A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression.

Large-scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome-scale, gain-of-function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor-suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA-mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.

Clustering algorithms for Stokes space modulation format recognition.

Stokes space modulation format recognition (Stokes MFR) is a blind method enabling digital coherent receivers to infer modulation format information directly from a received polarization-division-multiplexed signal. A crucial part of the Stokes MFR is a clustering algorithm, which largely influences the performance of the detection process, particularly at low signal-to-noise ratios. This paper reports on an extensive study of six different clustering algorithms: k-means, expectation maximization, density-based DBSCAN and OPTICS, spectral clustering and maximum likelihood clustering, used for discriminating between dual polarization: BPSK, QPSK, 8-PSK, 8-QAM, and 16-QAM. We determine essential performance metrics for each clustering algorithm and modulation format under test: minimum required signal-to-noise ratio, detection accuracy and algorithm complexity.

A high-throughput screen identifies miRNA inhibitors regulating lung cancer cell survival and response to paclitaxel.

microRNAs (miRNAs) are small RNAs endogenously expressed in multiple organisms that regulate gene expression largely by decreasing levels of target messenger RNAs (mRNAs). Over the past few years, numerous studies have demonstrated critical roles for miRNAs in the pathogenesis of many cancers, including lung cancer. Cellular miRNA levels can be easily manipulated, showing the promise of developing miRNA-targeted oligos as next-generation therapeutic agents. In a comprehensive effort to identify novel miRNA-based therapeutic agents for lung cancer treatment, we combined a high-throughput screening platform with a library of chemically synthesized miRNA inhibitors to systematically identify miRNA inhibitors that reduce lung cancer cell survival and those that sensitize cells to paclitaxel. By screening three lung cancer cell lines with different genetic backgrounds, we identified miRNA inhibitors that potentially have a universal cytotoxic effect on lung cancer cells and miRNA inhibitors that sensitize cells to paclitaxel treatment, suggesting the potential of developing these miRNA inhibitors as therapeutic agents for lung cancer. We then focused on characterizing the inhibitors of three miRNAs (miR-133a/b, miR-361-3p, and miR-346) that have the most potent effect on cell survival. We demonstrated that two of the miRNA inhibitors (miR-133a/b and miR-361-3p) decrease cell survival by activating caspase-3/7-dependent apoptotic pathways and inducing cell cycle arrest in S phase. Future studies are certainly needed to define the mechanisms by which the identified miRNA inhibitors regulate cell survival and drug response, and to explore the potential of translating the current findings into clinical applications.

Nonlinear impairment compensation using expectation maximization for dispersion managed and unmanaged PDM 16-QAM transmission.

In this paper, we show numerically and experimentally that expectation maximization (EM) algorithm is a powerful tool in combating system impairments such as fibre nonlinearities, inphase and quadrature (I/Q) modulator imperfections and laser linewidth. The EM algorithm is an iterative algorithm that can be used to compensate for the impairments which have an imprint on a signal constellation, i.e. rotation and distortion of the constellation points. The EM is especially effective for combating non-linear phase noise (NLPN). It is because NLPN severely distorts the signal constellation and this can be tracked by the EM. The gain in the nonlinear system tolerance for the system under consideration is shown to be dependent on the transmission scenario. We show experimentally that for a dispersion managed polarization multiplexed 16-QAM system at 14 Gbaud a gain in the nonlinear system tolerance of up to 3 dB can be obtained. For, a dispersion unmanaged system this gain reduces to 0.5 dB.

Experimental demonstration of a cognitive quality of transmission estimator for optical communication systems.

The impact of physical layer impairments in optical network design and operation has received significant attention in the last years, thereby requiring estimation techniques to predict the quality of transmission (QoT) of optical connections before being established. In this paper, we report on the experimental demonstration of a case-based reasoning (CBR) technique to predict whether optical channels fulfill QoT requirements, thus supporting impairment-aware networking. The validation of the cognitive QoT estimator is performed in a WDM 80 Gb/s PDM-QPSK testbed, and we demonstrate that even with a very small and not optimized underlying knowledge base, it achieves between 79% and 98.7% successful classifications based on the error vector magnitude (EVM) parameter, and approximately 100% when the classification is based on the optical signal to noise ratio (OSNR).

Experimental demonstration of adaptive digital monitoring and compensation of chromatic dispersion for coherent DP-QPSK receiver.

We experimentally demonstrate a digital signal processing (DSP)-based optical performance monitoring (OPM) algorithm for in-service monitoring of chromatic dispersion (CD) in coherent transport networks. Dispersion accumulated in 40 Gbit/s QPSK signal after 80 km of fiber transmission is successfully monitored and automatically compensated without prior knowledge of fiber dispersion coefficient. Four different metrics for assessing CD mitigation are implemented and simultaneously verified proving to have high estimation accuracy. No observable penalty is measured when the monitoring module drives an adaptive digital CD equalizer.

100 Gbit/s hybrid optical fiber-wireless link in the W-band (75-110 GHz).

We experimentally demonstrate an 100 Gbit/s hybrid optical fiber-wireless link by employing photonic heterodyning up-conversion of optical 12.5 Gbaud polarization multiplexed 16-QAM baseband signal with two free running lasers. Bit-error-rate performance below the FEC limit is successfully achieved for air transmission distances up to 120 cm.

GWAS and PheWAS of red blood cell components in a Northern Nevadan cohort.

In this study, we perform a full genome-wide association study (GWAS) to identify statistically significantly associated single nucleotide polymorphisms (SNPs) with three red blood cell (RBC) components and follow it with two independent PheWASs to examine associations between phenotypic data (case-control status of diagnoses or disease), significant SNPs, and RBC component levels. We first identified associations between the three RBC components: mean platelet volume (MPV), mean corpuscular volume (MCV), and platelet counts (PC), and the genotypes of approximately 500,000 SNPs on the Illumina Infimum DNA Human OmniExpress-24 BeadChip using a single cohort of 4,673 Northern Nevadans. Twenty-one SNPs in five major genomic regions were found to be statistically significantly associated with MPV, two regions with MCV, and one region with PC, with p<5x10-8. Twenty-nine SNPs and nine chromosomal regions were identified in 30 previous GWASs, with effect sizes of similar magnitude and direction as found in our cohort. The two strongest associations were SNP rs1354034 with MPV (p = 2.4x10-13) and rs855791 with MCV (p = 5.2x10-12). We then examined possible associations between these significant SNPs and incidence of 1,488 phenotype groups mapped from International Classification of Disease version 9 and 10 (ICD9 and ICD10) codes collected in the extensive electronic health record (EHR) database associated with Healthy Nevada Project consented participants. Further leveraging data collected in the EHR, we performed an additional PheWAS to identify associations between continuous red blood cell (RBC) component measures and incidence of specific diagnoses. The first PheWAS illuminated whether SNPs associated with RBC components in our cohort were linked with other hematologic phenotypic diagnoses or diagnoses of other nature. Although no SNPs from our GWAS were identified as strongly associated to other phenotypic components, a number of associations were identified with p-values ranging between 1x10-3 and 1x10-4 with traits such as respiratory failure, sleep disorders, hypoglycemia, hyperglyceridemia, GERD and IBS. The second PheWAS examined possible phenotypic predictors of abnormal RBC component measures: a number of hematologic phenotypes such as thrombocytopenia, anemias, hemoglobinopathies and pancytopenia were found to be strongly associated to RBC component measures; additional phenotypes such as (morbid) obesity, malaise and fatigue, alcoholism, and cirrhosis were also identified to be possible predictors of RBC component measures.

Genetic mutation of p53 and suppression of the miR-17∼92 cluster are synthetic lethal in non-small cell lung cancer due to upregulation of vitamin D Signaling.

Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We used a library of oligonucleotide inhibitors of microRNAs, a class of posttranscriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in non-small cell lung cancer (NSCLC). Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific downregulation of the miR-17∼92 polycistron, and this downregulation was toxic only in the context of p53 loss. Mechanistic studies indicated that the selective toxicity of miR-17∼92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1, a rate-limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach used in this study can identify clinically relevant synthetic lethal interactions and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients.

Safety and efficacy of low-dose intravenous enoxaparin and GP IIb/IIIa inhibitor therapy during PCI.

The use of intravenous enoxaparin, a glyco-protein (GP) IIb/IIIa inhibitor, during percutaneous coronary intervention (PCI) has been shown to be safe and to possibly reduce in-hospital and 30-day major adverse cardiac events(MACE). NICE-4, a recent PCI observational study, evaluated a reduced dose of intravenous (IV) enoxaparin (0.75 mg/kg) with abciximab. However, prior PCI studies evaluating IV enoxaparin have not used percutaneous closure devices. The purpose of this study was to observe the safety and efficacy of a lower dose of IV enoxaparin (0.5 mg/kg) in conjunction with any GP IIb/IIIa inhibitor. The Angio-Seal femoral closure device was also employed as part of the treatment strategy. We administered 0.5 mg/kg IV enoxaparin and a GP IIIb/IIIa inhibitor to 75 eligible PCI patients. None received anticoagulation 24 hours prior to PCI; all received pre-procedural aspirin, post-procedural deployment of the Angio-Seal and clopidogrel therapy, and were discharged home within 36 hours. TIMI minor bleeding was 1.3%; there were no TIMI major bleeding events or major adverse cardiac events during in-hospital stay or at 30-day follow-up. Our small observational study shows that IV enoxaparin is safe and efficacious during PCI when given at a dose 33% lower than previously reported in conjunction with any GP IIb/IIIa inhibitor and Angio-Seal. However, large, randomized PCI trials are needed to confirm the clinical efficacy, safety and cost-effectiveness of lower doses of enoxaparin with GPIIb/IIIa inhibitors and vascular closure devices.

miR-337-3p and its targets STAT3 and RAP1A modulate taxane sensitivity in non-small cell lung cancers.

NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC.