TRAIL delivery by MSC-derived extracellular vesicles is an effective anticancer therapy

Extracellular vesicles (EVs) are lipid membrane-enclosed nanoparticles released by cells. They mediate intercellular communication by transferring biological molecules and therefore have potential as innovative drug delivery vehicles. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of cancer cells. Unfortunately, the clinical application of recombinant rTRAIL has been hampered by its low bioavailability and resistance of cancer cells. EV-mediated TRAIL delivery may circumvent these problems. Mesenchymal stromal cells (MSCs) produce EVs and could be a good source for therapeutic EV production. We investigated if TRAIL could be expressed in MSC-derived EVs and examined their cancer cell-killing efficacy. EVs were isolated by ultracentrifugation and were membranous particles of 50–70 nm in diameter. Both MSC- and TRAIL-expressing MSC (MSCT)-derived EVs express CD63, CD9 and CD81, but only MSCT-EVs express surface TRAIL. MSCT-EVs induced apoptosis in 11 cancer cell lines in a dose-dependent manner but showed no cytotoxicity in primary human bronchial epithelial cells. Caspase activity inhibition or TRAIL neutralisation blocked the cytotoxicity of TRAIL-positive EVs. MSCT-EVs induced pronounced apoptosis in TRAIL-resistant cancer cells and this effect could be further enhanced using a CDK9 inhibitor. These data indicate that TRAIL delivery by MSC-derived EVs is an effective anticancer therapy

Optimal harvest-use-store design for delay-constrained energy harvesting wireless communications

Recent advances in energy harvesting (EH) technology have motivated the adoption of rechargeable mobile devices for communications. In this paper, we consider a point-to-point (P2P) wireless communication system in which an EH transmitter with a non-ideal rechargeable battery is required to send a given fixed number of bits to the receiver before they expire according to a preset delay constraint. Due to the possible energy loss in the storage process, the harvest-use-and-store (HUS) architecture is adopted. We characterize the properties of the optimal solutions, for additive white Gaussian channels (AWGNs) and then block-fading channels, that maximize the energy efficiency (i.e., battery residual) subject to a given rate requirement. Interestingly, it is shown that the optimal solution has a water-filling interpretation with double thresholds and that both thresholds are monotonic. Based on this, we investigate the optimal double-threshold based allocation policy and devise an algorithm to achieve the solution. Numerical results are provided to validate the theoretical analysis and to compare the optimal solutions with existing schemes

Physical Layer Security in Large-Scale Random Multiple Access Wireless Sensor Networks: A Stochastic Geometry Approach

This paper investigates physical layer security for a large-scale WSN with random multiple access, where each fusion center in the network randomly schedules a number of sensors to upload their sensed data subject to the overhearing of randomly distributed eavesdroppers. We propose an uncoordinated random jamming scheme in which those unscheduled sensors send jamming signals with a certain probability to defeat the eavesdroppers. With the aid of stochastic geometry theory and order statistics, we derive analytical expressions for the connection outage probability and secrecy outage probability to characterize transmission reliability and secrecy, respectively. Based on the obtained analytical results, we formulate an optimization problem for maximizing the sum secrecy throughput subject to both reliability and secrecy constraints, considering a joint design of the wiretap code rates for each scheduled sensor and the jamming probability for the unscheduled sensors. We provide both optimal and low-complexity sub-optimal algorithms to tackle the above problem, and further reveal various properties on the optimal parameters which are useful to guide practical designs. In particular, we demonstrate that the proposed random jamming scheme is beneficial for improving the sum secrecy throughput, and the optimal jamming probability is the result of trade-off between secrecy and throughput. We also show that the throughput performance of the sub-optimal scheme approaches that of the optimal one when facing a stringent reliability constraint or a loose secrecy constraint

Fast Meta Learning for Adaptive Beamforming

This paper studies the deep learning based adaptive downlink beamforming solution for the signal-to-interference-plus-noise ratio balancing problem. Adaptive beamforming is an important approach to enhance the performance in dynamic wireless environments in which testing channels have different distributions from training channels. We propose an adaptive method to achieve fast adaptation of beamforming based on the principle of meta learning. Specifically, our method first learns an embedding model by training a deep neural network as a transferable feature extractor. In the adaptation stage, it fits a support vector regression model using the extracted features and testing data of the new environment. Simulation results demonstrate that compared to the state of the art meta learning method, our proposed algorithm reduces the complexities in both training and adaptation processes by more than an order of magnitude, while achieving better adaptation performance

Cryopreservation of human mesenchymal stromal cells expressing TRAIL for human anti-cancer therapy

Background aims Mesenchymal stromal cells (MSCs) are being extensively researched for cell therapy and tissue engineering. We have engineered MSCs to express the pro-apoptotic protein tumor necrosis factor–related apoptosis inducing ligand (TRAIL) and are currently preparing this genetically modified cell therapy for a phase 1/2a clinical trial in patients with metastatic lung cancer. To do this, we need to prepare a cryopreserved allogeneic MSCTRAIL cell bank for further expansion before patient delivery. The effects of cryopreservation on a genetically modified cell therapy product have not been clearly determined. Methods We tested different concentrations of dimethyl sulfoxide (DMSO) added to the human serum albumin ZENALB 4.5 and measured post-thaw cell viability, proliferation ability and differentiation characteristics. In addition, we examined the homing ability, TRAIL expression and cancer cell–killing capacities of cryopreserved genetically modified MSCs compared with fresh, continually cultured cells. Results We demonstrated that the post-thaw viability of MSCs in 5% DMSO (v/v) with 95% ZENALB 4.5 (v/v) is 85.7 ± 0.4%, which is comparable to that in conventional freezing media. We show that cryopreservation does not affect the long-term expression of TRAIL and that cryopreserved TRAIL-expressing MSCs exhibit similar levels of homing and, importantly, retain their potency in triggering cancer cell death. Conclusions This study shows that cryopreservation is unlikely to affect the therapeutic properties of MSCTRAIL and supports the generation of a cryopreserved master cell bank

Physical-layer Security of Uplink mmWave Transmissions in Cellular V2X Networks

In this paper, we investigate physical-layer security of the uplink millimeter wave communications for a cellular vehicle-to-everything (C-V2X) network comprised of a large number of base stations (BSs) and different categories of V2X nodes, including vehicles, pedestrians, and road side units. Considering the dynamic change and randomness of the topology of the C-V2X network, we model the roadways, the V2X nodes on each roadway, and the BSs by a Poisson line process, a 1D Poisson point process (PPP), and a 2D PPP, respectively. We propose two uplink association schemes for a typical vehicle, namely, the smallest-distance association (SDA) scheme and the largest-power association (LPA) scheme, and we establish a tractable analytical framework to comprehensively assess the security performance of the uplink transmission, by leveraging the stochastic geometry theory. Specifically, for each association scheme, we first obtain new expressions for the association probability of the typical vehicle, and then derive the overall connection outage probability and secrecy outage probability by calculating the Laplace transform of the aggregate interference power. Numerical results are presented to validate our theoretical analysis, and we also provide interesting insights into how the security performance is influenced by various system parameters, including the densities of V2X nodes and BSs. Moreover, we show that the LPA scheme outperforms the SDA scheme in terms of secrecy throughput

Mesenchymal stromal cell delivery of full-length tumor necrosis factor-related apoptosis-inducing ligand is superior to soluble type for cancer therapy

Mesenchymal stromal cell (MSC) delivery of pro-apoptotic tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an attractive strategy for anticancer therapy. MSCs expressing full-length human TRAIL (flT) or its soluble form (sT) have previously been shown to be effective for cancer killing. However, a comparison between the two forms has never been performed, leaving it unclear which approach is most effective. This study addresses the issue for the possible clinical application of TRAIL-expressing MSCs in the future

Current Approaches to the Treatment of Early Hepatocellular Carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139902/1/onco0034.pd

Regulation of Neuronal Cell Death by c-Abl-Hippo/MST2 Signaling Pathway

BACKGROUND: Mammalian Ste20-like kinases (MSTs) are the mammalian homologue of Drosophila hippo and play critical roles in regulation of cell death, organ size control, proliferation and tumorigenesis. MSTs exert pro-apoptotic function through cleavage, autophosphorylation and in turn phosphorylation of downstream targets, such as Histone H2B and FOXO (Forkhead box O). Previously we reported that protein kinase c-Abl mediates oxidative stress-induced neuronal cell death through phosphorylating MST1 at Y433, which is not conserved among mammalian MST2, Drosophila Hippo and C.elegans cst-1/2. METHODOLOGY/PRINCIPAL FINDINGS: Using immunoblotting, in vitro kinase and cell death assay, we demonstrate that c-Abl kinase phosphorylates MST2 at an evolutionarily conserved site, Y81, within the kinase domain. We further show that the phosphorylation of MST2 by c-Abl leads to the disruption of the interaction with Raf-1 proteins and the enhancement of homodimerization of MST2 proteins. It thereby enhances the MST2 activation and induces neuronal cell death. CONCLUSIONS/SIGNIFICANCE: The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST2 suggests that the conserved c-Abl-MST signaling cascade plays an important role in oxidative stress-induced neuronal cell death

Dietary soy and meat proteins induce distinct physiological and gene expression changes in rats

This study reports on a comprehensive comparison of the effects of soy and meat proteins given at the recommended level on physiological markers of metabolic syndrome and the hepatic transcriptome. Male rats were fed semi-synthetic diets for 1 wk that differed only regarding protein source, with casein serving as reference. Body weight gain and adipose tissue mass were significantly reduced by soy but not meat proteins. The insulin resistance index was improved by soy, and to a lesser extent by meat proteins. Liver triacylglycerol contents were reduced by both protein sources, which coincided with increased plasma triacylglycerol concentrations. Both soy and meat proteins changed plasma amino acid patterns. The expression of 1571 and 1369 genes were altered by soy and meat proteins respectively. Functional classification revealed that lipid, energy and amino acid metabolic pathways, as well as insulin signaling pathways were regulated differently by soy and meat proteins. Several transcriptional regulators, including NFE2L2, ATF4, Srebf1 and Rictor were identified as potential key upstream regulators. These results suggest that soy and meat proteins induce distinct physiological and gene expression responses in rats and provide novel evidence and suggestions for the health effects of different protein sources in human diets