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921.
Jordan Shaun Bankiewicz Krzysztof S. Eberling Jamie L. VanBrocklin Henry F. O'Neil James P. Jagust William J. 《Neurochemical research》1998,23(4):513-517
In vivo brain microdialysis was used to monitor 6-[18F]fluoro-L-m-tyrosine (FMT) uptake and metabolism in the striatum of conscious freely moving rats for 3 hours after FMT injection (25 mg/kg, iv). Microdialysate collected 20 to 120 min post-dose, contained FMT at a concentration (0.2 to 0.3 nM) approximately ten-fold below that of its metabolite [18F]fluoro-3-hydroxyphenylacetic acid (FPAC; 3.2 to 3.3 nM). D-amphetamine (2.5 mg/kg, i.p.) injected 120 min after significantly increased microdialysate FPAC (3.27 ± 0.31 nM to 4.51 ± 0.45 nM) in control but not reserpinized rats. Taken together these data demonstrate FMT is heavily metabolized following its entry into the striatum yielding FPAC which appears to be stored, at least in part, in reserpine sensitive cytoplasmic vesicles. Presynaptic retention of FPAC may contribute to the preferential accumulation of FMT positron emission tomography (PET) signaling in dopaminergic brain areas. 相似文献
922.
We evaluate the grand potential of a cluster of two molecular species, equivalent to its free energy of formation from a binary vapour phase, using a non-equilibrium molecular dynamics technique where guide particles, each tethered to a molecule by a harmonic force, move apart to disassemble a cluster into its components. The mechanical work performed in an ensemble of trajectories is analysed using the Jarzynski equality to obtain a free energy of disassembly, a contribution to the cluster grand potential. We study clusters of sulphuric acid and water at 300 K, using a classical interaction scheme, and contrast two modes of guided disassembly. In one, the cluster is broken apart through simple pulling by the guide particles, but we find the trajectories tend to be mechanically irreversible. In the second approach, the guide motion and strength of tethering are modified in a way that prises the cluster apart, a procedure that seems more reversible. We construct a surface representing the cluster grand potential, and identify a critical cluster for droplet nucleation under given vapour conditions. We compare the equilibrium populations of clusters with calculations reported by Henschel et al. [J. Phys. Chem. A 2014;118:2599] based on optimised quantum chemical structures. 相似文献
923.
924.
925.
Fergus Noble Toby Mellows Leo H. McCormick Matthews Adrian C. Bateman Scott Harris Timothy J. Underwood James P. Byrne Ian S. Bailey Donna M. Sharland Jamie J. Kelly John N. Primrose Surinder S. Sahota Andrew R. Bateman Gareth J. Thomas Christian H. Ottensmeier 《Cancer immunology, immunotherapy : CII》2016,65(6):651-662
Background
Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.Materials and Methods
Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.Results
Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.Discussion
Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.926.
927.
James W. Larrick Mark R. Alfenito Jamie K. Scott Paul W. H. I. Parren Dennis R. Burton Andrew R. M. Bradbury 《MABS-AUSTIN》2016,8(8):1425-1434
Antibody Engineering & Therapeutics, the largest meeting devoted to antibody science and technology and the annual meeting of The Antibody Society, will be held in San Diego, CA on December 11-15, 2016. Each of 14 sessions will include six presentations by leading industry and academic experts. In this meeting preview, the session chairs discuss the relevance of their topics to current and future antibody therapeutics development. Session topics include bispecifics and designer polyclonal antibodies; antibodies for neurodegenerative diseases; the interface between passive and active immunotherapy; antibodies for non-cancer indications; novel antibody display, selection and screening technologies; novel checkpoint modulators / immuno-oncology; engineering antibodies for T-cell therapy; novel engineering strategies to enhance antibody functions; and the biological Impact of Fc receptor engagement. The meeting will open with keynote speakers Dennis R. Burton (The Scripps Research Institute), who will review progress toward a neutralizing antibody-based HIV vaccine; Olivera J. Finn, (University of Pittsburgh School of Medicine), who will discuss prophylactic cancer vaccines as a source of therapeutic antibodies; and Paul Richardson (Dana-Farber Cancer Institute), who will provide a clinical update on daratumumab for multiple myeloma. In a featured presentation, a representative of the World Health Organization's INN expert group will provide a perspective on antibody naming. “Antibodies to watch in 2017” and progress on The Antibody Society's 2016 initiatives will be presented during the Society's special session. In addition, two pre-conference workshops covering ways to accelerate antibody drugs to the clinic and the applications of next-generation sequencing in antibody discovery and engineering will be held on Sunday December 11, 2016. 相似文献
928.
Jamie L. Kuck Julie A. Bastarache Ciara M. Shaver Joshua P. Fessel Sergey I. Dikalov James M. May Lorraine B. Ware 《Biochemical and biophysical research communications》2018,495(1):433-437
Background
Increased endothelial permeability is central to shock and organ dysfunction in sepsis but therapeutics targeted to known mediators of increased endothelial permeability have been unsuccessful in patient studies. We previously reported that cell-free hemoglobin (CFH) is elevated in the majority of patients with sepsis and is associated with organ dysfunction, poor clinical outcomes and elevated markers of oxidant injury. Others have shown that Vitamin C (ascorbate) may have endothelial protective effects in sepsis. In this study, we tested the hypothesis that high levels of CFH, as seen in the circulation of patients with sepsis, disrupt endothelial barrier integrity.Methods
Human umbilical vein endothelial cells (HUVEC) were grown to confluence and treated with CFH with or without ascorbate. Monolayer permeability was measured by Electric Cell-substrate Impedance Sensing (ECIS) or transfer of 14C-inulin. Viability was measured by trypan blue exclusion. Intracellular ascorbate was measured by HPLC.Results
CFH increased permeability in a dose- and time-dependent manner with 1 mg/ml of CFH increasing inulin transfer by 50% without affecting cell viability. CFH (1 mg/ml) also caused a dramatic reduction in intracellular ascorbate in the same time frame (1.4 mM without CFH, 0.23 mM 18 h after 1 mg/ml CFH, p < 0.05). Pre-treatment of HUVECs with ascorbate attenuated CFH induced permeability.Conclusions
CFH increases endothelial permeability in part through depletion of intracellular ascorbate. Supplementation of ascorbate can attenuate increases in permeability mediated by CFH suggesting a possible therapeutic approach in sepsis. 相似文献929.
This article analyses 845 posts across 78 threads on an English Defence League message board from 20 September 2013 to 4 October 2013 that examined how online activists construct and develop their racial prejudice. Through seeing whites as blameless victims, the posts highlighted the presence of hostility towards Islam and Muslims in a clear in-group and out-group racial binary, where racist comments were never contested or challenged. Rather, they were wholeheartedly supported with social and cultural division at the centre of the prejudice, scapegoating and stereotyping directed towards Islam and Muslims. For a movement that presents itself as anti-racist, the real-life everyday narrative indicates the reality of its most ardent supporters. 相似文献
930.
Landscape genetics affords a potential analysis framework to evaluate the effect of contemporary land use on endangered species at a population level. However, historical patterns of population connectivity need to be accounted for prior to testing for the contemporary effect of threats. The goals of this study were to (1) optimally describe historical patterns in population connectivity for a diadromous fish species before (2) evaluating whether residual genetic variation was correlated with ecological changes arising from several types of land use. Using endangered Atlantic salmon populations as a case study, we evaluated whether historical patterns in population connectivity were more likely to result from dispersal limitation (isolation by distance) relative to habitat choice and reproductive success (isolation by environment). Second, we used Reciprocal Causal Modeling to identify the types of land use contributing to three threat indices, and subsequently Multiple Regression on Distance Matrices to evaluate the relative severity of each. These analyses suggest that straying Atlantic salmon avoid watersheds with reduced water quality (resulting from acidification and abandoned mines) and higher road density, yet are not responding to watershed fragmentation (from road-river crossings and dams) at a population level. This study is among the first to explicitly compare alternate behavioural hypotheses leading to dispersal patterns for diadromous fishes and to quantitatively assess freshwater threats for Atlantic salmon at a population level using landscape genetics. 相似文献