Identifying Candidate Polyphenols Beneficial for Oxidative Liver Injury through Multiscale Network Analysis.

Oxidative stress, a driver of liver pathology, remains a challenge in clinical management, necessitating innovative approaches. In this research, we delved into the therapeutic potential of polyphenols for oxidative liver injury using a multiscale network analysis framework. From the Phenol-Explorer database, we curated a list of polyphenols along with their corresponding PubChem IDs. Verified target information was then collated from multiple databases. We subsequently measured the propagative effects of these compounds and prioritized a ranking based on their correlation scores for oxidative liver injury. This result underwent evaluation to discern its effectiveness in differentiating between known and unknown polyphenols, demonstrating superior performance over chance level in distinguishing these compounds. We found that lariciresinol and isopimpinellin yielded high correlation scores in relation to oxidative liver injury without reported evidence. By analyzing the impact on a multiscale network, we found that lariciresinol and isopimpinellin were predicted to offer beneficial effects on the disease by directly acting on targets such as CASP3, NR1I2, and CYP3A4 or by modulating biological functions related to the apoptotic process and oxidative stress. This study not only corroborates the efficacy of identified polyphenols in liver health but also opens avenues for future investigations into their mechanistic actions.

U-Shape Pillar Strip for 3D Cell-Lumped Organoid Model (3D-COM) Mimicking Lung Cancer Hypoxia Conditions in High-Throughput Screening (HTS).

Hypoxia is a representative tumor characteristic associated with malignant progression in clinical patients. Engineered in vitro models have led to significant advances in cancer research, allowing for the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. In this study, we propose a U-shape pillar strip for a 3D cell-lumped organoid model (3D-COM) to study the effects of hypoxia on lung cancer in a high-throughput manner. We developed a U-pillar strip that facilitates the aggregation of PDCs mixed with an extracellular matrix to make the 3D-COM in 384-plate array form. The response to three hypoxia-activated prodrugs was higher in the 3D-COM than in the 2D culture model. The protein expression of hypoxia-inducible factor 1 alpha (HIF-1α) and HIF-2α, which are markers of hypoxia, was also higher in the 3D-COM than in the 2D culture. The results show that 3D-COM better recapitulated the hypoxic conditions of lung cancer tumors than the 2D culture. Therefore, the U-shape pillar strip for 3D-COM is a good tool to study the effects of hypoxia on lung cancer in a high-throughput manner, which can efficiently develop new drugs targeting hypoxic tumors.

Elucidating the callus-to-shoot-forming mechanism in Capsicum annuum 'Dempsey' through comparative transcriptome analyses.

BACKGROUND: The formation of shoots plays a pivotal role in plant organogenesis and productivity. Despite its significance, the underlying molecular mechanism of de novo regeneration has not been extensively elucidated in Capsicum annuum 'Dempsey', a bell pepper cultivar. To address this, we performed a comparative transcriptome analysis focusing on the differential expression in C. annuum 'Dempsey' shoot, callus, and leaf tissue. We further investigated phytohormone-related biological processes and their interacting genes in the C. annuum 'Dempsey' transcriptome based on comparative transcriptomic analysis across five species. RESULTS: We provided a comprehensive view of the gene networks regulating shoot formation on the callus, revealing a strong involvement of hypoxia responses and oxidative stress. Our comparative transcriptome analysis revealed a significant conservation in the increase of gene expression patterns related to auxin and defense mechanisms in both callus and shoot tissues. Consequently, hypoxia response and defense mechanism emerged as critical regulators in callus and shoot formation in C. annuum 'Dempsey'. Current transcriptome data also indicated a substantial decline in gene expression linked to photosynthesis within regenerative tissues, implying a deactivation of the regulatory system governing photosynthesis in C. annuum 'Dempsey'. CONCLUSION: Coupled with defense mechanisms, we thus considered spatial redistribution of auxin to play a critical role in the shoot morphogenesis via primordia outgrowth. Our findings shed light on shoot formation mechanisms in C. annuum 'Dempsey' explants, important information for regeneration programs, and have broader implications for precise molecular breeding in recalcitrant crops.

The adaptability of the Pulsta valve to the diverse main pulmonary artery shape of native right ventricular outflow tract disease.

BACKGROUND: Pulsta valve is increasingly used for percutaneous pulmonary valve implantation (PPVI) in patients with a large native right ventricular outflow tract (RVOT). This study aims to elucidate the outcomes of Pulsta valve implantation within the native RVOT and assess its adaptability to various native main pulmonary artery (PA) anatomies. METHODS: A multicenter retrospective study included 182 patients with moderate to severe pulmonary regurgitation in the native RVOT who underwent PPVI with Pulsta valves® between February 2016 and August 2023 at five Korean and Taiwanese tertiary referral centers. RESULTS: Pulsta valve implantation was successful in 179 out of 182 patients (98.4%) with an average age of 26.7 ± 11.0 years. The median follow-up duration was 29 months. Baseline assessments revealed enlarged right ventricle (RV) volume (mean indexed RV end-diastolic volume: 163.1 (interquartile range, IQR: 152.0-180.3 mL/m²), which significantly decreased to 123.6(IQR: 106.6-137.5 mL/m2  after 1 year. The main PA types were classified as pyramidal (3.8%), straight (38.5%), reverse pyramidal (13.2%), convex (26.4%), and concave (18.1%) shapes. Pulsta valve placement was adapted, with distal main PA for pyramidal shapes and proximal or mid-PA for reverse pyramidal shapes. Two patients experienced Pulsta valve embolization to RV, requiring surgical removal, and one patient encountered valve migration to the distal main PA, necessitating surgical fixation. CONCLUSIONS: Customized valve insertion sites are pivotal in self-expandable PPVI considering diverse native RVOT shape. The rather soft and compact structure of the Pulsta valve has characteristics to are adaptable to diverse native RVOT geometries.

Prognostic significance of MRI features in patients with solitary large hepatocellular carcinoma following surgical resection.

OBJECTIVE: To assess the prognostic impact of preoperative MRI features on outcomes for single large hepatocellular carcinoma (HCC) (≥ 8 cm) after surgical resection. MATERIAL AND METHODS: This retrospective study included 151 patients (mean age: 59.2 years; 126 men) with a single large HCC who underwent gadoxetic acid-enhanced MRI and surgical resection between 2008 and 2020. Clinical variables, including tumor markers and MRI features (tumor size, tumor margin, and the proportion of hypovascular component on hepatic arterial phase (AP) (≥ 50% vs. < 50% tumor volume) were evaluated. Cox proportional hazards model analyzed overall survival (OS), recurrence-free survival (RFS), and associated factors. RESULTS: Among 151 HCCs, 37.8% and 62.2% HCCs were classified as ≥ 50% and < 50% AP hypovascular groups, respectively. The 5- and 10-year OS and RFS rates in all patients were 62.0%, 52.6% and 41.4%, 38.5%, respectively. Multivariable analysis revealed that ≥ 50% AP hypovascular group (hazard ratio [HR] 1.7, p = 0.048), tumor size (HR 1.1, p = 0.006), and alpha-fetoprotein ≥ 400 ng/mL (HR 2.6, p = 0.001) correlated with poorer OS. ≥ 50% AP hypovascular group (HR 1.9, p = 0.003), tumor size (HR 1.1, p = 0.023), and non-smooth tumor margin (HR 2.1, p = 0.009) were linked to poorer RFS. One-year RFS rates were lower in the ≥ 50% AP hypovascular group than in the < 50% AP hypovascular group (47.4% vs 66.9%, p = 0.019). CONCLUSION: MRI with ≥ 50% AP hypovascular component and larger tumor size were significant factors associated with poorer OS and RFS after resection of single large HCC (≥ 8 cm). These patients require careful multidisciplinary management to determine optimal treatment strategies. CLINICAL RELEVANCE STATEMENT: Preoperative MRI showing a ≥ 50% arterial phase hypovascular component and larger tumor size can predict worse outcomes after resection of single large hepatocellular carcinomas (≥ 8 cm), underscoring the need for tailored, multidisciplinary treatment strategies. KEY POINTS: MRI features offer insights into the postoperative prognosis for large hepatocellular carcinoma. Hypovascular component on arterial phase ≥ 50% and tumor size predicted poorer overall survival and recurrence-free survival. These findings can assist in prioritizing aggressive and multidisciplinary approaches for patients at risk for poor outcomes.

Risk Factors for Coronary Artery Complications After Prosthetic Pulmonary Valve Implantation in Patients With Congenital Heart Disease.

BACKGROUND: Coronary artery complications (CACs) in patients who undergoing prosthetic pulmonary valve implantation for congenital heart disease can lead to fetal outcomes. However, the incidence of and risk factors for CACs in these patients remain unknown.Methods and Results: A retrospective cohort study was conducted on patients who underwent cardiac computed tomography or invasive coronary angiography after prosthetic pulmonary valve implantation at Seoul National University Hospital from June 1986 to May 2021. Among 341 patients, 25 (7.3%) were identified with CACs, and 2 of them died. Among the patients with CACs, congenital coronary anomalies and an interarterial course of the coronary artery were identified in 11 (44%) and 18 (72%) patients, respectively. Interarterial and intramural courses of the coronary artery were associated with a 4.4- and 10.6-fold increased risk of CACs, respectively. Among patients with tetralogy of Fallot and pulmonary atresia, the aortic root was rotated further clockwise in patients with coronary artery compression compared to those without it (mean [±SD] 128.0±19.9° vs. 113.5±23.7°; P=0.024). The cut-off rotation angle of the aorta for predicting the occurrence of coronary artery compression was 133°. CONCLUSIONS: Perioperative coronary artery evaluation and prevention of CACs are required in patients undergoing prosthetic pulmonary valve implantation, particularly in those with coronary artery anomalies or severe clockwise rotation of the aortic root.

Computed Tomography Measurement of the Aorta in Midaortic Syndrome in Children and Adolescents and Their Clinical Manifestations and Outcomes.

Midaortic syndrome (MAS) presents challenges in diagnosis due to the absence of well-defined diagnostic criteria in pediatric patients. This retrospective study aimed to aid in the diagnosis of MAS by employing computed tomography (CT) to measure the z-score of the aorta as well as to identify and understand its clinical features. CT images, echocardiography findings, and medical records of 17 patients diagnosed with MAS between 1997 and 2023 were reviewed, and z-scores were calculated. Aortic size on follow-up CT, blood pressure, and left ventricular function and hypertrophy at the last follow-up were analyzed, and possible prognostic factors were examined. Except for one patient, all individuals exhibited a z-score below - 2 at the level corresponding to stenosis. Left ventricular dysfunction occurred more frequently in patients aged < 5 years (p = 0.024). Patients with idiopathic MAS showed a better prognosis in terms of blood pressure and follow-up aortic size (p = 0.051 and 0.048, respectively). CT-measured aortic z-scores may be useful for the diagnosis and follow-up of MAS.

First report of soybean root rot caused by Fusarium proliferatum in the Republic of Korea.

Fusarium species are widespread soilborne pathogens that can cause damping-off, root rot, and wilting in soybean [Glycine max (L.) Merrill], subsequently leading to significant yield suppression. Several Fusarium spp. have already been documented for their pathogenicity on soybean plants in the Republic of Korea. The nationwide monitoring of soybean diseases continues to identify new pathogenic Fusarium spp. In 2016, five plant samples at R3-R4 growth stages, showing symptoms of wilting in the upper parts and root rot, were collected in Suwon, Gyeonggi, Republic of Korea. Fungal colonies were obtained from the diseased root samples, with the surface sterilized in 1% sodium hypochlorite for 2 min, rinsed thrice with sterile distilled water, and placed on water agar at 25°C. Five isolates were collected and purified by single-spore isolation. The fungal mycelium was subsequently cultivated on potato dextrose agar for ten days. The isolates produced abundant, aerial, and white mycelium and became purple in old cultures. Macroconidia were slender, falcate to almost straight, usually 3 to 5 septated, and thin-walled. Microconidia were formed in chains from polyphalides, clavate or oval, usually single-celled with a flattened base. These characteristics of isolates were consistent with the description of F. proliferatum (Leslie and Summerrell 2006), and the representative isolate 16-19 was selected for molecular identification to confirm its identity as F. proliferatum. Two evolutionarily conserved genes, the translation elongation factor 1-alpha (EF-1α) and the second-largest subunit of RNA polymerase II (RPB2) genes, were partially amplified using the primers described by O'Donnell et al. (2008), resulting in nucleotide sequences of 680 and 382 base pairs, respectively. These two sequences (GenBank accession numbers: OQ992720 and OR060666) showed 100 and 99.5% identity to the EF-1α and RPB2 of F. proliferatum A40 (GenBank accession numbers: KP964907 and KP964842). For the Petri-dish pathogenicity assay (Broders et al. 2007), five surface-sterilized seeds were placed on water agar media with either sterile water or actively growing '16-19' culture. After 7 days of incubation in a growth chamber (25°C; 12-hour photoperiod), brown lesions were observed on the roots of the inoculated plants, while no symptoms were observed in the sterile water-treated controls. The experiment was conducted three times. For root-cut pathogenicity assay, conidial suspension (1×106 conidia/ml) of the isolate '16-19' was prepared with harvested mycelia cultured on PDA for 10 days with sterile water. The roots of 10-day-old soybean seedlings were partially cut and soaked in either the suspension or sterile water for 2 hours. The seedlings were transplanted into 12 cm plastic pots (11 cm in height) and grew in a greenhouse (26 ± 3°C, 13-h photoperiod). The experiment followed a completely randomized design with three replicates (i.e. three plants in a pot), and it was repeated twice. The inoculated plants began to wilt 7 days after inoculation, while the sterile water-treated controls remained healthy. Ten days after inoculation, all plants were collected, washed under running tap water, and evaluated for the presence and severity of root rot using a 0-4 scale (Chang et al. 2015). The inoculated plants exhibited reduced vigor and developed dark brown lesions on their roots. F. proliferatum was reisolated from symptomatic root tissues of the infected plants, while not from those of the controls. Its colony and spores were morphologically identical to those of the original isolate. F. proliferatum was previously reported as a causative agent of soybean root rot in the United States (Díaz Arias et al. 2011) and Canada (Chang et al. 2015). This is the first report of soybean root rot caused by F. proliferatum in the Republic of Korea. This finding implies that F. proliferatum may potentially threaten soybean production in the Republic of Korea and suggests that effective disease management strategies should be established for soybean protection against the disease, along with continuous surveillance.

First report of soybean root rot caused by Fusarium falciforme in the Republic of Korea.

Phytopathogenic Fusarium species causing root and stem rot diseases in susceptible soybean (Glycine max (L.) Merrill) are a major threat to soybean production worldwide. Several Fusarium species have been reported to infect soybean plants in the Republic of Korea, including F. solani, F. oxysporum, F. fujikuroi, and F. graminearum (Cho et al., 2004; Choi et al., 2019; Kang et al., 2020). During the nationwide survey of soybean diseases in 2015, soybean plants showing symptoms of leaf chlorosis, wilting, and shoot death were found in soybean fields in Seosan, Chungnam. Fusarium isolates were obtained from the margins of sterilized necrotic symptomatic and asymptomatic regions of the stem tissues of diseased samples by culturing on potato dextrose agar (PDA). To examine the morphological characteristics, isolates were cultured on PDA at 25°C in the darkness for 10 days. Colonies produced white aerial mycelia with apricot pigments in the medium. Macroconidia were hyaline, slightly curved in shape with 3 or 4 septa, and their average length and width were 34.6± 0.56 µm (31.4 to 37.8 µm) and 4.7±0.16 µm (4.1 to 5.8 µm), respectively (n = 20). Microconidia were elongated, oval with 0 or 1 septum, and their average length and width were 11.4±0.87 and 5.2±0.32 µm, respectively (n = 20). The colonies and conidia exhibited morphological similarities to those of F. falciforme (Xu et al., 2022). Using the primers described by O'Donnell et al. (2008), identity of a representative strain '15-110' was further confirmed by sequencing portions of two genes, the translation elongation factor 1-alpha (EF-1α) and the second largest subunit of RNA polymerase II (RPB2). The two sequences (GenBank accession No. OQ992718 and OR060664) of 15-110 were 99% similar to those of two F. falciforme strains, 21BeanYC6-14 (GenBank accession nos. ON375419 and ON331931), and 21BeanYC6-16 (GenBank accession nos. ON697187 and ON331933). To test the pathogenicity, a single-spore isolate was cultured on carnation leaf agar (CLA) at 25℃ for 10 days. Pathogenicity test was performed by root-cutting assays using 14-day-old soybean seedlings of 'Daewon' and 'Taekwang'. Ten-day-old mycelia of 15-110 were collected from the CLA plates by scraping with distilled water, and the spore suspension was filtered and diluted to 1 × 106 conidia/mL. The roots of the soybean seedlings were partially cut and inoculated by soaking in the diluted spore suspension for two hours. The seedlings were then transplanted into 12 cm plastic pots (11 cm in height) and grown in a growth chamber at 25°C, 14h light/10h dark for 2 weeks. The infected plants exhibited wilting, observed brown discoloration on the root, and eventually died within 2 weeks, whereas the control plants inoculated with sterile water remained healthy. F. falciforme 15-110 was reisolated from infected plants, but not from the uninoculated controls. The morphology of the re-isolated fungus on PDA and its target gene sequences were identical to those of the original colony. To the best of our knowledge, this is the first report of root rot in soybean caused by F. falciforme in the Republic of Korea. Fusarium spp. induce a range of diseases in soybean plants, including root rot, damping-off, and wilt. Given the variable aggressiveness and susceptibility to fungicides among different Fusarium species, it is imperative to identify the Fusarium species posing a threat to soybean production. This understanding is crucial for developing a targeted and tailored disease management strategy to control Fusarium diseases.

An extreme case of cor triatriatum mimicking hypoplastic left heart syndrome and combined pulmonary vein stenosis.

A 65-day-old girl presented to the emergency room with lethargy, requiring emergency venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock. Initially, hypoplastic left heart syndrome was suspected. However, cor triatriatum with a pinpoint opening on the membrane was diagnosed based on a detailed echocardiographic examination. After membrane resection, the left heart size was restored. However, follow-up echocardiography performed 4 months later showed occlusion of both upper pulmonary veins and stenosis in both lower pulmonary veins. Hybrid balloon angioplasty was performed in all pulmonary veins, and stents were inserted into the right upper and lower pulmonary veins. Despite repeated balloon angioplasty, all pulmonary vein stenosis progressed over 6 months and the patient expired while waiting for a heart-lung transplant. Even after successful repair of cor triatriatum, short-term close follow-up is required for detecting the development of pulmonary vein stenosis.

Can We Control Lateral Shoulder Balance Through Proximal Thoracic Curve Correction in Lenke Type 2 Adolescent Idiopathic Scoliosis?

BACKGROUND: Proximal thoracic curve (PTC) correction has been considered to prevent lateral shoulder imbalance in Lenke Type 2 adolescent idiopathic scoliosis (AIS) patients; however, postoperative shoulder imbalance (PSI) commonly occurs despite these strategies with PTC correction. We investigated the hypothesis that PTC correction would not directly affect PSI in the majority of Lenke type 2 AIS cases. Furthermore, we investigated the risk factors for lateral PSI after corrective surgery. METHODS: This study examined the records for AIS patients with Lenke type 2 who underwent corrective surgery and followed up for >2 years. Patients were categorized into PSI (-); radiologic shoulder height (RSH)<15 mm, and PSI (+); RSH≥15 mm. Repeated measures analysis of variance was performed at preoperatively, postoperatively, 1 month, and final follow-up. Postoperative lateral shoulder imbalance was predicted by the identification of univariate analysis and multivariate analysis. RESULTS: Among the 151 patients reviewed, 29 (19.2%) showed PSI at final follow-up. Lateral shoulder balance parameters showed different directionalities between PSI (-) and (+) groups at postoperatively, 1 month, and final follow-up ( P <0.01 each). Preoperative PTC, middle thoracic curve (MTC) curve and MTC correction showed strong correlations with the RSH ( P =0.01, 0.03, and 0.04, respectively). However, PTC correction did not show a significant correlation with the RSH. Moreover, only a smaller MTC curve and larger MTC correction rate were related to lateral PSI in multivariate analysis. CONCLUSIONS: In Lenke type 2 AIS curves, the MTC curve and its correction predominantly influence lateral shoulder imbalance after corrective surgery, irrespective of the PTC correction extent. Consequently, overemphasizing the correction of the PTC curve may not necessarily lead to an improved lateral shoulder balance. When MTC curve is smaller, surgeons should be more careful for MCT overcorrection leading to a lateral shoulder imbalance. LEVEL OF EVIDENCE: Level III.

CD133-containing microvesicles promote cancer progression by inducing M2-like tumor-associated macrophage polarization in the tumor microenvironment of colorectal cancer.

Tumor-associated macrophages (TAMs) are among the most abundant cell types in the tumor microenvironment (TME). The immunosuppressive TME formed by TAMs is an essential prerequisite for cancer progression. Tumor-derived microvesicles (MVs), a subtype of extracellular vesicle shed directly from the plasma membrane, are important regulators of intercellular communication and TME modulation during tumorigenesis. However, the exact mechanism by which tumor-derived MVs induce the generation of the immunosuppressive TME and polarization of TAMs remains unclear. Here, we investigated the role of CD133-containing MVs derived from colorectal cancer (CRC) cells in macrophage polarization and cancer progression. CD133-containing MVs from CRC cells were incorporated into macrophages, and M0 macrophages were morphologically transformed into M2-like TAMs. CD133-containing MVs were found to increase the mRNA expression of M2 macrophage markers. Additionally, cytokine array analysis revealed that M2-like TAMs induced by CD133-containing MVs increased the secretion of interleukin 6, which activated the STAT3 pathway in CRC cells. Furthermore, the conditioned medium of M2-like TAMs promoted cell motility, epithelial-mesenchymal transition, and cell proliferation. However, MVs from CD133-knockdown cells had little effect on TAM polarization and CRC progression. These results demonstrate that CD133-containing MVs induce M2-like TAM polarization and contribute to cancer progression by mediating crosstalk between tumor cells and TAMs in the TME of CRC.

Antidiabetic Effect of Fermented Mesembryanthemum crystallinum L. in db/db Mice Involves Regulation of PI3K-Akt Pathway.

Type 2 diabetes (T2D) is a serious health issue with increasing incidences worldwide. However, current medications have limitations due to side effects such as decreased appetite, stomach pain, diarrhea, and extreme tiredness. Here, we report the effect of fermented ice plant (FMC) in the T2M mouse model of db/db mice. FMC showed a greater inhibition of lipid accumulation compared to unfermented ice plant extract. Two-week oral administration with FMC inhibited body weight gain, lowered fasting blood glucose, and improved glucose tolerance. Serum parameters related to T2D including insulin, glycosylated hemoglobin, adiponectin, and cholesterols were improved as well. Histological analysis confirmed the protective effect of FMC on pancreas and liver destruction. FMC treatment significantly increased the expression and phosphorylation of IRS-1, PI3K, and AKT. Additionally, AMP-activated protein kinase phosphorylation and nuclear factor erythroid 2-related factor 2 were also increased in the liver tissues of db/db mice treated with FMC. Overall, our results indicate the anti-diabetic effect of FMC; therefore, we suggest that FMC may be useful as a therapeutic agent for T2D.

Cardiovascular Characteristics and Progressions of Hypertrophic Cardiomyopathy and Pulmonary Stenosis in RASopathy Syndrome in the Genomic Era.

INTRODUCTION: To investigate cardiovascular characteristics and progressions of hypertrophic cardiomyopathy (HCM) and pulmonary stenosis (PS) and determine whether any genotype-phenotype correlations exist in patients with gene-confirmed RASopathy syndrome. STUDY DESIGN: Eighty patients (male, 55%) confirmed as having RASopathy syndrome by genetic testing at a single tertiary center were enrolled. Subjects' medical and echocardiography records were reviewed and the changes in the z scores of left ventricular wall thickness (LVWT) and the degree of PS over time were examined during follow-up of 5.7 ± 3.1 and 7.5 ± 5.2 years, respectively. RESULTS: The most common RASopathy gene identified was PTPN11 (56%), followed by RAF1 (10%). Eighty-five percent of patients had cardiovascular diseases, wherein 42% had HCM, and 38% PS. Mean maximal LVWT z score on the initial echocardiography (mean age 5.0 ± 6.0 years) was 3.4 ± 1.3 (median 2.8, range 2.1-6.6) in the HCM group. Overall, the maximal LVWT increased with time, especially in the HCM group (z = 3.4 ± 1.3 to 3.7 ± 1.6, P = .008) and RAF1-variant group (z = 3.7 ± 1.7 to 4.6 ± 1.8, P = .031). Five patients newly developed HCM during the study period. Genotype-phenotype correlation was significant for HCM (P = .002); 31% of patients with PTPN11 and 88% with RAF1 variants had HCM. PS did not progress in this study cohort. CONCLUSIONS: In this study, progression of ventricular hypertrophy was seen in a significant number of patients with genotype correlation. Thus, long-term follow up of cardiovascular problems in patients with RASopathy is necessary.

Noncanonical mode of ERK action controls alternative αß and γδ T cell lineage fates.

Gradations in extracellular regulated kinase (ERK) signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid-fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as RSK, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of γδ T cells. Instead, development of γδ T cells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the γδ fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes.

Prognostic significance of location index in resected T1-sized early-stage non-small cell lung cancer.

BACKGROUND: While the central location is a known adverse prognostic factor in lung cancer, a precise definition of central lung cancer has not yet emerged. PURPOSE: To determine the prognostic significance of central lung cancer (defined by location index) in resected T1-sized early-stage non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients with resected T1-sized early-stage NSCLC between 2010 and 2015 at a single tertiary cancer center were retrospectively reviewed. Central lung cancer was defined by a location index of the second tertile or less. Kaplan-Meier analysis with log-rank test and multivariable Cox regression analysis were performed to analyze the relationship between central lung cancer and the prognosis of relapse-free survival (RFS) and overall survival (OS). Inter-observer agreement was assessed using Cohen's kappa value and intraclass correlation coefficient (ICC). RESULTS: Overall, 289 patients (169 men; median age 65 years; interquartile range 58-70 years) were evaluated. Central lung cancer (defined by location index) was adversely associated with RFS (P = 0.005) and OS (P = 0.01). Multivariable Cox regression analysis showed that central lung cancer was independently associated with poor RFS (adjusted hazard ratio 1.91; 95% confidence interval [CI] 1.12-3.24; P = 0.017) and OS (adjusted hazard ratio 1.69; 95% CI 1.04-2.74; P = 0.033). Location index demonstrated excellent inter-observer agreement (Cohen's kappa value 0.88; 95% CI 0.82-0.93) with a high ICC (0.98; 95% CI 0.97-0.98). CONCLUSION: Central lung cancer defined by a location index of the second tertile or lower is an independent adverse prognostic factor in resected T1-sized early-stage NSCLC.

Risk factors for postoperative complaints in patients following lumbar decompression and fusion: Analyses focusing on preoperative symptoms.

BACKGROUND: Several patients complained of residual symptoms following lumbar decompressive surgery for lumbar degenerative disease (LDD). However, few studies analyze this dissatisfaction by focusing on preoperative patients' symptoms. This study was conduct to determine the factors that could predict the patients' postoperative complaints by focusing on their preoperative symptoms. METHODS: Four hundred and seventeen consecutive patients who underwent lumbar decompression and fusion surgery for LDD were included. Postoperative complaint was defined by at least twice same complaint during the outpatient follow-up of 6,12, 18 and 24 months after surgery. A comparative analysis was performed between complaint group (group C, N = 168) and non-complaint group (group NC, N = 249). Demographic, operative, symptomatic, and clinical factors were compared between the groups by univariate and multivariate analyses. RESULTS: The main preoperative chief complaints were radiating pain (318/417, 76.2%). However, most common postoperative complaint was residual radiating pain (60/168, 35.7%) followed by tingling sensation (43/168, 25.6%). The presence of psychiatric disease (adjusted odds ratio [aOR], 4.666; P = 0.017), longer pain duration (aOR, 1.021; P < 0.001), pain to below the knee (aOR, 2.326; P = 0.001), preoperative tingling sensation (aOR, 2.631; P < 0.001), preoperative sensory and motor power decrease (aOR, 2.152 and 1.678; P = 0,047 and 0.011, respectively) were significantly correlated with postoperative patients' complaints in multivariate analysis. CONCLUSIONS: The postoperative patients' complaints could be predicted and explained in advance by checking the preoperative characteristics of patients' symptoms, including the duration and site carefully. This could be helpful to enhance the understanding of the surgical results preoperatively, which could control the anticipation of the patients.

Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) has one of the highest mortality rates among solid cancers. Late diagnosis and a lack of efficacious treatment options contribute to the dismal prognosis of HCC. Immune checkpoint inhibitor (ICI)-based immunotherapy has presented a new milestone in the treatment of cancer. Immunotherapy has yielded remarkable treatment responses in a range of cancer types including HCC. Based on the therapeutic effect of ICI alone (programmed cell death (PD)-1/programmed death-ligand1 (PD-L)1 antibody), investigators have developed combined ICI therapies including ICI + ICI, ICI + tyrosine kinase inhibitor (TKI), and ICI + locoregional treatment or novel immunotherapy. Although these regimens have demonstrated increasing treatment efficacy with the addition of novel drugs, the development of biomarkers to predict toxicity and treatment response in patients receiving ICI is in urgent need. PD-L1 expression in tumor cells received the most attention in early studies among various predictive biomarkers. However, PD-L1 expression alone has limited utility as a predictive biomarker in HCC. Accordingly, subsequent studies have evaluated the utility of tumor mutational burden (TMB), gene signatures, and multiplex immunohistochemistry (IHC) as predictive biomarkers. In this review, we aim to discuss the current state of immunotherapy for HCC, the results of the predictive biomarker studies, and future direction.

Cell Proliferation Receptor-Enhanced 3D High-Throughput Screening Model for Optimized Drug Efficacy Evaluation in Breast Cancer Cells.

A higher correlation of epidermal growth factor receptor (EGFR)-targeting drugs has been reported with the use of the cell proliferation receptor-enhanced three-dimensional high-throughput screening model (CPRE 3D-HTS model) compared with two-dimensional (2D) cell-based HTS. A greater expression of differential human EGFR 2 (HER2) protein between HER2-positive and HER2-negative cell lines was observed in breast cancer (BC) cell lines cultured using the CPRE 3D-HTS model compared with 2D-cultured cells. When using 2D-cultured cells, properties such as the expression of the cell proliferation receptor are lost as the cells attach to the bottom of the well plate. In an effort to solve this problem, the CPRE 3D-HTS model expressing high cell proliferation receptors was optimized by the selection of alginate as the extracellular matrix. Results from the use of the CPRE 3D-HTS model showed higher drug resistance with increased expression of drug resistance-related proteins. Of particular interest, a higher correlation of HER2-targeted drugs was observed with the use of the CPRE 3D-HTS model. In order to validate this higher correlation of target drugs observed in the CPRE 3D-HTS model, the results of Western blot analysis and high content imaging analysis were analyzed, which confirmed that 3D-cultured BC cell lines showed a greater difference in the expression of HER2-positive and HER2-negative BC cell lines than 2D-cultured cells. Thus, the use of CPRE 3D-HTS using a 384-pillar plate resulted in increased accuracy when screening HER2-targeted drugs in BC, and it is a very useful platform for analyzing the efficacy of targeted drugs by enhancing the expression of HER2.

Simplified in vitro 3D co-culture-based blood-brain barrier model using transwell.

The blood-brain barrier (BBB) is a major hurdle for treatment of brain diseases. To overcome this, precise and reproducible BBB model is one of the key factors for successful evaluation of BBB-penetrating efficacy of developmental drugs. Thus, in vitro BBB model recapitulating the physiological structure of the BBB is a valuable tool for drug discovery and development for brain diseases. Here, we develop a simplified 3D co-culture-based BBB model using immortalized human brain endothelial cells and immortalized human astrocytes mixed with Matrigel allowing model preparation within 30 min. We directly compare our 3D BBB model to a 2D BBB model comprised solely of immortalized brain endothelial cells, to demonstrate that our 3D BBB model blocks penetration of Dextran molecules with various molecular weights, remain durable and impermeable even in a BBB-degrading condition, and rapidly form tight junctions while the 2D BBB model do not. In conclusion, this establishes our simplified 3D BBB model as a valuable tool for high throughput screening of drug candidates for brain diseases.