5,469 research outputs found
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
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
On the complexity of color-avoiding site and bond percolation
The mathematical analysis of robustness and error-tolerance of complex
networks has been in the center of research interest. On the other hand, little
work has been done when the attack-tolerance of the vertices or edges are not
independent but certain classes of vertices or edges share a mutual
vulnerability. In this study, we consider a graph and we assign colors to the
vertices or edges, where the color-classes correspond to the shared
vulnerabilities. An important problem is to find robustly connected vertex
sets: nodes that remain connected to each other by paths providing any type of
error (i.e. erasing any vertices or edges of the given color). This is also
known as color-avoiding percolation. In this paper, we study various possible
modeling approaches of shared vulnerabilities, we analyze the computational
complexity of finding the robustly (color-avoiding) connected components. We
find that the presented approaches differ significantly regarding their
complexity.Comment: 14 page
Electrically controlled long-distance spin transport through an antiferromagnetic insulator
Spintronics uses spins, the intrinsic angular momentum of electrons, as an
alternative for the electron charge. Its long-term goal is in the development
of beyond-Moore low dissipation technology devices. Recent progress
demonstrated the long-distance transport of spin signals across ferromagnetic
insulators. Antiferromagnetically ordered materials are however the most common
class of magnetic materials with several crucial advantages over ferromagnetic
systems. In contrast to the latter, antiferromagnets exhibit no net magnetic
moment, which renders them stable and impervious to external fields. In
addition, they can be operated at THz frequencies. While fundamentally their
properties bode well for spin transport, previous indirect observations
indicate that spin transmission through antiferromagnets is limited to short
distances of a few nanometers. Here we demonstrate the long-distance, over tens
of micrometers, propagation of spin currents through hematite (\alpha-Fe2O3),
the most common antiferromagnetic iron oxide, exploiting the spin Hall effect
for spin injection. We control the spin current flow by the interfacial
spin-bias and by tuning the antiferromagnetic resonance frequency with an
external magnetic field. This simple antiferromagnetic insulator is shown to
convey spin information parallel to the compensated moment (N\'eel order) over
distances exceeding tens of micrometers. This newly-discovered mechanism
transports spin as efficiently as the net magnetic moments in the best-suited
complex ferromagnets. Our results pave the way to ultra-fast, low-power
antiferromagnet-insulator-based spin-logic devices that operate at room
temperature and in the absence of magnetic fields
On the behaviour of lung tissue under tension and compression
Lung injuries are common among those who suffer an impact or trauma. The relative severity of injuries up to physical tearing of tissue have been documented in clinical studies. However, the specific details of energy required to cause visible damage to the lung parenchyma are lacking. Furthermore, the limitations of lung tissue under simple mechanical loading are also not well documented. This study aimed to collect mechanical test data from freshly excised lung, obtained from both Sprague-Dawley rats and New Zealand White rabbits. Compression and tension tests were conducted at three different strain rates: 0.25, 2.5 and 25 min−1. This study aimed to characterise the quasi-static behaviour of the bulk tissue prior to extending to higher rates. A nonlinear viscoelastic analytical model was applied to the data to describe their behaviour. Results exhibited asymmetry in terms of differences between tension and compression. The rabbit tissue also appeared to exhibit stronger viscous behaviour than the rat tissue. As a narrow strain rate band is explored here, no conclusions are being drawn currently regarding the rate sensitivity of rat tissue. However, this study does highlight both the clear differences between the two tissue types and the important role that composition and microstructure can play in mechanical response
Experimental demonstration of a BDCZ quantum repeater node
Quantum communication is a method that offers efficient and secure ways for
the exchange of information in a network. Large-scale quantum communication (of
the order of 100 km) has been achieved; however, serious problems occur beyond
this distance scale, mainly due to inevitable photon loss in the transmission
channel. Quantum communication eventually fails when the probability of a dark
count in the photon detectors becomes comparable to the probability that a
photon is correctly detected. To overcome this problem, Briegel, D\"{u}r, Cirac
and Zoller (BDCZ) introduced the concept of quantum repeaters, combining
entanglement swapping and quantum memory to efficiently extend the achievable
distances. Although entanglement swapping has been experimentally demonstrated,
the implementation of BDCZ quantum repeaters has proved challenging owing to
the difficulty of integrating a quantum memory. Here we realize entanglement
swapping with storage and retrieval of light, a building block of the BDCZ
quantum repeater. We follow a scheme that incorporates the strategy of BDCZ
with atomic quantum memories. Two atomic ensembles, each originally entangled
with a single emitted photon, are projected into an entangled state by
performing a joint Bell state measurement on the two single photons after they
have passed through a 300-m fibre-based communication channel. The entanglement
is stored in the atomic ensembles and later verified by converting the atomic
excitations into photons. Our method is intrinsically phase insensitive and
establishes the essential element needed to realize quantum repeaters with
stationary atomic qubits as quantum memories and flying photonic qubits as
quantum messengers.Comment: 5 pages, 4 figure
Impact of Investor's Varying Risk Aversion on the Dynamics of Asset Price Fluctuations
While the investors' responses to price changes and their price forecasts are
well accepted major factors contributing to large price fluctuations in
financial markets, our study shows that investors' heterogeneous and dynamic
risk aversion (DRA) preferences may play a more critical role in the dynamics
of asset price fluctuations. We propose and study a model of an artificial
stock market consisting of heterogeneous agents with DRA, and we find that DRA
is the main driving force for excess price fluctuations and the associated
volatility clustering. We employ a popular power utility function,
with agent specific and
time-dependent risk aversion index, , and we derive an approximate
formula for the demand function and aggregate price setting equation. The
dynamics of each agent's risk aversion index, (i=1,2,...,N), is
modeled by a bounded random walk with a constant variance . We show
numerically that our model reproduces most of the ``stylized'' facts observed
in the real data, suggesting that dynamic risk aversion is a key mechanism for
the emergence of these stylized facts.Comment: 17 pages, 7 figure
Steps in the bacterial flagellar motor
The bacterial flagellar motor is a highly efficient rotary machine used by
many bacteria to propel themselves. It has recently been shown that at low
speeds its rotation proceeds in steps [Sowa et al. (2005) Nature 437,
916--919]. Here we propose a simple physical model that accounts for this
stepping behavior as a random walk in a tilted corrugated potential that
combines torque and contact forces. We argue that the absolute angular position
of the rotor is crucial for understanding step properties, and show this
hypothesis to be consistent with the available data, in particular the
observation that backward steps are smaller on average than forward steps. Our
model also predicts a sublinear torque-speed relationship at low torque, and a
peak in rotor diffusion as a function of torque
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
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