Antitumor effect of oncolytic virus and paclitaxel encapsulated in extracellular vesicles for lung cancer treatment

Standard of care for cancer is commonly a combination of surgery with radiotherapy or chemoradiotherapy. However, in some advanced cancer patients this approach might still remaininefficient and may cause many side effects, including severe complications and even death. Oncolytic viruses exhibit different anti-cancer mechanisms compared with conventional therapies, allowing the possibility for improved effect in cancer therapy. Chemotherapeutics combined with oncolytic viruses exhibit stronger cytotoxic responses and oncolysis. Here, we have investigated the systemic delivery of the oncolytic adenovirus and paclitaxel encapsulated in extracellular vesicles (EV) formulation that, in vitro, significantly increased the transduction ratio and the infectious titer when compared with the virus and paclitaxel alone. We demonstrated that the obtained EV formulation reduced the in vivo tumor growth in animal xenograft model of human lung cancer. Indeed, we found that combined treatment of oncolytic adenovirus and paclitaxel encapsulated in EV has enhanced anticancer effects both in vitro and in vivo in lung cancer models. Transcriptomic comparison carried out on the explanted xenografts from the different treatment groups revealed that only 5.3% of the differentially expressed genes were overlapping indicating that a de novo genetic program is triggered by the presence of the encapsulated paclitaxel: this novel genetic program might be responsible of the observed enhanced antitumor effect. Our work provides a promising approach combining anticancer drugs and viral therapies by intravenous EV delivery as a strategy for the lung cancer treatment.Peer reviewe

A Cretaceous carbonate delta drift in the Montagna della Maiella, Italy

The Upper Cretaceous (Campanian\u2013Maastrichtian) bioclastic wedge of the Orfento Formation in the Montagna della Maiella, Italy, is compared to newly discovered contourite drifts in the Maldives. Like the drift deposits in the Maldives, the Orfento Formation fills a channel and builds a Miocene delta-shaped and mounded sedimentary body in the basin that is similar in size to the approximately 350 km 2 large coarse-grained bioclastic Miocene delta drifts in the Maldives. The composition of the bioclastic wedge of the Orfento Formation is also exclusively bioclastic debris sourced from the shallow-water areas and reworked clasts of the Orfento Formation itself. In the near mud-free succession, age-diagnostic fossils are sparse. The depositional textures vary from wackestone to float-rudstone and breccia/conglomerates, but rocks with grainstone and rudstone textures are the most common facies. In the channel, lensoid convex-upward breccias, cross-cutting channelized beds and thick grainstone lobes with abundant scours indicate alternating erosion and deposition from a high-energy current. In the basin, the mounded sedimentary body contains lobes with a divergent progradational geometry. The lobes are built by decametre thick composite megabeds consisting of sigmoidal clinoforms that typically have a channelized topset, a grainy foreset and a fine-grained bottomset with abundant irregular angular clasts. Up to 30 m thick channels filled with intraformational breccias and coarse grainstones pinch out downslope between the megabeds. In the distal portion of the wedge, stacked grainstone beds with foresets and reworked intraclasts document continuous sediment reworking and migration. The bioclastic wedge of the Orfento Formation has been variously interpreted as a succession of sea-level controlled slope deposits, a shoaling shoreface complex, or a carbonate tidal delta. Current-controlled delta drifts in the Maldives, however, offer a new interpretation because of their similarity in architecture and composition. These similarities include: (i) a feeder channel opening into the basin; (ii) an excavation moat at the exit of the channel; (iii) an overall mounded geometry with an apex that is in shallower water depth than the source channel; (iv) progradation of stacked lobes; (v) channels that pinch out in a basinward direction; and (vi) smaller channelized intervals that are arranged in a radial pattern. As a result, the Upper Cretaceous (Campanian\u2013Maastrichtian) bioclastic wedge of the Orfento Formation in the Montagna della Maiella, Italy, is here interpreted as a carbonate delta drift

The coupled boundary layers and air-sea transfer experiment in low winds

Author Posting. © American Meteorological Society, 2007. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Bulletin of the American Meteorological Society 88 (2007): 341-356, doi:10.1175/bams-88-3-341.The Office of Naval Research's Coupled Boundary Layers and Air–Sea Transfer (CBLAST) program is being conducted to investigate the processes that couple the marine boundary layers and govern the exchange of heat, mass, and momentum across the air–sea interface. CBLAST-LOW was designed to investigate these processes at the low-wind extreme where the processes are often driven or strongly modulated by buoyant forcing. The focus was on conditions ranging from negligible wind stress, where buoyant forcing dominates, up to wind speeds where wave breaking and Langmuir circulations play a significant role in the exchange processes. The field program provided observations from a suite of platforms deployed in the coastal ocean south of Martha's Vineyard. Highlights from the measurement campaigns include direct measurement of the momentum and heat fluxes on both sides of the air–sea interface using a specially constructed Air–Sea Interaction Tower (ASIT), and quantification of regional oceanic variability over scales of O (1–104 mm) using a mesoscale mooring array, aircraft-borne remote sensors, drifters, and ship surveys. To our knowledge, the former represents the first successful attempt to directly and simultaneously measure the heat and momentum exchange on both sides of the air–sea interface. The latter provided a 3D picture of the oceanic boundary layer during the month-long main experiment. These observations have been combined with numerical models and direct numerical and large-eddy simulations to investigate the processes that couple the atmosphere and ocean under these conditions. For example, the oceanic measurements have been used in the Regional Ocean Modeling System (ROMS) to investigate the 3D evolution of regional ocean thermal stratification. The ultimate goal of these investigations is to incorporate improved parameterizations of these processes in coupled models such as the Coupled Ocean–Atmosphere Mesoscale Prediction System (COAMPS) to improve marine forecasts of wind, waves, and currents.This work was supported by the Office of Naval Research

Measurement of Directional Wave Spectra Using Aircraft Laser Altimeters

A remote sensing method to measure directional oceanic surface waves by three laser altimeters on the NOAA LongEZ aircraft is investigated. To examine feasibility and sensitivity of the wavelet analysis method to various waves, aircraft motions, and aircraft flight directions relative to wave propagation directions, idealized surface waves are simulated from various idealized aircraft flights. In addition, the wavelet analysis method is also applied to two cases from field measurements, and the results are compared with traditional wave spectra from buoys. Since the wavelet analysis method relies on the “wave slopes” measured through phase differences between the time series of the laser distances between the aircraft and sea surface at spatially separated locations, the resolved directional wavenumber and wave propagation direction are not affected by aircraft motions if the resolved frequencies of the aircraft motion and the wave are not the same. However, the encounter wave frequency, which is directly resolved using the laser measurement from the moving aircraft, is affected by the Doppler shift due to aircraft motion relative to wave propagations. The wavelet analysis method could fail if the aircraft flies in the direction such that the aircraft speed along the wave propagation direction is the same as the wave phase speed (i.e., the aircraft flies along wave crests or troughs) or if two waves with different wavelengths and phase speed have the same encountered wavelength from the aircraft. In addition, the data noise due to laser measurement uncertainty or natural isotropic surface elevation perturbations can also affect the relative phase difference between the laser distance measurements, which in turn affects the accuracy of the resolved wavenumber and wave propagation direction. The smallest waves measured by the lasers depend on laser sampling rate and horizontal distances between the lasers (for the LongEZ this is 2 m). The resolved wave direction and wavenumber at the peak wave from the two field experiments compared well with on-site buoy observations. Overall, the study demonstrates that three spatially separated laser altimeters on moving platforms can be utilized to resolve two-dimensional wave spectra

Inhibition of SIRT1 deacetylase and p53 activation uncouples the anti-inflammatory and chemopreventive actions of NSAIDs

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as chemopreventive agents for many tumours; however, the mechanism responsible for their anti-neoplastic activity remains elusive and the side effects due to cyclooxygenase (COX) inhibition prevent this clinical application. Methods: Molecular biology, in silico, cellular and in vivo tools, including innovative in vivo imaging and classical biochemical assays, were applied to identify and characterise the COX-independent anti-cancer mechanism of NSAIDs. Results: Here, we show that tumour-protective functions of NSAIDs and exisulind (a sulindac metabolite lacking anti-inflammatory activity) occur through a COX-independent mechanism. We demonstrate these NSAIDs counteract carcinogen-induced proliferation by inhibiting the sirtuin 1 (SIRT1) deacetylase activity, augmenting acetylation and activity of the tumour suppressor p53 and increasing the expression of the antiproliferative gene p21. These properties are shared by all NSAIDs except for ketoprofen lacking anti-cancer properties. The clinical interest of the mechanism identified is underlined by our finding that p53 is activated in mastectomy patients undergoing intraoperative ketorolac, a treatment associated with decreased relapse risk and increased survival. Conclusion: Our study, for the first-time, links NSAID chemopreventive activity with direct SIRT1 inhibition and activation of the p53/p21 anti-oncogenic pathway, suggesting a novel strategy for the design of tumour-protective drugs

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Ocean Wave Slope Observations Using Radar Backscatter and Laser Altimeters

Abstract Combination of laser and radar aboard an aircraft is used to directly measure long gravity wave surface tilting simultaneously with nadir-viewing microwave backscatter from the sea surface. The presented dataset is extensive, encompassing varied wind conditions over coastal and open-ocean wave regimes. Laser-derived slope statistics and Ka-band (36 GHz) radar backscatter are detailed separately to document their respective variations versus near-surface wind speed. The slope statistics, measured for λ > 1–2 m, show good agreement with Cox and Munk's oil-slickened sea measurements. A notable exception is elevated distribution peakedness and an observed wind dependence in this likely proxy for nonlinear wave–wave interactions. Aircraft Ka-band radar data nearly mimic Ku-band satellite altimeter observations in their mean wind dependence. The present calibrated radar data, along with relevant observational and theoretical studies, suggest a large (−5 dB) bias in previous Ka-band results. Next, wave-diverse inland, coastal, and open-ocean observations are contrasted to show wind-independent long-wave slope variance changes of a factor of 2–3, always increasing as one heads to sea. Combined long-wave and radar data demonstrate that this long-wave tilt field variability is largely responsible for radar backscatter variations observed at a given wind speed, particularly at wind speeds below 5–7 m s−1. Results are consistent with, and provide quantititative support for, recent satellite altimeter studies eliciting signatures of long-wave impacts resident in the radar backscatter. Under a quasi-optical scattering assumption, the results illustrate long-wave control on the variance of the total mean square slope parameter due to changes in the directional long-wave spectrum, with high-wavenumbers being relatively unaffected in a mean sense. However, further analysis suggests that for winds above 7 m s−1 the high-wavenumber subrange also varies with change in the longer wave field slope and/or energy, the short gravity wave roughness being measurably greater for smoother seas