Hepatic resection is the most curative treatment option for early‐stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. ...Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early‐stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high‐copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer‐specific and recurrence‐free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). Conclusion: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti‐FGF19 treatment in these patients. (Hepatology 2014;60:1971–1981)
Organic light-emitting diodes (OLEDs) are remarkably promising display devices that can function in mechanically flexible configurations on a plastic substrate due to various compelling properties, ...including organic constituents, ultrathin and simple structure, and low-temperature fabrication. In spite of successful demonstrations of flexible OLEDs, some technical issues of containing relatively thick transparent electrodes made of ceramic materials and an unstable flexible encapsulation system have impeded reaching high levels of reliability and durability toward full commercialization. This review covers recent developments in structure designs for highly durable flexible OLEDs, ranging from alternative transparent electrodes to thin-film encapsulation layers, in which solution concepts for the existing critical issues of flexible OLEDs are addressed. Emerging unusual substrates and their application strategies are additionally introduced to find intimations of future display technologies and hence to disclose nonclassic flexible OLEDs.
The development of sustainable oxidation chemistry demands strategies to harness O
as a terminal oxidant. Oxidase catalysis, in which O
serves as a chemical oxidant without necessitating ...incorporation of oxygen into reaction products, would allow diverse substrate functionalization chemistry to be coupled to O
reduction. Direct O
utilization suffers from intrinsic challenges imposed by the triplet ground state of O
and the disparate electron inventories of four-electron O
reduction and two-electron substrate oxidation. Here, we generate hypervalent iodine reagents-a broadly useful class of selective two-electron oxidants-from O
. This is achieved by intercepting reactive intermediates of aldehyde autoxidation to aerobically generate hypervalent iodine reagents for a broad array of substrate oxidation reactions. The use of aryl iodides as mediators of aerobic oxidation underpins an oxidase catalysis platform that couples substrate oxidation directly to O
reduction. We anticipate that aerobically generated hypervalent iodine reagents will expand the scope of aerobic oxidation chemistry in chemical synthesis.
This paper presents a deep learning method for faster magnetic resonance imaging (MRI) by reducing k-space data with sub-Nyquist sampling strategies and provides a rationale for why the proposed ...approach works well. Uniform subsampling is used in the time-consuming phase-encoding direction to capture high-resolution image information, while permitting the image-folding problem dictated by the Poisson summation formula. To deal with the localization uncertainty due to image folding, a small number of low-frequency k-space data are added. Training the deep learning net involves input and output images that are pairs of the Fourier transforms of the subsampled and fully sampled k-space data. Our experiments show the remarkable performance of the proposed method; only 29 of the k-space data can generate images of high quality as effectively as standard MRI reconstruction with the fully sampled data.
Purpose
To enhance the visibility of nigrosome 1 in substantia nigra, which has recently been suggested as an imaging biomarker for Parkinson's disease (PD) at 3T magnetic resonance imaging (MRI).
...Materials and Methods
The substantia nigra structure was visualized at 3T MRI using multiecho susceptibility map‐weighted imaging (SMWI) in 15 healthy volunteers and 6 patients with Parkinson's disease (PD). The visibility of nigrosome 1 was further enhanced by acquiring data in an oblique‐coronal imaging plane at a high spatial resolution (0.5 × 0.5 × 1.0 mm3). To compare the visibility, the contrast‐to‐noise ratios (CNR) of the nigrosome 1 structure relative to the neighboring substantia nigra structure were evaluated in the SMWI and other conventional susceptibility contrast images (magnitude, frequency, quantitative susceptibility map QSM and susceptibility‐weighted image).
Results
In healthy volunteers, the CNRs of the nigrosome 1 structure were 1.04 ± 0.38, 0.84 ± 0.32, 1.04 ± 0.40, 0.86 ± 0.41, and 1.45 ± 0.48 for magnitude, frequency, quantitative susceptibility map, susceptibility‐weighted image, and SMWI, respectively. Compared to conventional susceptibility contrast images, the SMWI method significantly improved the CNR of nigrosome 1 (P = 0.014 for magnitude, P = 0.030 for QSM, and P < 0.001 for frequency and SWI, respectively). The magnetic susceptibility difference between nigrosome 1 and neighboring substantia nigra structures was 0.037 ± 0.016 ppm (measured in QSM, P < 0.001) in healthy volunteers. In the PD patients, the visibility of the nigrosome 1 structures was reduced.
Conclusion
The SMWI method enhances the visibility of nigrosome 1 structures at 3T MRI when compared to conventional susceptibility contrast images.
Level of Evidence: 3
Technical Efficacy: Stage 2
J. MAGN. RESON. IMAGING 2017;46:528–536
Hypervalent iodine(V) reagents, such as Dess–Martin periodinane (DMP) and 2‐iodoxybenzoic acid (IBX), are broadly useful oxidants in chemical synthesis. Development of strategies to generate these ...reagents from dioxygen (O2) would immediately enable use of O2 as a terminal oxidant in a broad array of substrate oxidation reactions. Recently we disclosed the aerobic synthesis of I(III) reagents by intercepting reactive oxidants generated during aldehyde autoxidation. In this work, aerobic oxidation of iodobenzenes is coupled with disproportionation of the initially generated I(III) compounds to generate I(V) reagents. The aerobically generated I(V) reagents exhibit substrate oxidation chemistry analogous to that of DMP. The developed aerobic generation of I(V) has enabled the first application of I(V) intermediates in aerobic oxidation catalysis.
Aerobic oxidation of iodobenzenes is coupled with disproportionation of iodine(III) compounds to generate iodine(V) reagents. The aerobically generated iodine(V) reagents exhibit substrate oxidation chemistry analogous to that of Dess–Martin periodinane. Examples of aerobic oxidation catalyzed by the hypervalent iodine species include coupling of O2 reduction with oxidation of alcohols, diols, and amines.
Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the ...host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut–hepatic–brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy.
A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and ...programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68
macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (
< 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8
T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4
and CD8
T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8
T cells in HCC.
Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling ...human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development.
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•hMGEOs and hCOs recapitulate human brain organization and fetal brain transcriptomes•Transcriptome and chromatin accessibility distinguish hMGEOs and hCOs•hMGEOs and hCOs display activity-dependent and synchronized calcium oscillations•Interneurons migrate from hMGEOs and functionally integrate in hCOs
Xiang and colleagues report a method for generating human medial ganglionic eminence (MGE)-like organoids (hMGEOs) and cortical-like organoids (hCOs), which resemble the developing human MGE and cortex, respectively. By fusing hMGEOs and hCOs, they establish a 3D model to investigate human interneuron migration.
TAGLN is an actin-binding protein family that comprises three isoforms with theorized roles in smooth muscle differentiation, tumour development, lymphocyte activation, and brain chemistry. However, ...their fundamental characteristics in regulation of the actin-based cytoskeleton are not fully understood. Here we show that TAGLN2 (including TAGLN1 and TAGLN3) extensively nucleates G-actin polymerization under low-salt conditions, where polymerization would be completely suppressed. The calponin homology domain and actin-binding loop are essential to mechanically connect two adjacent G-actins, thereby mediating multimeric interactions. However, TAGLN2 blocked the Arp2/3 complex binding to actin filaments under physiological salt conditions, thereby inhibiting branched actin nucleation. In HeLa and T cells, TAGLN2 enhanced filopodium-like membrane protrusion. Collectively, the dual functional nature of TAGLN2-G-actin polymerization and Arp2/3 complex inhibition-may account for the mechanisms of filopodia development at the edge of Arp2/3-rich lamellipodia in various cell types.
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