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BackgroundPrevious studies have identified three single nucleotide polymorphisms (SNPs): GALNT14-rs9679162, WWOX-rs13338697 and rs6025211. Their genotypes are associated with therapeutic outcomes in hepatocellular carcinoma (HCC). Herein, we examined whether these SNP genotypes could predict the clinical outcome of HCC patients treated with ADI-PEG 20.MethodsTotally 160 patients with advanced HCC, who had previously been enrolled in clinical trials, including 113 receiving ADI-PEG 20 monotherapy (cohort-1) and 47 receiving FOLFOX/ADI-PEG 20 combination treatment (cohort-2), were included retrospectively.ResultsThe WWOX-rs13338697-GG genotype was associated with favorable overall survival in cohort-1 patients (P = 0.025), whereas the rs6025211-TT genotype was associated with unfavorable time-to-tumor progression in cohort-1 (P = 0.021) and cohort-1 plus 2 patients (P = 0.008). As ADI-PEG 20 can reduce plasma arginine levels, we examined its pretreatment levels in relation to the WWOX-rs13338697 genotypes. Pretreatment plasma arginine levels were found to be significantly higher in patients carrying the WWOX-rs13338697-GG genotype (P = 0.006). We next examined the association of the WWOX-rs13338697 genotypes with WWOX tissue protein levels in 214 paired (cancerous/noncancerous) surgically resected HCC tissues (cohort-3). The WWOX-rs13338697-GG genotype was associated with decreased tissue levels of WWOX and ASS1. Mechanistic studies showed that WWOX and ASS1 levels were downregulated in hypoxic HCC cells. Silencing WWOX to mimic low WWOX protein expression in HCC in patients with the WWOX-rs13338697-GG genotype, enhanced HIF1A increment under hypoxia, further decreased ASS1, and increased cell susceptibility to ADI-PEG 20.ComclusionIn summary, the WWOX-rs13338697 and rs6025211 genotypes predicted treatment outcomes in ADI-PEG 20-treated advanced HCC patients. The WWOX-rs13338697-GG genotype was associated with lower tissue WWOX and ASS1 levels and higher pretreatment plasma arginine levels, resembling an arginine auxotrophic phenotype requires excessive extracellular arginine supply. Silencing WWOX to mimic HCC with the WWOX-rs13338697-GG genotype further stimulated HCC cell response to hypoxia through increased HIF1A expression, leading to further reduction of ASS1 and thus increased cell susceptibility to ADI-PEG 20.

This paper proposes a novel hybrid equalizer circuit (HEC) for a battery management system (BMS) to implement the passive HEC (P-HEC), active HEC (A-HEC), or active/passive (AP-HEC) with the same equalizer circuit architecture. The advantages of an HEC are that it is simple, cost-effective, highly energy efficient, and fail safe. The P-HEC can further use a cooling fan or heater instead of a conventional resistor as a power dissipation element to convert the energy of the waste heat generated by the resistor to adjust the battery temperature. Even if the P-HEC uses the resistor to consume energy as in conventional methods, the P-HEC still dramatically improves the component lifetime and reliability of the BMS because the waste heat generated by the equalizer resistor is outside of the BMS board. Three significant advantages of an A-HEC are its (1) low cost, (2) small volume, and (3) higher energy efficiency than the conventional active equalizer circuits (AECs). In the HEC design, the MOSFETs of the switch array do not need high-speed switching to transfer energy as conventional AECs with DC/DC converter architecture because the A-HEC uses an isolated battery charger to charge the string cell. Therefore, the switch array is equal to a cell selector with a simple ON/OFF function. In summary, the HEC provides a small volume, cost-effective, high efficiency, and fail-safe equalizer circuit design to satisfy cell balancing demands for all kinds of electric vehicles (EVs) and energy storage systems (ESSs).

Background: In head and neck squamous cell carcinoma (HNSCC), invasiveness and metastasis of cancer cells contribute to make this insidious disease a major cause of mortality. Epithelial-mesenchymal transition (EMT) is generally considered to be the major mechanism of cancer metastasis. We previously demonstrated the crucial role of the EMT regulator Twist1 in HNSCC. A growing body of evidence suggests that microRNAs play essential roles in cancer progression and metastasis. The aim of this study was to investigate the role of microRNA in Twist1-mediated cancer metastasis. Materials and methods: The HNSCC cell lines FaDu, SAS, OECM1 and CAL-27, were used in this study. Quantitative RT-PCR for microRNAs and Western blot were performed on four HNSCC cell lines to study the molecular mechanisms involved. Results: Expression of the miR-29 family, including miR-29a, b, and c were increased in Twist1-overexpressing HNSCC cells. Furthermore, we discovered that SIN3A, a co-repressor of another EMT regulator Snail, is a target of miR-29s. With our results, we demonstrated that Twist1 modifies the function of gene expression through microRNA machinery. Conclusion: We herein have delineated the regulatory mechanism of the Twist1-miR29-SIN3A axis in HNSCC.

A chromosome is the structure that organizes DNA and protein in cells. It is a single piece of coiled DNA containing coding and non-coding sequences. Human cells have 23 pairs of chromosomes including 22 pairs of autosomes and one pair of sex chromosome, giving a total of 46 per cell. In tumor cells, chromosomal instability has been considered to be one of the hallmarks of tumor formation. Here we use the karyotype analysis to separate the chromosomes and observe the chromosomes in tumor cells with a microscope.

This paper investigates a novel joint problem of routing, scheduling, and channel allocation for single-radio multichannel wireless mesh networks in which multiple channel widths can be adjusted dynamically through a new software technology so that more concurrent transmissions and suppressed overlapping channel interference can be achieved. Although the previous works have studied this joint problem, their linear programming models for the problem were not incorporated with some delicate constraints. As a result, this paper first constructs a linear programming model with more practical concerns and then proposes a simulated annealing approach with a novel encoding mechanism, in which the configurations of multiple time slots are devised to characterize the dynamic transmission process. Experimental results show that our approach can find the same or similar solutions as the optimal solutions for smaller-scale problems and can efficiently find good-quality solutions for a variety of larger-scale problems.

Chromosomal instability (CIN) is widely considered a hallmark of cancer, but its precise roles in cancer stem cells (CSC) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin-modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis, and poor prognosis. Here, we report that BMI1 mediates its diverse effects through upregulation of the mitotic kinase Aurora A, which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the b-catenin/TCF4 transcription factor complex. Second, BMI1 repressed miRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let- 7i suppression. AURKA upregulation by BMI1 exerts several effects, including centrosomal amplification and aneuploidy, antiapoptosis, and cell-cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting Aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that coamplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT, and CIN through the BMI1-AURKA axis and suggest therapeutic use from inhibiting Aurora A in head and neck cancers, which overexpress BMI1. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogram-ming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through avb3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC. [ABSTRACT FROM AUTHOR]