The survey on cellular and tissue-engineered therapies in Europe and neighboring Eurasian countries in 2014 and 2015

Background aims

With the support of five established scientific organizations, this report, the seventh of its kind, describes activity in Europe for the years 2014 and 2015 in the area of cellular and tissue-engineered therapies, excluding hematopoietic stem cell (HSC) treatments for the reconstitution of hematopoiesis.

Half a century of oligochaete research in Estonian running waters

About 51500 specimens from 1542 samples, collected over the years 1954–1975 and 1986–1999 in different running water bodies throughout Estonia, were identified. Tubificidae prevailed in the material, with Limnodrilus hoffmeisteri forming about 40%. This species was followed by the tubificids Tubifex tubifex, Potamothrix hammoniensis, Psammoryctides barbatus, L. udekemianus and Spirosperma ferox, the naidid Stylaria lacustris, and the lumbriculid Stylodrilus heringianus. Two main ecological assemblages were distinguished: the pelophilous assemblage, dominated by L. hoffmeisteri, and the psammophilous one, where usually P. barbatus was dominant. The relationships between different species and the chemical parameters of water were usually weak but in contrast, correlated well with sediment preferences. In organically enriched reaches, L. hoffmeisteri usually dominated. The fauna of the streams of the islands was poorer in species due to their small size rather than geographical isolation. Some recent antropochorous Ponto-Caspian invaders have only reached the lowermost reaches of the two largest rivers. Some brackish water species were found in the mouth of the Pärnu River. No essential differences were found between the comparable sets of oligochaete samples collected in 1954–1975 and 1987–1997 in the Estonian running waters.     

Species-specific responses to atmospheric carbon dioxide and tropospheric ozone mediate changes in soil carbon

We repeatedly sampled the surface mineral soil (0–20 cm depth) in three northern temperate forest communities over an 11-year experimental fumigation to understand the effects of elevated carbon dioxide (CO₂) and/or elevated phyto-toxic ozone (O₃) on soil carbon (C). After 11 years, there was no significant main effect of CO₂ or O₃ on soil C. However, within the community containing only aspen ( Populus tremuloides Michx.), elevated CO₂ caused a significant decrease in soil C content. Together with the observations of increased litter inputs, this result strongly suggests accelerated decomposition under elevated CO_2. In addition, an initial reduction in the formation of new (fumigation-derived) soil C by O₃ under elevated CO₂ proved to be only a temporary effect, mirroring trends in fine root biomass. Our results contradict predictions of increased soil C under elevated CO₂ and decreased soil C under elevated O₃ and should be considered in models simulating the effects of Earth's altered atmosphere.     

Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity

Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.     

LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer

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生长期SD大鼠对日粮常规营养物质和氨基酸消化率的研究

目的了解SD大鼠对营养物质消化特点,研究不同结构日粮营养物质的可消化性,为筛选适合SD生长大鼠的日粮营养物质水平和日粮配方提供科学参数. 方法采用饲养试验结束时的90 d龄体重相近的90只SD大鼠,分为9个组,每组10 只,雌雄各半,分笼、每笼5只,采用全收粪法对9个配方日粮进行5 d消化试验,测定9个日粮的能量和6种常规营养物质以及17种氨基酸(AA)的表观消化率.结果以第3组日粮的可消化性为最好,它的总能(GE)、粗蛋白(CP)、粗纤维(CF)、粗脂肪(EE)、无氮浸出物(NFE)、钙(Ca)、磷(P)和17种氨基酸的表观消化率(%)依次分别为85.7、88.0、2 9.5、89.2、90.0、47.6、35.7和85.0(17个氨基酸AA平均值);这些营养物质在9个组的总平均表现消化率(%)依次分别为82.1、79.1、24.7、84.9、88.4、37.1、33.1和 81.5,结果表明,生长期SD大鼠对不同结构的日粮,不同水平的营养物质的可消化性不同 ,不同营养物质的消化率差别较大,以第3组日粮配方及其营养水平较适宜于生长期SD大鼠 ,它的DE、CP、EE、CF、NFE、Ca和P水平依次为14MJ.kg-1、18%、4.5%、4.0%、5 5.0%、1.00%和0.66%,它的苏氨酸,胱氨酸、缬氨酸、蛋氨酸、异亮氨酸、亮氨酸、酪氨酸、苯丙氨酸、赖氨酸、组氨酸和精氨酸水(%)依次为0.74、0.38、1.00、0.40、0. 93、1.65、0.62、0.94、1.00、0.58和1.22,它的可消化氨基酸水平(%)依次为0.60 、0.29、0.84、0.31、0.76、1.45、0.52、0.82、0.87、0.52和1.12.结论日粮能量具有较高的可消化性,对于其他营养物质的消化吸收利用有正效应影响.     

Effects of long-term antibiotic treatment on mice urinary aromatic amino acid profiles

The gut microbiota–host co-metabolites are good indicators for representing the cross-talk between host and gut microbiota in a bi-direct manner. There is increasing evidence that levels of aromatic amino acids (AAAs) are associated with the alteration of intestinal microbial community though the effects of long-term microbial disturbance remain unclear. Here we monitored the gut microbiota composition and host–microbiota co-metabolites AAA profiles of mice after gentamicin and ceftriaxone treatments for nearly 4 months since their weaning to reveal the relationship between host and microbiome in long- term microbial disturbances. The study was performed employing targeted LC-MS measurement of AAA-related metabolites and 16S RNA sequence of mice cecal contents. The results showed obvious decreased gut microbial diversity and decreased Firmicutes/Bacteroidetes ratio in the cecal contents after long-term antibiotics treatment. The accumulated AAA (tyrosine, phenylalanine and tryptophan) and re-distribution of their downstreaming metabolites that produced under the existence of intestinal flora were found in mice treated with antibiotics for 4 months. Our results suggested that the long-term antibiotic treatment significantly changed the composition of the gut microbiota and destroyed the homeostasis in the intestinal metabolism. And the urinary AAA could be an indicator for exploring interactions between host and gut microbiota.     

Long-term release of clodronate from biodegradable microspheres

This paper describes the formulation of a biodegradable microparticulate drug delivery system containing clodronate, a bisphosphonate intended for the treatment of bone diseases. Microspheres were prepared with several poly(D,L-lactide-co-glycolide) (PLGA) copolymers of various molecular weights and molar compositions and 1 poly(D,L-lactide) (PDLLA) homopolymer by a water-in-oil-in-water (w/o/w) double emulsion solvent evaporation procedure. Critical process parameters and formulation variables (ie, addition of stabilizing agents) were evaluated for their effect on drug encapsulation efficiency and clodronate release rate from microparticles Well-formed clodronate-loaded microspheres were obtained for all polymers by selecting suitable process parameters (inner water/oil volume ratio 1∶16, temperature-raising rate in the solvent evaporation step 1°C/min, 2% wt/vol NaCl in the external aqueous phase). Good yields were obtained in all batches of clodronate microspheres (above 60%); drug encapsulation efficiencies ranged between 49% and 75% depending on the polymer used. Clodronate release from all copolymer microspheres was completed in about 48 hours, while those from PDLLA microspheres required about 20 days. The change of microsphere composition by adding a surfactant such as Span 20 or a viscosing agent such as carboxymethylcellulose extended the long-term release up to 3 months. Clodronate was successfully entrapped in PLGA and PDLLA microspheres, and drug release could be modulated from 48 hours up to 3 months by suitable selection of polymer, composition, additives, and manufacturing conditions. Published: July 11, 2001.     

从美国 FDA 审评角度探讨新药研发的风险控制

众所周知,新药研发是一个漫长而艰难的过程,投入大,但成功率低。从项目的选择、分子结构最优化、靶点的选择、体外实 验结果与体内反应的一致性、药物安全性、临床试验设计优化以及对新药研发相关法规的理解、与监管部门的有效沟通等诸方面,探讨 对新药研发风险的把控。