Extended-p+ Stepped Gate (ESG) LDMOS for Improved Performance

In this paper, we propose a new Extended-p+ Stepped Gate (ESG) thin film SOI LDMOS with an extended-p+ region beneath the source and a stepped gate structure in the drift region of the LDMOS. The hole current generated due to impact ionization is now collected from an n+p+ junction instead of an n+p junction thus delaying the parasitic BJT action. The stepped gate structure enhances RESURF in the drift region, and minimizes the gate-drain capacitance. Based on two-dimensional simulation results, we show that the ESG LDMOS exhibits approximately 63% improvement in breakdown voltage, 38% improvement in on-resistance, 11% improvement in peak transconductance, 18% improvement in switching speed and 63% reduction in gate-drain charge density compared with the conventional LDMOS with a field plate.Comment: Journal Pape

Engineered Bivalent Ligands to Bias ErbB Receptor-mediated Signaling and Phenotypes

The ErbB receptor family is dysregulated in many cancers, and its therapeutic manipulation by targeted antibodies and kinase inhibitors has resulted in effective chemotherapies. However, many malignancies remain refractory to current interventions. We describe a new approach that directs ErbB receptor interactions, resulting in biased signaling and phenotypes. Due to known receptor-ligand affinities and the necessity of ErbB receptors to dimerize to signal, bivalent ligands, formed by the synthetic linkage of two neuregulin-1β (NRG) moieties, two epidermal growth factor (EGF) moieties, or an EGF and a NRG moiety, can potentially drive homotypic receptor interactions and diminish formation of HER2-containing heterodimers, which are implicated in many malignancies and are a prevalent outcome of stimulation by native, monovalent EGF, or NRG. We demonstrate the therapeutic potential of this approach by showing that bivalent NRG (NN) can bias signaling in HER3-expressing cancer cells, resulting in some cases in decreased migration, inhibited proliferation, and increased apoptosis, whereas native NRG stimulation increased the malignant potential of the same cells. Hence, this new approach may have therapeutic relevance in ovarian, breast, lung, and other cancers in which HER3 has been implicated

Essential function for ErbB3 in breast cancer proliferation

The overexpression of the ErbB family of tyrosine kinase receptors is thought to be important in the development of many breast tumours. To date, most attention has focused on the ErbB2 receptor. Now, in a recent report, it has been shown that ErbB3 is a critical partner for the transforming activity of ErbB2 in breast cancer cells. Importantly, the proliferative signals from this transforming complex appear to act via the PI-3 kinase pathway

Stabilization of ribozyme-like cis-noncoding rRNAs induces apoptotic and nonapoptotic death in lung cells

Bidirectional non-protein-coding RNAs are ubiquitously transcribed from the genome. Convergent sense and antisense transcripts may regulate each other. Here, we examined the convergent cis-noncoding rRNAs (nc-rRNAs) in A5 and E9 lung cancer models. Sense nc-rRNAs extending from rDNA intergenic region to internal transcribed spacer of around 10 kb in length were identified. nc-rRNAs in sense direction exhibited in vitro characteristics of ribozymes, namely, degradation upon incubation with MgCl2 and stabilization by complementary oligonucleotides. Detection of endogenous cleavage-ligation products carrying internal deletion of hundreds to thousands nucleotides by massively parallel sequencing confirmed the catalytic properties. Transfection of oligonucleotides pairing with antisense nc-rRNAs stabilized both target and complementary transcripts, perturbed rRNA biogenesis, and induced massive cell death via apoptotic and/or nonapoptotic mechanisms depending on cell type and treatment. Oligonucleotides targeting cellular sense transcripts are less responsive. Spontaneously detached cells, though rare, also showed accumulation of nc-rRNAs and perturbation of rRNA biogenesis. Direct participation of nc-rRNAs in apoptotic and nonapoptotic death was demonstrated by transfection of synthetic nc-rRNAs encompassing the rDNA promoter. In sum, convergent cis-nc-rRNAs follow a feed-forward mechanism to regulate each other and rRNA biogenesis. This opens an opportunity to disrupt rRNA biogenesis, commonly upregulated in cancers, via inhibition of ribozyme-like activities in nc-rRNAs

A Neutralizing RNA Aptamer against EGFR Causes Selective Apoptotic Cell Death

Nucleic acid aptamers have been developed as high-affinity ligands that may act as antagonists of disease-associated proteins. Aptamers are non immunogenic and characterised by high specificity and low toxicity thus representing a valid alternative to antibodies or soluble ligand receptor traps/decoys to target specific cancer cell surface proteins in clinical diagnosis and therapy. The epidermal growth factor receptor (EGFR) has been implicated in the development of a wide range of human cancers including breast, glioma and lung. The observation that its inhibition can interfere with the growth of such tumors has led to the design of new drugs including monoclonal antibodies and tyrosine kinase inhibitors currently used in clinic. However, some of these molecules can result in toxicity and acquired resistance, hence the need to develop novel kinds of EGFR-targeting drugs with high specificity and low toxicity. Here we generated, by a cell-Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach, a nuclease resistant RNA-aptamer that specifically binds to EGFR with a binding constant of 10 nM. When applied to EGFR-expressing cancer cells the aptamer inhibits EGFR-mediated signal pathways causing selective cell death. Furthermore, at low doses it induces apoptosis even of cells that are resistant to the most frequently used EGFR-inhibitors, such as gefitinib and cetuximab, and inhibits tumor growth in a mouse xenograft model of human non-small-cell lung cancer (NSCLC). Interestingly, combined treatment with cetuximab and the aptamer shows clear synergy in inducing apoptosis in vitro and in vivo. In conclusion, we demonstrate that this neutralizing RNA-aptamer is a promising bio-molecule that can be developed as a more effective alternative to the repertoire of already existing EGFR-inhibitors

Post-transcriptional regulation of androgen receptor mRNA by an ErbB3 binding protein 1 in prostate cancer

Androgen receptor (AR)-mediated pathways play a critical role in the development and progression of prostate cancer. However, little is known about the regulation of AR mRNA stability and translation, two central processes that control AR expression. The ErbB3 binding protein 1 (EBP1), an AR corepressor, negatively regulates crosstalk between ErbB3 ligand heregulin (HRG)-triggered signaling and the AR axis, affecting biological properties of prostate cancer cells. EBP1 protein expression is also decreased in clinical prostate cancer. We previously demonstrated that EBP1 overexpression results in decreased AR protein levels by affecting AR promoter activity. However, EBP1 has recently been demonstrated to be an RNA binding protein. We therefore examined the ability of EBP1 to regulate AR post-transcriptionally. Here we show that EBP1 promoted AR mRNA decay through physical interaction with a conserved UC-rich motif within the 3′-UTR of AR. The ability of EBP1 to accelerate AR mRNA decay was further enhanced by HRG treatment. EBP1 also bound to a CAG-formed stem-loop in the 5′ coding region of AR mRNA and was able to inhibit AR translation. Thus, decreases of EBP1 in prostate cancer could be important for the post-transcriptional up-regulation of AR contributing to aberrant AR expression and disease progression

Molecular Effects of Doxycycline Treatment on Pterygium as Revealed by Massive Transcriptome Sequencing

Pterygium is a lesion of the eye surface which involves cell proliferation, migration, angiogenesis, fibrosis, and extracellular matrix remodelling. Surgery is the only approved method to treat this disorder, but high recurrence rates are common. Recently, it has been shown in a mouse model that treatment with doxycycline resulted in reduction of the pterygium lesions. Here we study the mechanism(s) of action by which doxycycline achieves these results, using massive sequencing techniques. Surgically removed pterygia from 10 consecutive patients were set in short term culture and exposed to 0 (control), 50, 200, and 500 µg/ml doxycycline for 24 h, their mRNA was purified, reverse transcribed and sequenced through Illumina’s massive sequencing protocols. Acquired data were subjected to quantile normalization and analyzed using cytoscape plugin software to explore the pathways involved. False discovery rate (FDR) methods were used to identify 332 genes which modified their expression in a dose-dependent manner upon exposure to doxycycline. The more represented cellular pathways included all mitochondrial genes, the endoplasmic reticulum stress response, integrins and extracellular matrix components, and growth factors. A high correlation was obtained when comparing ultrasequencing data with qRT-PCR and ELISA results