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11.
Einar Osland Vik-Mo Marta Nyakas Birthe Viftrup Mikkelsen Morten Carstens Moe Paulina Due-Tønnesen Else Marit Inderberg Suso Stein Sæbøe-Larssen Cecilie Sandberg Jan E. Brinchmann Eirik Helseth Anne-Marie Rasmussen Knut Lote Steinar Aamdal Gustav Gaudernack Gunnar Kvalheim Iver A. Langmoen 《Cancer immunology, immunotherapy : CII》2013,62(9):1499-1509
Background
The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting.Methods
We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9–18 vaccines containing 107 cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456.Results
Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test).Conclusion
These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival. 相似文献12.
Nikita Chopra Thomas E. Wales Raji E. Joseph Scott E. Boyken John R. Engen Robert L. Jernigan Amy H. Andreotti 《PLoS computational biology》2016,12(3)
Bruton’s tyrosine kinase (Btk) is a Tec family non-receptor tyrosine kinase that plays a critical role in immune signaling and is associated with the immunological disorder X-linked agammaglobulinemia (XLA). Our previous findings showed that the Tec kinases are allosterically activated by the adjacent N-terminal linker. A single tryptophan residue in the N-terminal 17-residue linker mediates allosteric activation, and its mutation to alanine leads to the complete loss of activity. Guided by hydrogen/deuterium exchange mass spectrometry results, we have employed Molecular Dynamics simulations, Principal Component Analysis, Community Analysis and measures of node centrality to understand the details of how a single tryptophan mediates allostery in Btk. A specific tryptophan side chain rotamer promotes the functional dynamic allostery by inducing coordinated motions that spread across the kinase domain. Either a shift in the rotamer population, or a loss of the tryptophan side chain by mutation, drastically changes the coordinated motions and dynamically isolates catalytically important regions of the kinase domain. This work also identifies a new set of residues in the Btk kinase domain with high node centrality values indicating their importance in transmission of dynamics essential for kinase activation. Structurally, these node residues appear in both lobes of the kinase domain. In the N-lobe, high centrality residues wrap around the ATP binding pocket connecting previously described Catalytic-spine residues. In the C-lobe, two high centrality node residues connect the base of the R- and C-spines on the αF-helix. We suggest that the bridging residues that connect the catalytic and regulatory architecture within the kinase domain may be a crucial element in transmitting information about regulatory spine assembly to the catalytic machinery of the catalytic spine and active site. 相似文献
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14.
Saether BE Engen S 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2002,357(1425):1185-1195
A central question in population ecology is to understand why population growth rates differ over time. Here, we describe how the long-term growth of populations is not only influenced by parameters affecting the expected dynamics, for example form of density dependence and specific population growth rate, but is also affected by environmental and demographic stochasticity. Using long-term studies of fluctuations of bird populations, we show an interaction between the stochastic and the deterministic components of the population dynamics: high specific growth rates at small densities r(1) are typically positively correlated with the environmental variance sigma(e)(2). Furthermore, theta, a single parameter describing the form of the density regulation in the theta-logistic density-regulation model, is negatively correlated with r(1). These patterns are in turn correlated with interspecific differences in life-history characteristics. Higher specific growth rates, larger stochastic effects on the population dynamics and stronger density regulation at small densities are found in species with large clutch sizes or high adult mortality rates than in long-lived species. Unfortunately, large uncertainties in parameter estimates, as well as strong stochastic effects on the population dynamics, will often make even short-term population projections unreliable. We illustrate that the concept of population prediction interval can be useful in evaluating the consequences of these uncertainties in the population projections for the choice of management actions. 相似文献
15.
Lande R Engen S Saether BE 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2002,357(1425):1179-1184
For a life history with age at maturity alpha, and stochasticity and density dependence in adult recruitment and mortality, we derive a linearized autoregressive equation with time-lags of from 1 to alpha years. Contrary to current interpretations, the coefficients for different time-lags in the autoregressive dynamics do not simply measure delayed density dependence, but also depend on life-history parameters. We define a new measure of total density dependence in a life history, D, as the negative elasticity of population growth rate per generation with respect to change in population size, D = - partial differential lnlambda(T)/partial differential lnN, where lambda is the asymptotic multiplicative growth rate per year, T is the generation time and N is adult population size. We show that D can be estimated from the sum of the autoregression coefficients. We estimated D in populations of six avian species for which life-history data and unusually long time-series of complete population censuses were available. Estimates of D were in the order of 1 or higher, indicating strong, statistically significant density dependence in four of the six species. 相似文献
16.
The ability to form full-length intron RNA circles is a general property of nuclear group I introns 总被引:1,自引:1,他引:0
Nielsen H Fiskaa T Birgisdottir AB Haugen P Einvik C Johansen S 《RNA (New York, N.Y.)》2003,9(12):1464-1475
In addition to splicing, group I intron RNA is capable of an alternative two-step processing pathway that results in the formation of full-length intron circular RNA. The circularization pathway is initiated by hydrolytic cleavage at the 3′ splice site and followed by a transesterification reaction in which the intron terminal guanosine attacks the 5′ splice site presented in a structure analogous to that of the first step of splicing. The products of the reactions are full-length circular intron and unligated exons. For this reason, the circularization reaction is to the benefit of the intron at the expense of the host. The circularization pathway has distinct structural requirements that differ from those of splicing and appears to be specifically suppressed in vivo. The ability to form full-length circles is found in all types of nuclear group I introns, including those from the Tetrahymena ribosomal DNA. The biological function of the full-length circles is not known, but the fact that the circles contain the entire genetic information of the intron suggests a role in intron mobility. 相似文献
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18.
One aspect of community ecology that has been given particular attention is the pattern of species abundances in a community. The species may have a wide range of abundances; some are very common and others rare. When species abundance models are fitted to observations, the lognormal model and one of the gamma models (e.g., the log-series model) are usually applied. The model that gives the best fit according to some goodness-of-fit test is then chosen. By applying a diffusion approximation for each species' dynamics with density regulation of the straight theta-logistic type, we here present a general species abundance model that embraces the two most widely applied species abundance models, the lognormal and the gamma. Our general model will, therefore, provide a better fit than the two special cases, except when it corresponds to one of them. In contrast to the classical models, ours is also dynamic, making it possible to evaluate the fluctuations in species abundance over time through both biotic and abiotic factors. The model is fitted to several species abundance data sets and our results compared to previous attempts to fit a model, usually either the lognormal or the log-series. 相似文献
19.
Environmental stochasticity and extinction risk in a population of a small songbird, the great tit 总被引:2,自引:0,他引:2
Using a long-term demographic data set, we estimated the separate effects of demographic and environmental stochasticity in the growth rate of the great tit population in Wytham Wood, United Kingdom. Assuming logistic density regulation, both the demographic (sigma2d = 0.569) and environmental (sigma2e = 0.0793) variance, with interactions included, were significantly greater than zero. The estimates of the demographic variance seemed to be relatively insensitive to the length of the study period, whereas reliable estimates of the environmental variance required long time series (at least 15 yr of data). The demographic variance decreased significantly with increasing population density. These estimates are used in a quantitative analysis of the demographic factors affecting the risk of extinction of this population. The very long expected time to extinction of this population (approximately 10(19) yr) was related to a relatively large population size (>/=120 pairs during the study period). However, for a given population size, the expected time to extinction was sensitive to both variation in population growth rate and environmental stochasticity. Furthermore, the form of the density regulation strongly affected the expected time to extinction. Time to extinction decreased when the maximum density regulation approached K. This suggests that estimates of viability of small populations should be given both with and without inclusion of density dependence. 相似文献
20.
This investigation examined the effects ofNaHCO3 loading on lactateconcentration ([La]), acid-base balance, and performance for a 603.5-m sprint task. Ten greyhounds completed aNaHCO3 (300 mg/kg body weight) andcontrol trial in a crossover design. Results are expressed as means ± SE. Presprint differences (P < 0.05) were found for NaHCO3 vs.control, respectively, for blood pH (7.47 ± 0.01 vs. 7.42 ± 0.01), HCO3 (28.4 ± 0.4 vs. 23.5 ± 0.3 meq/l), and base excess (5.0 ± 0.3 vs. 0.2 ± 0.3 meq/l). Peak blood [La] increased(P < 0.05) inNaHCO3 vs. control (20.4 ± 1.6 vs. 16.9 ± 1.3 mM, respectively). Relative to control,NaHCO3 produced a greater(P < 0.05) reduction in blood baseexcess (18.5 ± 1.4 vs. 14.1 ± 0.8 meq/l) andHCO3 (17.4 ± 1.2 vs.12.8 ± 0.7 meq/l) from presprint to postexercise. Postexercise peak muscle H+concentration ([H+])was higher (P < 0.05) inNaHCO3 vs. control (158.8 ± 8.8 vs. 137.0 ± 5.3 nM, respectively). Muscle[H+] recoveryhalf-time (7.2 ± 1.6 vs. 11.3 ± 1.6 min) and time to predosevalues (22.2 ± 2.4 vs. 32.9 ± 4.0 min) were reduced(P < 0.05) inNaHCO3 vs. control, respectively.No differences were found in blood[H+] or blood[La] recovery curves or performance times.NaHCO3 increased postexerciseblood [La] but did not reduce the muscle or blood acid-basedisturbance associated with a 603.5-m sprint or significantly affectperformance. 相似文献