Remote sensing of mesospheric dust layers using active modulation of PMWE by high-power radio waves

This paper presents the first study of the modulation of polar mesospheric winter echoes (PMWE) by artificial radio wave heating using computational modeling and experimental observation in different radar frequency bands. The temporal behavior of PMWE response to HF pump heating can be employed to diagnose the charged dust layer associated with mesospheric smoke particles. Specifically, the rise and fall time of radar echo strength as well as relaxation and recovery time after heater turn-on and turnoff are distinct parameters that are a function of radar frequency. The variation of PMWE strength with PMWE source region parameters such as electron-neutral collision frequency, photodetachment current, electron temperature enhancement ratio, dust density, and radius is considered. The comparison of recent PMWE measurements at 56 MHz and 224 MHz with computational results is discussed, and dust parameters in the PMWE generation regime are estimated. Predictions for HF PMWE modification and its connection to the dust charging process by free electrons is investigated. The possibility for remote sensing of dust and plasma parameters in artificially modified PMWE regions using simultaneous measurements in multiple frequency bands are discussed. © 2016. American Geophysical Union. All Rights Reserved

Expression profiling of plac1 in murine cancer cell lines

Aim: Placenta-specific 1 (PLAC1) is among recently-discovered placental antigens which exerts fundamental role in placental function and development. Increasing body of literature shows that PLAC1 is frequently activated and expressed in a wide variety of human cancers and promote cancer progression. However, no data is available regarding the expression of mouse orthologue, plac1, in murine cancer cell lines. Materials and Methods: We investigated the expression of plac1 in a series of murine cell lines from different histological origins, mammary carcinoma (4T1), melanoma (B16F10), colorectal carcinoma (CT26), renal carcinoma (Renca), glioma (GL26), B-cell lymphoma (A20 and BCL1) and also two fibroblast cell lines (NIH3T3 and L929), using RT-PCR, Western blotting and flow cytometry. Results: Our data demonstrated that plac1 transcript and plac1 protein were expressed in all examined cell lines, as judged by RT-PCR and Western blot, respectively. The molecular weight of mouse plac1 was experimentally observed to be approximately 24 kD. Flow cytometric analysis showed surface expression of plac1 in aforesaid cell lines ranging from 2 to 42.5. Conclusion: Based on the ubiquitous expression of plac1, the investigated cancer cell lines or immortalized cell lines can be used to examine the role of plac1 in the process of immortalization. Copyright © Experimental Oncology 2019

Alterations in early auditory evoked potentials and brainstem transmission time associated with tinnitus residual inhibition induced by auditory electrical stimulation

Introduction: Residual inhibition (RI) is the temporary inhibition of tinnitus by use of masking stimuli when the device is turned off. Objective: The main aim of this study was to evaluate the effects of RI induced by auditory electrical stimulation (AES) in the primary auditory pathways using early auditory-evoked potentials (AEPs) in subjective idiopathic tinnitus (SIT) subjects. Materials and Methods: A randomized placebo-controlled study was conducted on forty-four tinnitus subjects. All enrolled subjects based on the responses to AES, were divided into two groups of RI and Non-RI (NRI). The results of the electrocochleography (ECochG), auditory brain stem response (ABR) and brain stem transmission time (BTT) were determined and compared pre- and post-AES in the studied groups. Results: The mean differences in the compound action potential (CAP) amplitudes and III/V and I/V amplitude ratios were significantly different between the RI, NRI and PES controls. BTT was significantly decreased associated with RI. Conclusion: The observed changes in AEP associated with RI suggested some peripheral and central auditory alterations. Synchronized discharges of the auditory nerve fibers and inhibition of the abnormal activity of the cochlear nerve by AES may play important roles associated with RI. Further comprehensive studies are required to determine the mechanisms of RI more precisely

Evaluation and statistical optimization of a method for methylated cell-free fetal DNA extraction from maternal plasma

Purpose: Methylated cell-free fetal DNA (cffDNA) in maternal plasma can potentially be used as a biomarker for accurate noninvasive prenatal testing (NIPT) of fetal disorders. Recovery and purification of cffDNA are key steps for downstream applications. In this study, we aimed to developed and evaluated different aspects of an optimized method and compared its efficiency with common methods used for extraction of methylated cffDNA. Methods: Single factor experiments, Plackett-Burman (PB) design, and response surface methodology (RSM) were conducted for conventional Triton/Heat/Phenol (cTHP) method optimization. The total cell-free DNA (cfDNA) was extracted from pooled maternal plasma using the optimized method called the Triton/Heat/Phenol/Glycogen (THPG), cTHP method, a column-based kit, and a magnetic bead-based kit. In the next step, methylated cfDNA from the extracted total cfDNA was enriched using a methylated DNA immunoprecipitation (MeDIP) kit. Real-time quantitative polymerase chain reaction was performed on the RASSF1 gene and hyper region to determine the genomic equivalents per milliliter (GEq/ml) values of the methylated cfDNA and cffDNA, respectively. Results: The optimum values of the significant factors affecting cfDNA extraction from 200 μl of plasma were 3% SDS, 1% Triton X-100, 0.9 μg/μl glycogen, and 0.3 M sodium acetate. The GEq/ml values of methylated cffDNA extracted using the THPG method were significantly higher than for the tested extraction methods (p < 0.001). Conclusions: Our results indicate that the THPG method is more efficient than the other tested methods for extraction of low copy number methylated cffDNA from a small volume of maternal plasm

Antitumor Activity of Noscapine in Combination with Doxorubicin in Triple Negative Breast Cancer

The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues. values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells. Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150–550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC

New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective.

Benzodiazepines represent the first-line treatment for the acute management of epileptic seizures and status epilepticus. The emergency use of benzodiazepines must be timely, and because most seizures occur outside of the hospital environment, there is a significant need for delivery methods that are easy for nonclinical caregivers to use and administer quickly and safely. In addition, the ideal route of administration should be reliable in terms of absorption. Rectal diazepam is the only licensed formulation in the USA, whereas rectal diazepam and buccal midazolam are currently licensed in the EU. However, the sometimes unpredictable absorption with rectal and buccal administration means they are not ideal routes. Several alternative routes are currently being explored. This is a narrative review of data about delivery methods for benzodiazepines alternative to the intravenous and oral routes for the acute treatment of seizures. Unconventional delivery options such as direct delivery to the central nervous system or inhalers are reported. Data show that intranasal diazepam or midazolam and the intramuscular auto-injector for midazolam are as effective as rectal or intravenous diazepam. Head-to-head comparisons with buccal midazolam are urgently needed. In addition, the majority of trials focused on children and adolescents, and further trials in adults are warranted

A Novel Small Molecule Inhibitor of Influenza A Viruses that Targets Polymerase Function and Indirectly Induces Interferon

Influenza viruses continue to pose a major public health threat worldwide and options for antiviral therapy are limited by the emergence of drug-resistant virus strains. The antiviral cytokine, interferon (IFN) is an essential mediator of the innate immune response and influenza viruses, like many viruses, have evolved strategies to evade this response, resulting in increased replication and enhanced pathogenicity. A cell-based assay that monitors IFN production was developed and applied in a high-throughput compound screen to identify molecules that restore the IFN response to influenza virus infected cells. We report the identification of compound ASN2, which induces IFN only in the presence of influenza virus infection. ASN2 preferentially inhibits the growth of influenza A viruses, including the 1918 H1N1, 1968 H3N2 and 2009 H1N1 pandemic strains and avian H5N1 virus. In vivo, ASN2 partially protects mice challenged with a lethal dose of influenza A virus. Surprisingly, we found that the antiviral activity of ASN2 is not dependent on IFN production and signaling. Rather, its IFN-inducing property appears to be an indirect effect resulting from ASN2-mediated inhibition of viral polymerase function, and subsequent loss of the expression of the viral IFN antagonist, NS1. Moreover, we identified a single amino acid mutation at position 499 of the influenza virus PB1 protein that confers resistance to ASN2, suggesting that PB1 is the direct target. This two-pronged antiviral mechanism, consisting of direct inhibition of virus replication and simultaneous activation of the host innate immune response, is a unique property not previously described for any single antiviral molecule

One-pot bio-synthesis: N-acetyl-d-neuraminic acid production by a powerful engineered whole-cell catalyst

Whole cell biocatalysis is an important tool for pharmaceutical intermediates synthesis, although it is hindered by some shortcomings, such as high cost and toxicity of inducer, mass transfer resistance caused by cell membrane and side reactions. Whole-cell catalysis using N-acetyl-d-glucosamine 2-epimerase (EC 5.1.3.8) and N-acetyl-d-neuraminic acid (Neu5Ac) aldolase (EC 4.1.3.3) is a promising approach for the production of Neu5Ac, a potential precursor of many anti-viral drugs. A powerful catalyst was developed by packaging the enzymes in an engineered bacterium and using a safe temperature-induced vector. Since the mass transfer resistance and the side reactions were substantially reduced, a high Neu5Ac amount (191 mM) was achieved. An efficient method was also presented, which allows one-pot synthesis of Neu5Ac with a safe and economic manner. The results highlight the promise of large-scale Neu5Ac synthesis and point at a potential of our approach as a general strategy to improve whole-cell biocatalysis

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer : development of a prognostic model through a crowdsourced challenge with open clinical trial data

Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0.791; Bayes factor >5) and surpassed the reference model (iAUC 0.743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3.32, 95% CI 2.39-4.62, p Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer.Peer reviewe