Various cancer stem cell (CSC) biomarkers have been identified for hepatocellular carcinoma (HCC), but little is known about the implications of heterogeneity and shared molecular networks within the CSC population. Through miRNA profile analysis in an HCC cohort (n ¼ 241) for five groups of CSC þ HCC tissues, i.e., EpCAM þ , CD90 þ , CD133 þ , CD44 þ , and CD24 þ HCC, we identified a 14-miRNA signature commonly altered among these five groups of CSC þ HCC. miR-192-5p, the top-ranked CSC miRNA, was liver-abundant and-specific and markedly downregulated in all five groups of CSC þ HCC from two independent cohorts (n ¼ 613). Suppressing miR-192-5p in HCC cells significantly increased multiple CSC populations and CSC-related features through targeting PABPC4. Both TP53 mutation and hypermethylation of the mir-192 promoter impeded transcriptional activation of miR-192-5p in HCC cell lines and primary CSC þ HCC. This study reveals the circuit from hypermethylation of the mir-192 promoter through the increase in PABPC4 as a shared genetic regulatory pathway in various groups of primary CSC þ HCC. This circuit may be the driver that steers liver cells toward hepatic CSC cells, leading to hepatic carcinogenesis. Significance: miR-192-5p and its regulatory pathway is significantly abolished in multiple groups of HCC expressing high levels of CSC markers, which may represent a key event for hepatic carcinogenesis.

Background and Aims Transarterial chemoembolization (TACE) is a standard locoregional therapy for patients with hepatocellular carcinoma (HCC) patients with a variable overall response in efficacy. We aimed to identify key molecular signatures and related pathways leading to HCC resistance to TACE, with the hope of developing effective approaches in preselecting patients with survival benefit from TACE. Approach and Results Four independent HCC cohorts with 680 patients were used. MicroRNA (miRNA) transcriptome analysis in patients with HCC revealed a 41‐miRNA signature related to HCC recurrence after adjuvant TACE, and miR‐125b was the top reduced miRNA in patients with HCC recurrence. Consistently, patients with HCC with low miR‐125b expression in tumor had significantly shorter time to recurrence following adjuvant TACE in two independent cohorts. Loss of miR‐125b in HCC noticeably activated the hypoxia inducible factor 1 alpha subunit (HIF1α)/pAKT loop in vitro and in vivo. miR‐125b directly attenuated HIF1α translation through binding to HIF1A internal ribosome entry site region and targeting YB‐1, and blocked an autocrine HIF1α/platelet‐derived growth factor β (PDGFβ)/pAKT/HIF1α loop of HIF1α translation by targeting the PDGFβ receptor. The miR‐125b‐loss/HIF1α axis induced the expression of CD24 and erythropoietin (EPO) and enriched a TACE‐resistant CD24‐positive cancer stem cell population. Consistently, patients with high CD24 or EPO in HCC had poor prognosis following adjuvant TACE therapy. Additionally, in patients with HCC having TACE as their first‐line therapy, high EPO in blood before TACE was also noticeably related to poor response to TACE. Conclusions MiR‐125b loss activated the HIF1α/pAKT loop, contributing to HCC resistance to TACE and the key nodes in this axis hold the potential in assisting patients with HCC to choose TACE therapy.

The electron temperature gradient ͑ETG͒ mode, which is believed to be one of the strongest candidates for the anomalous electron energy transport in plasmas, is difficult to detect in experiments because of its high frequency ͑ϳMHz͒ and short wavelength ͑k Ќ e Յ 1͒. Using a dc bias heating scheme of the core plasma, we are able to produce a sufficiently strong ETG for exciting ETG modes in the Columbia linear machine ͓R. Scarmozzino, A. K. Sen, and G. A. Navratil, Phys. Fluids 31, 1773 ͑1988͔͒. A high frequency mode at ϳ2 MHz, with azimuthal wave numbers m ϳ 14-16 and parallel wave number k ʈ ϳ 0.01 cm −1 , has been observed. The frequency range is consistent with the result of a kinetic dispersion relation of slab ETG modes with appropriate E ៝ ϫ B ៝ Doppler shift. The scaling of its fluctuation level with the temperature gradient scale length and the radial structure are found to be roughly consistent with theoretical expectations. Therefore, this is one of the first direct definitive identifications of ETG modes.

Transarterial chemoembolization (TACE) is a commonly used treatment modality in hepatocellular carcinoma (HCC). The ability to identify patients who will respond to TACE represents an important clinical need, and tumor gene expression patterns may be associated with TACE response. We investigated whether tumor transcriptome is associated with TACE response in patients with HCC. We analyzed transcriptome data of treatment-naïve tumor tissues from a Chinese cohort of 191 HCC patients, including 105 patients who underwent TACE following resection with curative intent. We then developed a gene signature, TACE Navigator, which was associated with improved survival in patients that received either adjuvant or post-relapse TACE. To validate our findings, we applied our signature in a blinded manner to three independent cohorts comprising an additional 130 patients with diverse ethnic backgrounds enrolled in three different hospitals who received either adjuvant TACE or palliative TACE.TACE Navigator stratified patients into Responders and Non-Responders which was associated with improved survival following TACE in our test cohort (Responders: 67 months vs Non-Responders: 39.5 months, p<0.0001). In addition, multivariable Cox model demonstrates that TACE Navigator was independently associated with survival (HR: 9.31, 95% CI: 3.46-25.0, p<0.001). In our validation cohorts, the association between TACE Navigator and survival remained robust in both Asian patients who received adjuvant TACE (Hong Kong: 60 months vs 25.6 months p=0.007; Shandong: 61.3 months vs 32.1 months, p=0.027) and European patients who received TACE as primary therapy (Mainz: 60 months vs 41.5 months, p=0.041). These results indicate that a TACE-specific molecular classifier is robust in predicting TACE response. This gene signature can be used to identify patients who will have the greatest survival benefit after TACE treatment and enable personalized treatment modalities for patients with HCC.

The role of self-generated zonal flows (ZF) in transport regulation in magnetic confinement devices via its shear is a potent concept and a physics issue. However, as the experimental evidence of its existence in tokamaks is meagre, a basic physics experimental study of ZF associated with ion temperature gradient (ITG) drift modes has been performed in the Columbia Linear Machine. The difficult problem of detection of ZF has been solved via a novel diagnostic using the paradigm of frequency modulation (FM) in radio transmission. Using this and discrete short time Fourier transform, we find a power spectrum peak at ITG ('carrier') frequency of ∼120 kHz and FM sidebands at frequency of ∼2 kHz, which is identified as a ZF. It has all the signatures of a ZF: a potential at near zero frequency and poloidal symmetry (m = 0), toroidal symmetry (k = 0) and radial variations only. The results roughly agree with theoretical estimates given here.