23 research outputs found
Galactose-modified duocarmycin prodrugs as senolytics
No full textSenescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of β-catenin-positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.</jats:p
Instabilities in oblique shock wave/laminar boundary-layer interactions
No full textInternational audienceThe interaction of an oblique shock wave and a laminar boundary layer developing over a flat plate is investigated by means of numerical simulation and global linear-stability analysis. Under the selected flow conditions (free-stream Mach numbers, Reynolds numbers and shock-wave angles), the incoming boundary layer undergoes separation due to the adverse pressure gradient. For a wide range of flow parameters, the oblique shock wave/boundary-layer interaction (OSWBLI) is seen to be globally stable. We show that the onset of two-dimensional large-scale structures is generated by selective noise amplification that is described for each frequency, in a linear framework, by wave-packet trains composed of several global modes. A detailed analysis of both the eigenspectrum and eigenfunctions gives some insight into the relationship between spatial scales (shape and localization) and frequencies. In particular, OSWBLI exhibits a universal behaviour. The lowest frequencies correspond to structures mainly located near the separated shock that emit radiation in the form of Mach waves and are scaled by the interaction length. The medium frequencies are associated with structures mainly localized in the shear layer and are scaled by the displacement thickness at the impact. The linear process by which OSWBLI selects frequencies is analysed by means of the global resolvent. It shows that unsteadiness are mainly associated with instabilities arising from the shear layer. For the lower frequency range, there is no particular selectivity in a linear framework. Two-dimensional numerical simulations show that the linear behaviour is modified for moderate forcing amplitudes by nonlinear mechanisms leading to a significant amplification of low frequencies. Finally, based on the present results, we draw some hypotheses concerning the onset of unsteadiness observed in shock wave/turbulent boundary-layer interactions
Global Instability in Shock Wave Laminar Boundary-Layer Interaction
No full textThe linear global stability of an interaction between an oblique shock wave and a laminar boundary layer is carried out for various oblique shock angles. It is illustrated that such a flow acts as a noise amplifier. The least temporally damped global modes are classified into three main categories, low, medium and high frequencies. The high frequencies are localized into the attached boundary layer, the medium frequencies are associated with Kelvin–Helmholtz like structures along the shear layer and convective waves in the separated flow downstream whereas the low frequencies are driven by the interaction zone. In particular, a low frequency mode emerges which is scaled by the interaction length and the freestream velocity
Bringing sensation to prosthetic hands—chronic assessment of implanted thin-film electrodes in humans
No full textDirect stimulation of peripheral nerves with implantable electrodes successfully provided sensory feedback to amputees while using hand prostheses. Longevity of the electrodes is key to success, which we have improved for the polyimide-based transverse intrafascicular multichannel electrode (TIME). The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. We present a comprehensive assessment of the electrical properties of the thin-film metallization as well as material status post explantationem. The TIMEs stayed within the electrochemical safe limits while enabling consistent and precise amplitude modulation. This lead to a reliable performance in terms of eliciting sensation. No signs of corrosion or morphological change to the thin-film metallization of the probes was observed by means of electrochemical and optical analysis. The presented longevity demonstrates that thin-film electrodes are applicable in permanent implant systems
TRAIL-based therapy in pediatric bone tumors: how to overcome resistance
No full textOsteosarcoma and Ewing’s sarcoma, the two most frequent malignant primary
tumors preferentially arise in children and young adults, and have a poor prognosis. TRAIL
represents a promising therapeutic approach for most cancers but in the case of primary
bone tumors, osteosarcoma cell lines are highly resistant to this pro-apoptotic cytokine.
In addition, another signaling pathway mediating cell proliferation and migration may be
even activated in this subset of resistant cells leading to protumoral effect. Therapeutic
perspectives are linked to possibility to overcome TRAIL resistance by combining other
drugs with TRAIL or death receptors agonistic antibodies. We hypothesized that the bone
microenvironment may provide a favorable niche for TRAIL resistance that might be targeted
by new resensitizing agents
Global analysis of the convective instabilities in laminar shock-wave/boundary-layer interactions
No full textThe interaction between a laminar boundary layer and an oblique shock wave is investigated through BiGlobal stability analysis. Previous studies have revealed the presence of a stationary mode (J.-Ph. Boin et al., TCFD 20(3), 2006, and J.-Ch. Robinet, JFM 579, 2007) and a convective instability mechanism (F. Guiho et al., JFM 789, 2016). In the latter analyses, non-localized eigenmodes are obtained that are artificially affected by the finite size of the chosen computational domain. In the present work, we obtain localized wave packets, that are independent of domain size and truncation boundary conditions, by applying the stability analysis in a moving frame of reference. The long-time behavior is subsequently determined by time integration, which results in the propagation of the localized wave packets in the flow. Finally, we highlight the mechanisms constituting the convective instabilities through a Reynolds-Orr energy budget analysis. To obtain the unstable basic state solution to the compressible Navier-Stokes equations, we have coupled Direct Numerical Simulations to the selective frequency damping method
TRAIL Delivered by Mesenchymal Stromal/Stem Cells Counteracts Tumor Development in Orthotopic Ewing Sarcoma Models.
No full textEwing sarcoma (EWS) is the second most frequent pediatric malignant bone tumor. EWS patients have not seen any major therapeutic progress in the last thirty years, in particular in the case of metastatic disease, which requires new therapeutic strategies. The pro-apoptotic cytokine TNF-Related Apoptosis Inducing Ligand (TRAIL) can selectively kill tumor cells while sparing normal cells, making it a promising therapeutic tool in several types of cancer. However, certain EWS cell lines appear resistant to recombinant human (rh) TRAIL-induced apoptosis. We therefore hypothesized that a TRAIL presentation at the surface of the carrier cells might overcome this resistance and trigger apoptosis. For this purpose, human adipose mesenchymal stromal/stem cells (MSC) transfected in a stable manner to express full-length human TRAIL were co-cultured with several human EWS cell lines, inducing apoptosis by cell-to-cell contact even in cell lines initially resistant to rhTRAIL or AMG655, an antibody agonist to the death receptor, DR5. In vivo, TRAIL delivered by MSCs was able to counteract tumor progression in two orthotopic models of Ewing sarcoma, associated with caspase activation, indicating that a cell-based delivery of a potent apoptosis-inducing factor could be relevant in EWS. This article is protected by copyright. All rights reserved
Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma
No full textPurpose: Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges in improving the response to chemotherapy warrants new strategies still needed to improve overall patient survival. Among new therapeutic approaches, zoledronic acid (ZOL) represents a promising adjuvant molecule to chemotherapy to limit the osteolytic component of bone tumors. However, ZOL triggers the elevation of heat shock proteins (Hsp), including Hsp27 and clusterin (CLU), which could enhance tumor cell survival and treatment resistance. We hypothesized that targeting CLU using siRNA or the antisense drug, OGX-011, will suppress treatment-induced CLU induction and enhance ZOL-induced cell death in osteosarcoma (OS) cells.
Methods: The combined effects of OGX-011 and ZOL were investigated in vitro on cell growth, viability, apoptosis and cell cycle repartition of ZOL-sensitive or -resistant human OS cell lines (SaOS2, U2OS, MG63 and MNNG/HOS).
Results: In OS cell lines, ZOL increased levels of HSPs, especially CLU, in a dose- and time-dependent manner by mechanism including increased HSF1 transcription activity. The OS resistant cells to ZOL exhibited higher CLU expression level than the sensitive cells. Moreover, CLU overexpression protects OS sensitive cells to ZOL-induced cell death by modulating the MDR1 and farnesyl diphosphate synthase expression. OGX-011 suppressed treatment-induced increases in CLU and synergistically enhanced the activity of ZOL on cell growth and apoptosis. These biologic events were accompanied by decreased expression of HSPs, MDR1 and HSF1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 20mg/kg), potentiated the effect of ZOL (s.c; 50µg/kg), significantly inhibiting tumor growth by 50% and prolonging survival in MNNG/HOS xenograft model compared to ZOL alone.
Conclusion: These results indicate that ZOL-mediated induction of CLU can be attenuated by OGX-011, with synergistic effects on delaying progression of osteosarcoma
Validating planning domain models using B-AMN
No full textThe validation of planning domain models is an important issue and can present problems. In this paper we describe ongoing work which attempts to overcome these problems through the construction of a B-AMN specication which models the domain. The B-Method utilises B-AMN, a state-based formal specication language with tool support provided by the B-Toolkit. We describe how this tool support provides facilities for both animation and proof, and we propose the use of the B-Method at an initial level of domain capture. The approach is illustrated using a simple transport domain, where a high-level model, which can be reasoned with, is produced. In addition, animation allows validation by users
