953 research outputs found
Creating tissue on chip constructs in microtitre plates for drug discovery
We report upon a novel coplanar dielectrophoresis (DEP) based cell patterning system for generating
transferrable hepatic cell constructs, resembling a liver-lobule, in culture. The use of paper reinforced gel
substrates provided sufficient strength to enable these constructs to be transfered into 96-well plates for
long term functional studies, including in the future, drug development studies. Experimental results
showed that hepatic cells formed DEP field-induced structures corresponding to an array of lobulemimetic patterns. Hepatic viability was observed over a period of 3 days by the use of a fluorescent cell
staining technique, whilst the liver specific functionality of albumin secretion showed a significant
enhancement due to the layer patterning of cell lines (HepG2/C3A), compared to 2D patterned cells and
un-patterned control. This ābuild and transferā concept could, in future, also be adapted for the layer-bylayer construction of organs-on-chip in microtitre formats
Can We Understand the Clinical Biology of Gastric Cancer and Exploit it? May be, but It is a Challenge!
Spatio-temporal Models of Lymphangiogenesis in Wound Healing
Several studies suggest that one possible cause of impaired wound healing is
failed or insufficient lymphangiogenesis, that is the formation of new
lymphatic capillaries. Although many mathematical models have been developed to
describe the formation of blood capillaries (angiogenesis), very few have been
proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a
markedly different process from angiogenesis, occurring at different times and
in response to different chemical stimuli. Two main hypotheses have been
proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the
edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic
endothelial cells first pool in the wound region following the lymph flow and
then, once sufficiently populated, start to form a network. Here we present two
PDE models describing lymphangiogenesis according to these two different
hypotheses. Further, we include the effect of advection due to interstitial
flow and lymph flow coming from open capillaries. The variables represent
different cell densities and growth factor concentrations, and where possible
the parameters are estimated from biological data. The models are then solved
numerically and the results are compared with the available biological
literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total
A phase I dose-escalation study to evaluate safety and tolerability of sorafenib combined with sirolimus in patients with advanced solid cancer
Contains fulltext :
87630.pdf (publisher's version ) (Closed access)BACKGROUND: The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically. METHODS: A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination. RESULTS: Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar-plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0-96) and C(max) of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8-24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d. CONCLUSION: The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination
Toxicity assessment of individual ingredients of synthetic-based drilling muds (SBMs)
Synthetic-based drilling muds (SBMs) offer excellent technical characteristics while providing improved environmental performance over other drilling muds. The low acute toxicity and high biodegradability of SBMs suggest their discharge at sea would cause minimal impacts on marine ecosystems, however, chronic toxicity testing has demonstrated adverse effects of SBMs on fish health. Sparse environmental monitoring data indicate effects of SBMs on bottom invertebrates. However, no environmental toxicity assessment has been performed on fish attracted to the cutting piles. SBM formulations are mostly composed of synthetic base oils, weighting agents, and drilling additives such as emulsifiers, fluid loss agents, wetting agents, and brine. The present study aimed to evaluate the impact of exposure to individual ingredients of SBMs on fish health. To do so, a suite of biomarkers [ethoxyresorufin-O-deethylase (EROD) activity, biliary metabolites, sorbitol dehydrogenase (SDH) activity, DNA damage, and heat shock protein] have been measured in pink snapper (Pagrus auratus) exposed for 21 days to individual ingredients of SBMs. The primary emulsifier (Emul S50) followed by the fluid loss agent (LSL 50) caused the strongest biochemical responses in fish. The synthetic base oil (Rheosyn) caused the least response in juvenile fish. The results suggest that the impact of Syndrill 80:20 on fish health might be reduced by replacement of the primary emulsifier Emul S50 with an alternative ingredient of less toxicity to aquatic biota. The research provides a basis for improving the environmental performance of SBMs by reducing the environmental risk of their discharge and providing environmental managers with information regarding the potential toxicity of individual ingredients. Ā© 2011 Springer Science+Business Media B.V
The Obesity and Fatty Liver Are Reduced by Plant-Derived Pediococcus pentosaceus LP28 in High Fat Diet-Induced Obese Mice
We evaluated the effect of an oral administration of a plant-derived lactic acid bacterium, Pediococcus pentosaceus LP28 (LP28), on metabolic syndrome by using high fat diet-induced obese mice. The obese mice were divided into 2 groups and fed either a high fat or regular diet for 8 weeks. Each group was further divided into 3 groups, which took LP28, another plant-derived Lactobacillus plantarum SN13T (SN13T) or no lactic acid bacteria (LAB). The lean control mice were fed a regular diet without inducing obesity prior to the experiment. LP28 reduced body weight gain and liver lipid contents (triglyceride and cholesterol), in mice fed a high fat diet for 8 weeks (40%, 54%, and 70% less than those of the control group without LAB, and Pā=ā0.018, P<0.001, and Pā=ā0.021, respectively), whereas SN13T and the heat treated LP28 at 121Ā°C for 15 min were ineffective. Abdominal visceral fat in the high fat diet mice fed with LP28 was also lower than that without LAB by 44%, although it was not significant but borderline (Pā=ā0.076). The sizes of the adipocytes and the lipid droplets in the livers were obviously decreased. A real-time PCR analyses showed that lipid metabolism-related genes, such as CD36 (Pā=ā0.013), SCD1 encoding stearoyl-CoA desaturase 1 (not significant but borderline, Pā=ā0.066), and PPARĪ³ encoding peroxisome proliferator-activated receptor gamma (Pā=ā0.039), were down-regulated by taking LP28 continuously, when compared with those of the control group. In conclusion, LP28 may be a useful LAB strain for the prevention and reduction of the metabolic syndrome
Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at ā s = 8 TeV with the ATLAS detector
Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fbā1 of ā s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente
Mesenchymal Stromal Cells Improve Salivary Function and Reduce Lymphocytic Infiltrates in Mice with Sjƶgren's-Like Disease
Non-obese diabetic (NOD) mice develop Sjƶgren's-like disease (SS-like) with loss of saliva flow and increased lymphocytic infiltrates in salivary glands (SGs). There are recent reports using multipotent mesenchymal stromal cells (MSCs) as a therapeutic strategy for autoimmune diseases due to their anti-inflammatory and immunomodulatory capabilities. This paper proposed a combined immuno- and cell-based therapy consisting of: A) an injection of complete Freund's adjuvant (CFA) to eradicate autoreactive T lymphocytes, and B) transplantations of MSCs to reselect lymphocytes. The objective of this was to test the effectiveness of CD45(-)/TER119(-) cells (MSCs) in re-establishing salivary function and in reducing the number of lymphocytic infiltrates (foci) in SGs. The second objective was to study if the mechanisms underlying a decrease in inflammation (focus score) was due to CFA, MSCs, or CFA+MSCs combined.Donor MSCs were isolated from bones of male transgenic eGFP mice. Eight week-old female NOD mice received one of the following treatments: insulin, CFA, MSC, or CFA+MSC (combined therapy). Mice were followed for 14 weeks post-therapy. CD45(-)/TER119(-) cells demonstrated characteristics of MSCs as they were positive for Sca-1, CD106, CD105, CD73, CD29, CD44, negative for CD45, TER119, CD11b, had high number of CFU-F, and differentiated into osteocytes, chondrocytes and adipocytes. Both MSC and MSC+CFA groups prevented loss of saliva flow and reduced lymphocytic infiltrations in SGs. Moreover, the influx of T and B cells decreased in all foci in MSC and MSC+CFA groups, while the frequency of Foxp3(+) (T(reg)) cell was increased. MSC-therapy alone reduced inflammation (TNF-Ī±, TGF-Ī²), but the combination of MSC+CFA reduced inflammation and increased the regenerative potential of SGs (FGF-2, EGF).The combined use of MSC+CFA was effective in both preventing saliva secretion loss and reducing lymphocytic influx in salivary glands
GABAA receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation
PurposeThe purpose of this review is to summarize current knowledge of detailed biochemical evidence for the role of Ī³-aminobutyric acid type A receptors (GABA(A)-Rs) in the mechanisms of general anesthesia.Principal findingsWith the knowledge that all general anesthetics positively modulate GABA(A)-R-mediated inhibitory transmission, site-directed mutagenesis comparing sequences of GABA(A)-R subunits of varying sensitivity led to identification of amino acid residues in the transmembrane domain that are critical for the drug actions in vitro. Using a photo incorporable analogue of the general anesthetic, R(+)etomidate, we identified two transmembrane amino acids that were affinity labelled in purified bovine brain GABA(A)-R. Homology protein structural modelling positions these two residues, Ī±M1-11' and Ī²M3-4', close to each other in a single type of intersubunit etomidate binding pocket at the Ī²/Ī± interface. This position would be appropriate for modulation of agonist channel gating. Overall, available information suggests that these two etomidate binding residues are allosterically coupled to sites of action of steroids, barbiturates, volatile agents, and propofol, but not alcohols. Residue Ī±/Ī²M2-15' is probably not a binding site but allosterically coupled to action of volatile agents, alcohols, and intravenous agents, and Ī±/Ī²M1-(-2') is coupled to action of intravenous agents.ConclusionsEstablishment of a coherent and consistent structural model of the GABA(A)-R lends support to the conclusion that general anesthetics can modulate function by binding to appropriate domains on the protein. Genetic engineering of mice with mutation in some of these GABA(A)-R residues are insensitive to general anesthetics in vivo, suggesting that further analysis of these domains could lead to development of more potent and specific drugs
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