kinds of milk-based reinforcers to directly compare the incentive values of plain milk (PM, high-calorie: high-fat/low-sugar), strawberry-flavored milk (SM, high-calorie: low-fat/high-sugar), and semi-skimmed low-fat milk (LM, low-calorie: low-fat/low-sugar) on the basis of differences in caloric content, sugar/fat content, and flavor. Use of a higher caloric content reward was effective in increasing operant training acquisition rate. Total trial number completed in FR and breakpoint in PR were higher using the two isocaloric milk products (PM and SM) than the lower caloric LM, with comparable outcomes between PM and SM conditions, suggesting that total caloric content determines reward strength. Analysis of within-session changes in response rate revealed that overall outputs in FR and PR primarily depend on the response rate at the initial phase of a session, which itself was dependent on reinforcer caloric content. Interestingly, the rate of satiation, indicated by decay in response rate within a FR session, was highest when reinforced with SM, suggesting a rapid satiating effect of sugar. The key contribution of reward caloric content to operant performance was confirmed in a multi-laboratory study using the touchscreen 5-choice serial reaction time task (5-CSRTT) reinforced by two isocaloric milk-based liquid rewards with different countries of origin, which yielded consistent performance parameters across sites. Our results indicate that milk-based liquid reinforcer standardization can be facilitated by matching caloric content across laboratories despite regional or national differences in other non-caloric aspects of the reinforcers.

Abstract This paper presents a bio-inspired adaptive micro-lens with electrically tunable focus made of non-ionic high-molecular-weight polyvinyl chloride (PVC) gel. The optical device mimics the design of the crystalline lens and ciliary muscle of the human eye. It consists of a plano-convex PVC gel micro-lens on Indium Tin Oxide (ITO) glass, confined with an annular electrode operating as an artificial ciliary muscle. Upon electrical activation, the electroactive adhesive force of the PVC gel is exerted on the annular anode electrode, which reduces the sagittal height of the plano-convex PVC gel lens, resulting in focal length variation of the micro-lens. The focal length increases from 3.8 mm to 22.3 mm as the applied field is varied from 200 V/mm to 800 V/mm, comparable to that of the human lens. The device combines excellent optical characteristics with structural simplicity, fast response speed, silent operation, and low power consumption. The results show the PVC gel micro-lens is expected to open up new perspectives on practical tunable optics.

Endoscopic thyroidectomy is considered appropriate for follicular neoplasms, but on occasion, it leads to unexpected complications such as seeding along the port insertion site. Only 4 cases of operative track seeding after endoscopic thyroidectomy have been reported. Furthermore, simultaneous seeding at both operative track of upper chest wall and operative bed is also very rare. We present a case of thyroid follicular adenoma seeding at both the subcutaneous tunnel of the upper chest wall and the operative bed after endoscopic thyroidectomy, with an emphasis on magnetic resonance imaging and ultrasonography with pathologic correlations.

Stroke is a life-threatening condition that leads to the death of many people around the world. Reperfusion injury after ischemic stroke is a recurrent problem associated with various surgical procedures that involve the removal of blockages in the brain arteries. Lipid emulsion was recently shown to attenuate ischemic reperfusion injury in the heart and to protect the brain from excitotoxicity. However, investigations on the protective mechanisms of lipid emulsion against ischemia in the brain are still lacking. This study aimed to determine the neuroprotective effects of lipid emulsion in an in vivo rat model of ischemic reperfusion injury through middle cerebral artery occlusion (MCAO). Under sodium pentobarbital anesthesia, rats were subjected to MCAO surgery and were administered with lipid emulsion through intra-arterial injection during reperfusion. The experimental animals were assessed for neurological deficit wherein the brains were extracted at 24 h after reperfusion for triphenyltetrazolium chloride staining, immunoblotting and qPCR. Neuroprotection was found to be dosage-dependent and the rats treated with 20% lipid emulsion had significantly decreased infarction volumes and lower Bederson scores. Phosphorylation of Akt and glycogen synthase kinase 3-β (GSK3-β) were increased in the 20% lipid-emulsion treated group. The Wnt-associated signals showed a marked increase with a concomitant decrease in signals of inflammatory markers in the group treated with 20% lipid emulsion. The protective effects of lipid emulsion and survival-related expression of genes such as Akt, GSK-3β, Wnt1 and β-catenin were reversed by the intra-peritoneal administration of XAV939 through the inhibition of the Wnt/β-catenin signaling pathway. These results suggest that lipid emulsion has neuroprotective effects against ischemic reperfusion injury in the brain through the modulation of the Wnt signaling pathway and may provide potential insights for the development of therapeutic targets.

Growing evidence suggests that the clinical use of neural progenitor cells (NPCs) is hampered by heterogeneity, poor neuronal yield and low survival rate. Recently, we reported that retrovirus-delivered human arginine decarboxylase (hADC) genes improve cell survival against oxidative insult in murine NPCs in vitro. This study investigates whether the induced expression of hADC gene in mNPCs induces any significant change in the cell fate commitment. The evaluation of induced hADC gene function was assessed by knockdown of hADC gene using specific siRNA. The hADC gene delivery triggered higher expression of N-CAM, cell adhesion molecule and MAP-2, neuronal marker. However, the hADC gene knockdown showed downregulation of N-CAM and MAP-2 expression suggesting that hADC gene delivery favors cell fate commitment of mNPCs towards neuronal lineage. Neurite outgrowth was significantly longer in the hADC infected cells. The neurotrophic signal, BDNF aided in the neuronal commitment, differentiation, and maturation of hADC-mNPCs through PI3K and ERK1/2 activation. The induction of neuron-like differentiation is believed to be regulated by the expression of GSK-3β and Wnt/β-catenin signaling pathways. Our findings suggest that hADC gene delivery favors cell fate commitment of mNPCs towards neuronal lineage, bring new advances in the field of neurogenesis and cell therapy.

Purpose: As the population of breast cancer survivors increasing, concerns for second primary cancer has been grown. The most frequent second primary tumor after breast cancer diagnosis is contralateral breast cancer (CBC). CBC developed less than five years showed poor prognosis. However, in Korea, little is known about the clinical characteristics of CBC regarding diagnosis interval. Methods: We retrospectively reviewed medical records of the patients who diagnosed stage I-III breast cancer from three tertiary medical centers and identified CBC patients. We divided those patients into early-onset CBC (ECBC), which diagnosed within five years, and late-onset CBC (LCBC) which developed after five years since primary cancer. We also searched available published original articles regarding bilateral breast cancer in Korean population for comparison. Results: Between January 2003 and December 2013, a total of 3,695 patients were included. During follow up, 22 patients diagnosed as CBC. Mean age of ECBC (n=10) was 50.9±15.4 and that of LCBC (n=12) was 45.5±14.3. There were no significant difference between ECBC and LCBC in menopausal status, menarcheal age, family history of breast cancer, clinical stage, and pathologic characteristics. ECBC was related worse disease-free survival than LCBC (P=0.017). With meta-analysis of published reports in Korean population, the incident rate calculated from person-month was 0.06. Conclusion: ECBC showed poor prognosis than LCBC with cut-off at five years since diagnosis of primary breast cancer, and it was consistent with Western reports. Intensive treatment might be needed in those patients with ECBC.

Immature stages of the genus Plagiosterna Motschulsky are described in detail for the first time in Korea. A key for identifying larvae and pupae of Korean Plagiosterna is provided, along with illustrations of their habitus and larval tubercle patterns. Some remarks on their systematics are also given.

The 70 kDa heat shock protein (HSP70) is a stress-inducible protein that has been shown to protect the brain from various nervous system injuries. It allows cells to withstand potentially lethal insults through its chaperone functions. Its chaperone properties can assist in protein folding and prevent protein aggregation following several of these insults. Although its neuroprotective properties have been largely attributed to its chaperone functions, HSP70 may interact directly with proteins involved in cell death and inflammatory pathways following injury. Through the use of mutant animal models, gene transfer, or heat stress, a number of studies have now reported positive outcomes of HSP70 induction. However, these approaches are not practical for clinical translation. Thus, pharmaceutical compounds that can induce HSP70, mostly by inhibiting HSP90, have been investigated as potential therapies to mitigate neurological disease and lead to neuroprotection. This review summarizes the neuroprotective mechanisms of HSP70 and discusses potential ways in which this endogenous therapeutic molecule could be practically induced by pharmacological means to ultimately improve neurological outcomes in acute neurological disease.

Animal and human mechanistic studies have consistently shown an association between obesity and Alzheimer’s disease (AD). AD, a degenerative brain disease, is the most common cause of dementia and is characterized by the presence of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles disposition. Some studies have recently demonstrated that Aβ and tau cannot fully explain the pathophysiological development of AD and that metabolic disease factors, such as insulin, adiponectin, and antioxidants, are important for the sporadic onset of nongenetic AD. Obesity prevention and treatment can be an efficacious and safe approach to AD prevention. Adiponectin is a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation. It has been shown to be inversely correlated with adipose tissue dysfunction and may enhance the risk of AD because a range of neuroprotection adiponectin mechanisms is related to AD pathology alleviation. In this study, we summarize the recent progress that addresses the beneficial effects and potential mechanisms of adiponectin in AD. Furthermore, we review recent studies on the diverse medications of adiponectin that could possibly be related to AD treatment, with a focus on their association with adiponectin. A better understanding of the neuroprotection roles of adiponectin will help clarify the precise underlying mechanism of AD development and progression.

High-mobility group box 1 (HMGB1), a well-known danger-associated molecular pattern molecule, acts as a pro-inflammatory molecule when secreted by activated immune cells or released after necrotic cell damage. HMGB1 binds to immunogenic bacterial components and augments septic inflammation. In this study, we show how HMGB1 mediates complement activation, promoting sterile inflammation. We show that HMGB1 activates the classical pathway of complement system in an antibody-independent manner after binding to C1q. The C3a complement activation product in human plasma and C5b-9 membrane attack complexes on cell membrane surface are detected after the addition of HMGB1. In an acetaminophen (APAP)-induced hepatotoxicity model, APAP injection reduced HMGB1 levels and elevated C3 levels in C1q-deficient mouse serum samples, compared to that in wild-type (WT) mice. APAP-induced C3 consumption was inhibited by sRAGE treatment in WT mice. Moreover, in a mouse model of brain ischemia–reperfusion injury based on middle cerebral arterial occlusion, C5b-9 complexes were deposited on vessels where HMGB1 was accumulated, an effect that was suppressed upon HMGB1 neutralization. We propose that the HMGB1 released after cell necrosis and in ischemic condition can trigger the classical pathway of complement activation to exacerbate sterile inflammation.