Genome-wide analyses of early-onset acute myocardial infarction identify 29 novel loci by whole genome sequencing.

Early-onset acute myocardial infarction (AMI) may have a higher genetic predisposition than late-onset AMI. The present study aimed to identify and characterize germline variants that affect early-onset AMI using whole-genome sequencing (WGS). We performed a genome-wide association study based on the WGS of 1239 Koreans, including 596 early-onset AMI patients and 643 healthy individuals. Patients with AMI who underwent percutaneous coronary intervention (PCI) caused by atherothrombotic occlusive lesions were included in the study. A total of 29 novel loci were found to be associated with early-onset AMI. These loci are involved in thrombosis, fibrinolysis, inflammation, and lipid metabolism. One of the associated single nucleotide variants (SNVs), rs1614576, located upstream of PRKCB, is known to be associated with thrombus formation. Additionally, the results revealed a novel locus, rs78631167, located upstream of PLAUR which plays a critical role in regulating plasminogen activation and is related to fibrinolysis. The association between early-onset AMI and rs9357455, which is located upstream of PHACTR1 and regulates inflammation in AMI, was found. Moreover, we identified a lipid metabolism related genetic risk locus, rs5072, in the APOA1-AS gene. This study provides new evidence supporting the genetic association between early-onset AMI and thrombosis and fibrinolysis, as well as inflammation and lipid metabolism, by analyzing the whole-genome of 596 patients with early-onset AMI who have been treated with PCI. Our findings highlight potential genetic markers for the prediction and management of AMI, as well as for understanding the etiology of AMI.

Road Map for In Situ Grown Binder-Free MOFs and Their Derivatives as Freestanding Electrodes for Supercapacitors.

Among several electrocatalysts for energy storage purposes including supercapacitors, metal-organic frameworks (MOFs), and their derivatives have spurred wide spread interest owing to their structural merits, multifariousness with tailor-made functionalities and tunable pore sizes. The electrochemical performance of supercapacitors can be further enhanced using in situ grown MOFs and their derivatives, eliminating the role of insulating binders whose "dead mass" contribution hampers the device capability otherwise. The expulsion of binders not only ensures better adhesion of catalyst material with the current collector but also facilitates the transport of electron and electrolyte ions and remedy cycle performance deterioration with better chemical stability. This review systematically summarizes different kinds of metal-ligand combinations for in situ grown MOFs and derivatives, preparation techniques, modification strategies, properties, and charge transport mechanisms as freestanding electrode materials in determining the performance of supercapacitors. In the end, the review also highlights potential promises, challenges, and state-of-the-art advancement in the rational design of electrodes to overcome the bottlenecks and to improve the capability of MOFs in energy storage applications.

Does the Probability of Survival Calculated by the Trauma and Injury Severity Score Method Accurately Reflect the Severity of Neurotrauma Patients Admitted to Regional Trauma Centers in Korea?

BACKGROUND: Assessing and improving the quality of trauma care is crucial in modern trauma systems and centers. In Korea, evaluations of regional trauma centers are conducted annually to assess and improve trauma management quality. This includes using the Trauma and Injury Severity Score (TRISS) method to calculate the W-score and mortality Observed-to-Expected ratio (O:E ratio), which are used to evaluate the quality of care. We analyzed the potential for overestimation of the probability of survival using TRISS method for patients with neurotrauma, as well as the potential for errors when evaluating and comparing regional trauma centers. METHODS: We included patients who visited the regional trauma center between 2019 and 2021 and compared their probability of survival of the TRISS method, W-score, mortality O:E ratio, and misclassification rates. The patient groups were further subdivided into smaller subgroups based on age, Glasgow Coma Scale (GCS), and Injury Severity Score, and comparisons were made between the neurotrauma and non-neurotrauma groups within each subgroup. RESULTS: A total of 4,045 patients were enrolled in the study, with 1,639 of them having neurotrauma. The neurotrauma patient group had a W-score of -0.68 and a mortality O:E ratio of 1.044. The misclassification rate was found to be 13.3%, and patients with a GCS of 8 or less had a higher misclassification rate of 37.4%. CONCLUSION: The limitations of using the TRISS method for predicting outcomes in patients with severe neurotrauma are exposed in this study. The TRISS methodology demonstrated a high misclassification rate of approximately 40% in subgroups of patients with GCS less than 9, indicating that it may be less reliable in predicting outcomes for severely injured patients with low GCS. Clinicians and researchers should be cautious when using the TRISS method and consider alternative methods to evaluate patient outcomes and compare the quality of care provided by different trauma centers.

Loss of Neutralizing Activity of Tixagevimab/Cilgavimab (Evusheld™) Against Omicron BN.1, a Dominant Circulating Strain Following BA.5 During the Seventh Domestic Outbreak in Korea in Early 2023.

Tixagevimab/cilgavimab is a monoclonal antibody used to prevent coronavirus disease 2019 among immunocompromised hosts and maintained neutralizing activity against early omicron variants. Omicron BN.1 became a dominant circulating strain in Korea early 2023, but its susceptibility to tixagevimab/cilgavimab is unclear. We conducted plaque reduction neutralization test (PRNT) against BN.1 in a prospective cohort (14 patients and 30 specimens). BN.1 PRNT was conducted for one- and three-months after tixagevimab/cilgavimab administration and the average PRNT ND50 of each point was lower than the positive cut-off value of 20 (12.9 ± 4.5 and 13.2 ± 4.2, respectively, P = 0.825). In the paired analyses, tixagevimab/cilgavimab-administered sera could not actively neutralize BN.1 (PRNT ND50 11.5 ± 2.9, P = 0.001), compared with the reserved activity against BA.5 (ND50 310.5 ± 180.4). Unlike virus-like particle assay, tixagevimab/cilgavimab was not active against BN.1 in neutralizing assay, and would not be effective in the present predominance of BA.2.75 sublineages.

Estimation of an Image Biomarker for Distant Recurrence Prediction in NSCLC Using Proliferation-Related Genes.

This study aimed to identify a distant-recurrence image biomarker in NSCLC by investigating correlations between heterogeneity functional gene expression and fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) image features of NSCLC patients. RNA-sequencing data and 18F-FDG PET images of 53 patients with NSCLC (19 with distant recurrence and 34 without recurrence) from The Cancer Imaging Archive and The Cancer Genome Atlas Program databases were used in a combined analysis. Weighted correlation network analysis was performed to identify gene groups related to distant recurrence. Genes were selected for functions related to distant recurrence. In total, 47 image features were extracted from PET images as radiomics. The relationship between gene expression and image features was estimated using a hypergeometric distribution test with the Pearson correlation method. The distant recurrence prediction model was validated by a random forest (RF) algorithm using image texture features and related gene expression. In total, 37 gene modules were identified by gene-expression pattern with weighted gene co-expression network analysis. The gene modules with the highest significance were selected (p-value < 0.05). Nine genes with high protein-protein interaction and area under the curve (AUC) were identified as hub genes involved in the proliferation function, which plays an important role in distant recurrence of cancer. Four image features (GLRLM_SRHGE, GLRLM_HGRE, SUVmean, and GLZLM_GLNU) and six genes were identified to be correlated (p-value < 0.1). AUCs (accuracy: 0.59, AUC: 0.729) from the 47 image texture features and AUCs (accuracy: 0.767, AUC: 0.808) from hub genes were calculated using the RF algorithm. AUCs (accuracy: 0.783, AUC: 0.912) from the four image texture features and six correlated genes and AUCs (accuracy: 0.738, AUC: 0.779) from only the four image texture features were calculated using the RF algorithm. The four image texture features validated by heterogeneity group gene expression were found to be related to cancer heterogeneity. The identification of these image texture features demonstrated that advanced prediction of NSCLC distant recurrence is possible using the image biomarker.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

Booster BNT162b2 COVID-19 Vaccination Increases Neutralizing Antibody Titers Against the SARS-CoV-2 Omicron Variant in Both Young and Elderly Adults.

Concerns about the effectiveness of current vaccines against the rapidly spreading severe acute respiratory syndrome-coronavirus-2 omicron (B.1.1.529) variant are increasing. This study aimed to assess neutralizing antibody activity against the wild-type (BetaCoV/Korea/KCDC03/2020), delta, and omicron variants after full primary and booster vaccinations with BNT162b2. A plaque reduction neutralization test was employed to determine 50% neutralizing dilution (ND50) titers in serum samples. ND50 titers against the omicron variant (median [interquartile range], 5.3 [< 5.0-12.7]) after full primary vaccination were lower than those against the wild-type (144.8 [44.7-294.0]) and delta (24.3 [14.3-81.1]) variants. Furthermore, 19/30 participants (63.3%) displayed lower ND50 titers than the detection threshold (< 10.0) against omicron after full primary vaccination. However, the booster vaccine significantly increased ND50 titers against BetaCoV/Korea/KCDC03/2020, delta, and omicron, although titers against omicron remained lower than those against the other variants (P < 0.001). Our study suggests that booster vaccination with BNT162b2 significantly increases humoral immunity against the omicron variant.

Inspection of Underwater Hull Surface Condition Using the Soft Voting Ensemble of the Transfer-Learned Models.

In this study, we propose a method for inspecting the condition of hull surfaces using underwater images acquired from the camera of a remotely controlled underwater vehicle (ROUV). To this end, a soft voting ensemble classifier comprising six well-known convolutional neural network models was used. Using the transfer learning technique, the images of the hull surfaces were used to retrain the six models. The proposed method exhibited an accuracy of 98.13%, a precision of 98.73%, a recall of 97.50%, and an F1-score of 98.11% for the classification of the test set. Furthermore, the time taken for the classification of one image was verified to be approximately 56.25 ms, which is applicable to ROUVs that require real-time inspection.

High Energy Density Heteroatom (O, N and S) Enriched Activated Carbon for Rational Design of Symmetric Supercapacitors.

Carbon-based symmetric supercapacitors (SCs) are known for their high power density and long cyclability, making them an ideal candidate for power sources in new-generation electronic devices. To boost their electrochemical performances, deriving activated carbon doped with heteroatoms such as N, O, and S are highly desirable for increasing the specific capacitance. In this regard, activated carbon (AC) self-doped with heteroatoms is directly derived from bio-waste (lima-bean shell) using different KOH activation processes. The heteroatom-enriched AC synthesized using a pretreated carbon-to-KOH ratio of 1:2 (ONS@AC-2) shows excellent surface morphology with a large surface area of 1508 m2 g-1 . As an SC electrode material, the presence of heteroatoms (N and S) reduces the interfacial charge-transfer resistance and increases the ion-accessible surface area, which inherently provides additional pseudocapacitance. The ONS@AC-2 electrode attains a maximum specific capacitance (Csp ) of 342 F g-1 at a specific current of 1 Ag-1 in 1 m NaClO4 electrolyte at the wide potential window of 1.8 V. Moreover, as symmetric SCs the ONS@AC-2 electrode delivers a maximum specific capacitance (Csc ) of 191 F g-1 with a maximum specific energy of 21.48 Wh kg-1 and high specific power of 14 000 W kg-1 and excellent retention of its initial capacitance (98 %) even after 10000 charge/discharge cycles. In addition, a flexible supercapacitor fabricated utilizing ONS@AC-2 electrodes and a LiCl/polyvinyl alcohol (PVA)-based polymer electrolyte shows a maximum Csc of 119 F g-1 with considerable specific energy and power.

Comparative Transcriptome Analysis of Human Adipose-Derived Stem Cells Undergoing Osteogenesis in 2D and 3D Culture Conditions.

Human adipose-derived stem cells (hADSCs) are types of mesenchymal stem cells (MSCs) that have been used as tissue engineering models for bone, cartilage, muscle, marrow stroma, tendon, fat and other connective tissues. Tissue regeneration materials composed of hADSCs have the potential to play an important role in reconstituting damaged tissue or diseased mesenchymal tissue. In this study, we assessed and investigated the osteogenesis of hADSCs in both two-dimensional (2D) and three-dimensional (3D) culture conditions. We confirmed that the hADSCs successfully differentiated into bone tissues by ARS staining and quantitative RT-PCR. To gain insight into the detailed biological difference between the two culture conditions, we profiled the overall gene expression by analyzing the whole transcriptome sequencing data using various bioinformatic methods. We profiled the overall gene expression through RNA-Seq and further analyzed this using various bioinformatic methods. During differential gene expression testing, significant differences in the gene expressions between hADSCs cultured in 2D and 3D conditions were observed. The genes related to skeletal development, bone development and bone remodeling processes were overexpressed in the 3D culture condition as compared to the 2D culture condition. In summary, our RNA-Seq-based study proves effective in providing new insights that contribute toward achieving a genome-wide understanding of gene regulation in mesenchymal stem cell osteogenic differentiation and bone tissue regeneration within the 3D culture system.

Efficient mutation screening for cervical cancers from circulating tumor DNA in blood.

BACKGROUND: Early diagnosis and continuous monitoring are necessary for an efficient management of cervical cancers (CC). Liquid biopsy, such as detecting circulating tumor DNA (ctDNA) from blood, is a simple, non-invasive method for testing and monitoring cancer markers. However, tumor-specific alterations in ctDNA have not been extensively investigated or compared to other circulating biomarkers in the diagnosis and monitoring of the CC. Therfore, Next-generation sequencing (NGS) analysis with blood samples can be a new approach for highly accurate diagnosis and monitoring of the CC. METHOD: Using a bioinformatics approach, we designed a panel of 24 genes associated with CC to detect and characterize patterns of somatic single-nucleotide variations, indels, and copy number variations. Our NGS CC panel covers most of the genes in The Cancer Genome Atlas (TCGA) as well as additional cancer driver and tumor suppressor genes. We profiled the variants in ctDNA from 24 CC patients who were being treated with systemic chemotherapy and local radiotherapy at the Jeonbuk National University Hospital, Korea. RESULT: Eighteen out of 24 genes in our NGS CC panel had mutations across the 24 CC patients, including somatic alterations of mutated genes (ZFHX3-83%, KMT2C-79%, KMT2D-79%, NSD1-67%, ATM-38% and RNF213-27%). We demonstrated that the RNF213 mutation could be used potentially used as a monitoring marker for response to chemo- and radiotherapy. CONCLUSION: We developed our NGS CC panel and demostrated that our NGS panel can be useful for the diagnosis and monitoring of the CC, since the panel detected the common somatic variations in CC patients and we observed how these genetic variations change according to the treatment pattern of the patient.

Small molecule inhibitors of IκB kinase ß: A chip-based screening and molecular docking simulation.

A chip-based screening system for IκB kinase ß (IKKß) has been developed by physically immobilizing the substrate IκBα on a glass matrix using a calixarene linker. Phosphorylation of IκBα by IKKß and ATP was quantitated using a fluorescently labeled antibody. Using this efficient assay system a chemical library of 2000 bioactive compounds was screened against IKKß and four were identified as good inhibitors, namely, aurintricarboxylic acid, diosmin, ellagic acid, and hematein. None of them have been reported to be an inhibitor of IKKß although they were implicated in various NFκB-mediated biological processes. Our enzyme-based assay showed that IC50 of the four inhibitors is comparable with that of IKK-16, a previously known strong inhibitor. Molecular docking simulation shows that the hydrophobic moiety of an inhibitor interacts with the four hydrophobic residues (Leu21, Val29, Val152, and Ile165) of the active site. The MM-PBSA calculation suggests that these hydrophobic interactions appear to be the predominant contributor to the binding free energy. As IKKß is ubiquitously expressed in various cell types and executes many biological functions, the enzyme and cell specificity of the four inhibitors need to be rigorously tested before accepted as a drug candidate.

Detection of association between periodontitis and polymorphisms of IL-1ß + 3954 and TNF-α -863 in the Korean population after controlling for confounding risk factors.

BACKGROUND AND OBJECTIVE: Interleukin (IL)-1 and tumor necrosis factor (TNF)-α are inflammatory cytokines that play an important role in periodontitis, and their genetic variations have been suggested to be associated with increased risk of periodontitis. Focusing on three single nucleotide polymorphisms (SNPs) of IL-1α + 4845, IL-1ß + 3954, and TNF-α -863, we aimed to investigate the relationship between periodontitis risk and the polymorphisms of IL-1 α/ß and TNF-α in Koreans. MATERIAL AND METHODS: Mouthwash samples from 548 subjects (135 controls without periodontitis, 387 generalized chronic periodontitis patients, and 26 generalized aggressive periodontitis patients) were collected for isolation of genomic DNA. Genotyping of selected SNPs was performed using real-time PCR. Univariable associations between the polymorphisms and periodontitis were assessed by chi-squared test or Fisher's exact test. To evaluate the association after controlling for confounding effects of various risk factors, we stratified the subjects according to the presence or absence of self-reported diseases and employed multiple logistic regression model to adjust for age, smoking status, and oral hygiene indices and behaviors. RESULTS: Significant association of IL-1ß + 3954 and TNF-α -863 polymorphisms with periodontitis was observed after adjusting for the confounding risk factors, but not in univariable association analysis. The significant association between genotype CT of IL-1ß + 3954 and increased risk of advanced periodontitis was consistently detected regardless of the status of self-reported diseases. In the polymorphism of TNF-α -863, the genotype with minor allele (CA + AA) was significantly associated with periodontitis susceptibility, which was observed only in the subjects with self-reported diseases. CONCLUSION: The results suggest that genetic variations of IL-1ß + 3954 and TNF-α -863 are associated with increased risk of periodontitis in Koreans. In addition, our findings underscore the importance of controlling for confounding risk factors to detect significant association between genetic factors and risk of periodontitis. A further well-designed large-scale study is needed to warrant our results.

Is ascites CEA a risk factor for peritoneal carcinomatosis in colorectal cancer?: a long-term follow-up study.

PURPOSE: Our previous study reported that carcinoembryonic antigen (CEA) levels in peritoneal fluid were significantly correlated with the prevalence of peritoneal carcinomatosis (PC) in colorectal cancer (CRC). The purpose of this study was a long-term follow up of the author's previous study, as well as the identification of correlations with the known risk factors of PC and the comparison of the predictive power of PC in CRC. METHODS: A total of 495 patients without PC who underwent CRC operations at St. Mary's Hospital, The Catholic University of Korea, from January 2006 to November 2014 were included in this study. Tumor markers of peritoneal fluid sampled at the beginning of each operation were prospectively analyzed and compared with the known risk factors for PC in CRC. RESULTS: Multivariate analysis of PC revealed that T4 cancer (OR 5.143, 95% CI 1.400-18.897, p = 0.014), T3 mucinous cancer (OR 17.480, 95% CI 1.577-193.714, p = 0.020), obstructed tumors (OR 6.030, 95% CI 1.627-22.343, p = 0.007), and peritoneal fluid CEA above 5 ng/dl (OR 4.073, 95% CI 1.315-12.615, p = 0.015) were significant risk factors. T4 cancer, obstructed tumors, and peritoneal fluid CEA above 5 ng/dl showed correlations with cancer-free survival. Generally, higher CEA levels in peritoneal fluid were correlated with previously known risk factors for PC in CRC. CONCLUSION: Peritoneal fluid CEA has predictive value for PC and prognostic value in CRC. Therefore, we recommend routinely performing ascites CEA analysis in colorectal cancer surgery.

Effect of basic oxygen furnace slag addition on enhanced alkaline sludge fermentation and simultaneous phosphate removal.

This study presents a promising approach that enhances the sludge fermentation by using basic oxygen furnace (BOF) slag as an alkaline source for the first time. BOF slag added to the reactors could maintain a stable alkaline condition due to continuous release of Ca(OH)2 from slag. The reactor pH could be adjusted to a target value by the choice of the BOF slag dose. Concentrations of soluble chemical oxygen demand (sCOD) and short-chain carboxylates (SCCs) were substantially increased in the presence of BOF slag. At a BOF slag mass to sludge volume ratio of 1/10 g slag/L sludge, the reactor pH was maintained at 10 and the concentration of SCCs produced was the highest (i.e., 3510 mg COD L-1 from 14,000 mg VS L-1 of sludge mixture), followed by B/S ratios of 1/20, 1.50, 1/5, and 1/2.5 g slag L-1 sludge with reactor pH of 9.4, 8.9, 10.5, and 11, respectively. Our data suggest that the pH value that best facilitates the degradation of sludge into SCCs and inhibit the conversion of SCCs into biogas is around 10. Interestingly, compositions of the accumulated SCCs varied greatly depending on the BOF slag dose. BOF slag showed phosphorus removal ability due to enhanced precipitation of Ca-PO43--P complexes, which significantly lowered PO43- concentration of the reactor effluent.

Heme oxygenase-1/carbon monoxide axis suppresses transforming growth factor-ß1-induced growth inhibition by increasing ERK1/2-mediated phosphorylation of Smad3 at Thr-179 in human hepatocellular carcinoma cell lines.

Heme oxygenase-1 (HO-1) has been implicated in tumor progression, but the underlying molecular mechanisms remain largely unknown. Transforming growth factor-ß1 (TGF-ß1) exhibits cytostatic and apoptotic effects in hepatocytes and several types of hepatocellular carcinoma (HCC) cell lines, and deregulation of its signaling pathway is linked to hepatic tumorigenesis. In the present study, we observed that HO-1 is expressed at higher levels in HCC tissues than in paired normal tissues. Moreover, TGF-ß1-induced cell cycle arrest and up-regulation of cyclin-dependent kinase inhibitors in HCC cell lines were significantly attenuated by overexpression of HO-1 or treatment with tricarbonyldichlororuthenium(II) dimer ([Ru(CO)3Cl2]2, suggesting an inhibitory role of the HO-1/CO axis in TGF-ß signaling to growth inhibition in HCC cell lines. Interestingly, we observed that [Ru(CO)3Cl2]2 inhibits TGF-ß1-induced Smad3-dependent reporter activity without affecting its C-terminus phosphorylation, complex formation with Smad4, and nuclear translocation. Additional experiments revealed that HO-1/CO axis selectively induces phosphorylation of Smad3 at Thr-179 residue in the linker region through activation of extracellular signal-activated kinase (ERK) 1/2. Transfection with a phospho-deficient Smad3 (T179A) mutant or treatment with FR180204, a specific inhibitor for ERK1/2, significantly reversed the inhibitory effects of HO-1 and [Ru(CO)3Cl2]2 on cell cycle arrest induced by TGF-ß1. These findings for the first time demonstrate that HO-1/CO axis confer resistance of HCC cells to TGF-ß growth inhibitory signal by increasing Smad3 phosphorylation at Thr-179 via ERK1/2 pathway.

Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas.

Despite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients. Whole transcriptome sequencing revealed that a subset of recurrent tumors initially diagnosed as locally recurrent medulloblastomas are secondary glioblastomas after radiotherapy, showing high similarity to the non-G-CIMP proneural subtype of glioblastoma. Further analysis, including whole exome sequencing, revealed missense mutations or complex gene fusion events in PDGFRA with augmented expression in the secondary glioblastomas after radiotherapy, implicating PDGFRA as a putative driver in the development of secondary glioblastomas after treatment exposure. This result provides insight into the possible application of PDGFRA-targeted therapy in these second malignancies. Furthermore, genomic alterations of TP53 including 17p loss or germline/somatic mutations were also found in most of the secondary glioblastomas after radiotherapy, indicating a crucial role of TP53 alteration in the process. On the other hand, analysis of recurrent medulloblastomas revealed that the most prevalent alterations are the loss of 17p region including TP53 and gain of 7q region containing EZH2 which already exist in primary tumors. The 7q gain events are frequently accompanied by high expression levels of EZH2 in both primary and recurrent medulloblastomas, which provides a clue to a new therapeutic target to prevent recurrence. Considering the fact that it is often challenging to differentiate between recurrent medulloblastomas and secondary glioblastomas after radiotherapy, our findings have major clinical implications both for correct diagnosis and for potential therapeutic interventions in these devastating diseases.

FAST: Size-Selective, Clog-Free Isolation of Rare Cancer Cells from Whole Blood at a Liquid-Liquid Interface.

Circulating tumor cells (CTCs) have great potential to provide minimally invasive ways for the early detection of cancer metastasis and for the response monitoring of various cancer treatments. Despite the clinical importance and progress of CTC-based cancer diagnostics, most of the current methods of enriching CTCs are difficult to implement in general hospital settings due to complex and time-consuming protocols. Among existing technologies, size-based isolation methods provide antibody-independent, relatively simple, and high throughput protocols. However, the clogging issues and lower than desired recovery rates and purity are the key challenges. In this work, inspired by antifouling membranes with liquid-filled pores in nature, clog-free, highly sensitive (95.9 ± 3.1% recovery rate), selective (>2.5 log depletion of white blood cells), rapid (>3 mL/min), and label-free isolation of viable CTCs from whole blood without prior sample treatment is achieved using a stand-alone lab-on-a-disc system equipped with fluid-assisted separation technology (FAST). Numerical simulation and experiments show that this method provides uniform, clog-free, ultrafast cell enrichment with pressure drops much less than in conventional size-based filtration, at 1 kPa. We demonstrate the clinical utility of the point-of-care detection of CTCs with samples taken from 142 patients suffering from breast, stomach, or lung cancer.

Engineering three dimensional micro nerve tissue using postnatal stem cells from human dental apical papilla.

The in vitro generation of cell-based three dimensional (3D) nerve tissue is an attractive subject to improve graft survival and integration into host tissue for neural tissue regeneration or to model biological events in stem cell differentiation. Although 3D organotypic culture strategies are well established for 3D nerve tissue formation of pluripotent stem cells to study underlying biology in nerve development, cell-based nerve tissues have not been developed using human postnatal stem cells with therapeutic potential. Here, we established a culture strategy for the generation of in vitro cell-based 3D nerve tissue from postnatal stem cells from apical papilla (SCAPs) of teeth, which originate from neural crest-derived ectomesenchyme cells. A stem cell population capable of differentiating into neural cell lineages was generated during the ex vivo expansion of SCAPs in the presence of EGF and bFGF, and SCAPs differentiated into neural cells, showing neural cell lineage-related molecular and gene expression profiles, morphological changes and electrophysical property under neural-inductive culture conditions. Moreover, we showed the first evidence that 3D cell-based nerve-like tissue with axons and myelin structures could be generated from SCAPs via 3D organotypic culture using an integrated bioprocess composed of polyethylene glycol (PEG) microwell-mediated cell spheroid formation and subsequent dynamic culture in a high aspect ratio vessel (HARV) bioreactor. In conclusion, the culture strategy in our study provides a novel approach to develop in vitro engineered nerve tissue using SCAPs and a foundation to study biological events in the neural differentiation of postnatal stem cells. Biotechnol. Bioeng. 2017;114: 903-914. © 2016 Wiley Periodicals, Inc.

Suppressor of cytokine signaling 1 is a positive regulator of TGF-ß-induced prostaglandin production in human follicular dendritic cell-like cells.

PGs are emerging as important immune modulators. Since our report on the expression of PG synthases in human follicular dendritic cells, we investigated the potential immunoregulatory function of PGs and their production mechanisms. In this study, we explored the intracellular signaling molecules mediating TGF-ß-induced cyclooxygenase (COX)-2 augmentation in follicular dendritic cell-like cells. TGF-ß triggered phosphorylation of Smad3 and ERK, which were essential for the increase in COX-2 protein. Interestingly, depletion of suppressor of cytokine signaling 1 (SOCS1) resulted in an almost complete inhibition of Smad3 phosphorylation and COX-2 induction. Nuclear translocation of Smad3 was inhibited in SOCS1-depleted cells. SOCS1 knockdown also downregulated TGF-ß-stimulated Snail expression and its binding to the Cox-2 promoter. In contrast, overexpression of SOCS1 gave rise to a significant increase in Snail and COX-2 proteins. SOCS1 was reported to be a negative regulator of cytokine signaling by various investigators. However, our current data suggest that SOCS1 promotes TGF-ß-induced COX-2 expression and PG production by facilitating Smad3 phosphorylation and Snail binding to the Cox-2 promoter. The complete understanding of the biological function of SOCS1 might be obtained via extensive studies with diverse cell types.