TRAIL receptor signaling and therapeutic option in bone tumors: the trap of the bone microenvironment

Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) has been reported to specifically induce malignant cell death being relatively nontoxic to normal cells. Since its identification 15 years ago, the antitumor activity and therapeutic value of TRAIL have been extensively studied. Five receptors quickly emerged, two of them being able to induce programmed cell death in tumor cells. This review takes a comprehensive look at this ligand and its receptors, and its potential role in primary bone tumors (osteosarcoma and Ewing's sarcoma) therapy. The main limit of clinical use of TRAIL being the innate or acquired resistance mechanisms, different possibilities to sensitize resistant cells are discussed in this review, together with the impact of bone microenvironment in the regulation of TRAIL activity

CHALLENGES OF DYNAMIC SIMULATION OF HIGH-SPEED ELECTROMAGNETIC VALVES OF GAS DISTRIBUTION DEVICES

High-speed electromagnetic valves of gas distribution devices are used in modern missile and space technology as jet micro-motors of the executive elements of missile stabilization systems, as well as to control the movement of spacecrafts in space. The problem of creating such valves which are simple and reliable in the operation is relevant. In this work, it is proposed at the development and design stage to perform computer modelling of mutually coupled electromechanical processes, such as: distribution of transient electromagnetic field, transients in an electric circuit, and movement of an electromagnet armature. Besides, the calculation of the force with which the compressed gas acts on the corresponding structural elements of the valve is proposed to be performed by solving the system of Navier-Stokes equations. All problems are solved by numerical methods in axisymmetrical formulation with the corresponding initial and boundary conditions. Improvement of the accuracy of electromagnetic calculations and taking into account the movement of the armature of an electromagnet in the process of multiphysics numerical simulation is achieved using so-called tunable elastic meshes. The paper presents a comparative analysis of the numerical results obtained for several designs of electromagnets. The features of the dynamics of high-speed electromagnets of gas distribution valves during on and off operations are analyzed, the corresponding dynamic characteristics calculated using the proposed technique are presented. Быстродействующие электромагнитные клапаны газораспределительных устройств применяются в современной ракетно-космической технике в качестве реактивных микродвигателей исполнительных органов систем стабилизации ракет, а также для управления движением космическими летательными аппаратами в пространстве. Проблема создания простых в эксплуатации и надежных в работе указанных клапанов является актуальной. В настоящей работе предлагается на стадии разработки и проектирования выполнять компьютерное моделирование взаимосвязанных электромеханических процессов, таких как: распределение нестационарного электромагнитного поля, переходные процессы в электрической цепи, движение якоря электромагнита. При этом расчет силы, с которой сжатый газ действует на соответствующие конструктивные элементы клапана, предлагается выполнять путем решения системы уравнений Навье-Стокса. Все задачи решаются численными методами в осесимметричной постановке с соответствующими начальными и граничными условиями. Повышение точности электромагнитных расчетов и учет движения якоря электромагнита в процессе мультифизического численного моделирования достигается благодаря использованию так называемых перестраиваемых упругих сеток. В работе приведен сравнительный анализ численных результатов, полученных для нескольких конструкций электромагнитов. Проанализированы особенности динамики быстродействующих электромагнитов газораспределительных клапанов при выполнении операций включения и отключения, приведены соответствующие динамические характеристики, рассчитанные по предложенной методике.

Calcifediol is a safe and effective metabolite for raising vitamin D status and improving growth and feed conversion in rainbow trout

The vitamin D endocrine system is required for the transcriptional regulation of a myriad of vertebrate genes including those involved in bone health, growth, nutrient metabolism and immunity. The requirements of salmonids for vitamin D are amongst the highest for any aquaculture species. With nuances, the metabolism of the pre-vitamin cholecalciferol (D3) via calcifediol (25-OH-D3), required to produce the physiologically active hormone calcitriol (1,25-OH-D3) is conserved in fish. The composition of modern aquafeeds, growth in seawater and production challenges, such as disease, may result in the suboptimal biochemical activation of vitamin D hormone in fish. A 91-day experimental feeding trial was used to test the safety and efficacy of calcifediol for the supply of vitamin D to rainbow trout with an initial body weight of 57.6 g. A practical diet containing cholecalciferol within recommended levels (5240 IU) was supplemented with either 69.8, 687 or 6854 μg/kg calcifediol. The efficacy of calcifediol was determined by the assessment of zootechnical performance and the appearance of vitamin D metabolites in the blood. The safety of the dietary interventions was assessed from generic health indices, examination of gross pathologies, hematology, and blood chemistry. Test fish increased body weight at least 5.6-fold to 323.5 g over the experimental feeding period. The supplementation of 687 or 6854 μg/kg calcifediol resulted in significant improvements in growth rate and feed conversion (FCR). Whilst not detectable in control fish, calcifediol increased linearly according to dietary levels in the blood and to a lesser extent in the white muscle. The increases of calcifediol in the blood were accompanied by saturable increases of circulating active vitamin D. At the end of the 91-day feeding period, survival was 100%, no gross pathologies relating to the diets were observed, and health indices, hematology, and blood chemistry, including calcium and phosphorus, were not significantly altered. The supplementation of calcifediol to practical diets containing recommended levels of cholecalciferol improves zootechnical performance and ensures that maximal levels of active vitamin D are present in the blood to meet physiological demands. With a lack of significant effects on health indices, hematology, and blood chemistry, including calcium and phosphorus, the tested high doses of calcifediol are concluded to be safe for salmonids

Superparamagnetic Liposomes for MRI Monitoring and External Magnetic Field-Induced Selective Targeting of Malignant Brain Tumors

Magnetic-fluid-loadedliposomes (MFLs) of optimized magnetic responsiveness are newly worked out from the entrapment of superparamagnetic maghemite nanocrystals in submicronic PEG-ylated rhodamine-labelled phospholipid vesicles. This nanoplatform provides an efficient tool for the selective magnetic targeting of malignant tumors localized in brain and non-invasive traceability by MRI through intravascular administration. As assessed by in vivo 7-T MRI and ex vivo electron spin resonance, 4-h exposure to 190-T m–1magnetic field gradient efficiently concentrates MFLs into human U87 glioblastoma implanted in the striatum of mice. The magnetoliposomes are then longer retained therein as checked by MRI monitoring over a 24-h period. Histological analysis by confocal fluorescence microscopy confirms the significantly boosted accumulation of MFLs in the malignant tissue up to the intracellular level. Electron transmission microscopy reveals effective internalization by endothelial and glioblastoma cells of the magnetically conveyed MFLs as preserved vesicle structures. The magnetic field gradient emphasizes MFL distribution solely in the tumors according to the enhanced permeability and retention (EPR) effect while comparatively very low amounts are recovered in the other cerebral areas. Such a selective targeting precisely traceable by MRI is promising for therapeutic applications since the healthy brain tissue can be expected to be spared during treatments by deleterious anticancer drugs carried by magnetically guided MFLs

Pre-clinical studies of bone regeneration with human bone marrow stromal cells and biphasic calcium phosphate

Introduction Repair of large bone defects remains a significant clinical challenge. Bone marrow stromal cells (BMSCs), a subset of which is known as bone marrow-derived mesenchymal stem cells, show therapeutic potential for bone regeneration. However, their isolation, expansion and implantation will need to be conducted under good manufacturing practices (GMP) at separate locations. An investigation which mimics this clinical scenario where large bone defects shall be regenerated is required before clinical trials can be initiated. Methods Seven batches of 100 million human ex-vivo expanded BMSCs from five donors were transported fresh in syringes from a GMP facility in Germany to France. BMSCs were mixed with biphasic calcium phosphate (BCP) biomaterial prior to subcutaneous implantation in nude mice. The capacity of BMSCs in unison with BCP to regenerate critical sized cranial bone defects was also evaluated. BMSCs expressing luciferase were used to assess the viability and bio-distribution of implanted cells. In situ hybridization, using the human-specific repetitive Alu sequence, was performed for the identification of human cells in explants. Results Eight weeks after implantation of BMSCs, mineralized bone containing mature bone marrow territories was formed in ectopic sites and in calvaria defects. Significant loss of cell viability was observed by bioluminescence imaging and only 1.5 percent of the initial number of transplanted cells remained after 37 days. After eight weeks, while explants were comprised primarily of host cells, there were also human cells attached along the periphery of BCP and embedded in osteocyte lacunae dispersed throughout the newly formed bone matrix. Conclusions This study demonstrates the safety and efficacy of BMSC/BCP combinations and provides crucial information for the implementation of BMSC therapy for bone regeneration

The transmission of unconventional monetary policy to bank credit supply : evidence from the TLTRO

We assess the transmission of the Targeted Longer-Term Refinancing Operations (TLTRO) to the bank credit supply for the Euro area (2014:05-2018:01) and for Portugal (2011:01-2018:01), using a panel data setup. For the Euro area, we find a positive relationship between the TLTRO and the amount of credit granted to the real economy. For the vulnerable countries, the effects of the TLTRO on the stock of credit increased from 2016 to 2017. Among the group of small banks, the effects are stronger in less vulnerable countries. We also find that competition has no statistically significant impact on the transmission of the TLTRO to the bank credit supply for the Euro area. For Portugal, using a difference-in-differences model, we find no statistically significant impact of the TLTRO on credit granted by banks. Finally, bidding banks set lower interest rates than non-bidding banks and the difference seems to be larger in 2017. In Portugal, the effects of the TLTRO on loan interest rates also increased from 2016 to 2017 and are stronger for small banks.info:eu-repo/semantics/publishedVersio

Nocardia transvalensis keratitis: an emerging pathology among travelers returning from Asia

<p>Abstract</p> <p>Background</p> <p>The incidence rate of <it>Nocardia </it>keratitis is increasing, with new species identified thanks to molecular methods. We herein report a case of <it>Nocardia transvalensis </it>keratitis, illustrating this emerging pathology among travellers returning from Asia.</p> <p>Case presentation</p> <p>A 23-year-old man presented with a 10-week history of ocular pain, redness, and blurred vision in his right eye following a projectile foreign body impacting the cornea while motor biking in Thaïland. At presentation, a central epithelial defect with a central whitish stromal infiltrate associated with pinhead satellite infiltrates was observed. Identification with 16S rRNA PCR sequencing and microbiological culture of corneal scraping and revealed <it>N. transvalensis </it>as the causative organism. Treatment was initiated with intensive topical amikacin, oral ketoconazole and oral doxycycline. After a four-week treatment period, the corneal infiltrate decreased so that only a faint subepithelial opacity remained.</p> <p>Conclusion</p> <p><it>Nocardia </it>organisms should be suspected as the causative agent of any case of keratitis in travelers returning from Asia. With appropriate therapy, <it>Nocardia </it>keratitis resolves, resulting in good visual outcome.</p

Morphology and foliar chemistry of containerized Abies fraseri (Pursh) Poir. seedlings as affected by water availability and nutrition

• We present the results of a two-year (2007–2008) greenhouse study investigating the effect of water availability and nitrogen fertilization on the growth, biomass partitioning, and foliar nutrient content of Abies fraseri (Pursh) Poir. • Fertilizer and moisture content (irrigation) were varied in a factorial experiment combining four levels of irrigation and three levels of fertilization to evaluate growth and foliar nutrient content. In addition, a numerical optimization was used to estimate appropriate levels of each factor necessary to achieve simulated goals for response variables. • Irrigation increased the height growth by 12 to 35% depending on the fertilization treatment (p = 0.0001). Fertilization increased height growth by 10 to 26% (p = 0.02). A similar response was observed for stem diameter growth (SDG). Total biomass accumulation increased as result of positive response of stem and root biomass development, and foliar nitrogen content was positively affected by nitrogen fertilization and negatively affected by irrigation. The numerical optimization for simulated target growth and nitrogen content responses produced levels of input combinations with high desirability factors to achieve the target responses. • These results suggest that nutrient addition is a strong determining factor for early development of this species. The improved growth efficiency in this study is likely attributed to a combination of factors including, improved photosynthetic capacity, decreased stomatal limitations, or increased resource allocation to stems