Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy

CD8(+) CTL play important roles against malignancy in both active and passive immunotherapy. Nonetheless, the success of antitumor CTL responses may be improved by additional therapeutic modalities. Radiotherapy, which has a long-standing use in treating neoplastic disease, has been found to induce unique biologic alterations in cancer cells affecting Fas gene expression, which, consequently, may influence the overall lytic efficiency of CTL. Here, in a mouse adenocarcinoma cell model, we examined whether exposure of these tumor cells to sublethal doses of irradiation 1) enhances Fas expression, leading to more efficient CTL killing via Fas-dependent mechanisms in vitro; and 2) improves antitumor activity in vivo by adoptive transfer of these Ag-specific CTL. Treatment of carcinoembryonic Ag-expressing MC38 adenocarcinoma cells with irradiation (20 Gy) in vitro enhanced Fas expression at molecular, phenotypic, and functional levels. Furthermore, irradiation sensitized these targets to Ag-specific CTL killing via the Fas/Fas ligand pathway. We examined the effect of localized irradiation of s.c. growing tumors on the efficiency of CTL adoptive immunotherapy. Irradiation caused up-regulation of Fas by these tumor cells in situ, based on immunohistochemistry. Moreover, localized irradiation of the tumor significantly potentiated tumor rejection by these carcinoembryonic Ag-specific CTL. Overall, these results showed for the first time that 1) regulation of the Fas pathway in tumor cells by irradiation plays an important role in their sensitization to Ag-specific CTL; and 2) a combination regimen of tumor-targeted irradiation and CTL promotes more effective antitumor responses in vivo, which may have implications for the combination of immunotherapy and radiation therapy.     

Adaptive Host Preference and the Dynamics of Host–Parasitoid Interactions

Models of two independent host populations and a common parasitoid are investigated. The hosts have density-dependent population growth and only interact indirectly by their effects on parasitoid behavior and population dynamics. The parasitoid is assumed to experience a trade-off in its ability to exploit the two hosts. Three alternative types of parasitoid are investigated: (i) fixed generalists whose consumption rates are those that maximize fitness; (ii) “ideal free” parasitoids, which modify their behavior to maximize their rate of finding unparasitized hosts within a generation; and (iii) “evolving” parasitoids, whose capture rates change between generations based on quantitative genetic determination of the relative attack rates on the two hosts. The primary questions addressed are: (1) Do the different types of adaptive processes stabilize or destabilize the population dynamics? (2) Do the adaptive processes tend to equalize or to magnify differences in host densities? The models show that adaptive behavior and evolution frequently destabilize population dynamics and frequently increase the average difference between host densities.     

Adaptive foraging by predators as a cause of predator-prey cycles

Summary When foraging has costs, it is generally adaptive for foragers to adjust their foraging effort in response to changes in the population density of their food. If effort decreases in response to increased food density, this can result in a type-2 functional response; intake rate increases in a negatively accelerated manner as prey density increases. Unlike other mechanisms for type-2 responses, adaptive foraging usually involves a timelag, because foraging behaviours do not often change instantaneously with changes in food density or risks. This paper investigates predator-prey models in which there are explicit dynamics for the rate of adaptive change. Models appropriate to both behavioural and evolutionary change are considered. Both types of change can produce cycles under similar circumstances, but under some evolutionary models there is not sufficient genetic variability for evolutionary change to produce cycles. If there is sufficient variability, the remaining conditions required for cycles are surprisingly insensitive to the nature of the adaptive process. A predator population that approaches the optimum foraging strategy very slowly usually produces cycles under similar conditions as does a very rapidly adapting population.     

Endogenous hormone profiles during early seed development of C. arietinum and C. anatolicum

Cicer anatolicum, a perennial species, has ascochyta blight resistance superior to that found in the cultivated chickpea. However, hybridization barriers during early stages of embryo development curtail access to this trait. Since hormones play an essential role in early embryo development, we have determined the hormone profiles of 4-, 8-, and 12-day old seeds from a Canadian chickpea (Cicer arietinum L.) cv. CDC Xena, from Indian cvs. Swetha and Bharati, and from a perennial accession of C. anatolicum (PI 383626). Indole-3-acetic acid content peaked on day 4 in CDC Xena, on day 8 in both Indian cultivars but only on day 12 in C. anatolicum. The cytokinins, isopentenyladenosine (iPA) and trans zeatin riboside (tZR) were predominant in CDC Xena and Swetha seeds on day 4, whereas cis zeatin riboside was the major component in Bharati. In C. anatolicum, iPA maxed out on day 4 and tZR on day 12. The bioactive gibberellin GA₁ spiked on day 4 in CDC Xena and Bharati, on day 8 in Swetha but only on day 12 in C. anatolicum. Eight-day old seeds had the highest abscisic acid content in the cultivars but spiked on day 12 in the perennial species. The hormone profiles of the perennial species showed delayed spikes in all four hormone groups indicating that there is a mismatch in the hormone requirements of the different embryos. Improving synchronization of early seed hormone profiles of cultivated and perennial chickpea should improve interspecific hybrid production.     

Degeneracy and repertoire of the human HIV-1 Gag p17(77-85) CTL response

CD8+ CTL responses are important for the control of HIV-1 infection. The immunodominant HLA-A2-restricted Gag epitope, SLYNTVATL (SL9), is considered to be a poor immunogen because reactivity to it is rare in acute infection despite its paradoxical dominance in patients with chronic infection. We have previously reported SL9 to be a help-independent epitope in that it primes highly activated CTLs ex vivo from CD8+ T cells of seronegative healthy donors. These CTLs produce sufficient cytokines for extended autocrine proliferation but are sensitive to activation-induced cell death, which may cause them to be eliminated by a proinflammatory cytokine storm. Here we identified an agonist variant of the SL9 peptide, p41 (SLYNTVAAL), by screening a large synthetic combinatorial nonapeptide library with ex vivo-primed SL9-specific T cells. p41 invariably immunized SL9-cross-reactive CTLs from other donors ex vivo and H-2Db beta2m double knockout mice expressing a chimeric HLA-A*0201/H2-Db MHC class I molecule. Parallel human T cell cultures showed p41-specific CTLs to be less fastidious than SL9-CTLs in the level of costimulation required from APCs and the need for exogenous IL-2 to proliferate (help dependent). TCR sequencing revealed that the same clonotype can develop into either help-independent or help-dependent CTLs depending on the peptide used to activate the precursor CD8+ T cells. Although Ag-experienced SL9-T cells from two patients were also sensitive to IL-2-mediated cell death upon restimulation in vitro, the loss of SL9 T cells was minimized with p41. This study suggests that agonist sequences can replace aberrantly immunogenic native epitopes for the rational design of vaccines targeting HIV-1.     

The impact of mortality on predator population size and stability in systems with stage-structured prey

The relationships between a predator population's mortality rate and its population size and stability are investigated for several simple predator-prey models with stage-structured prey populations. Several alternative models are considered; these differ in their assumptions about the nature of density dependence in the prey's population growth; the nature of stage-transitions; and the stage-selectivity of the predator. Instability occurs at high, rather than low predator mortality rates in most models with highly stage-selective predation; this is the opposite of the effect of mortality on stability in models with homogeneous prey populations. Stage-selective predation also increases the range of parameters that lead to a stable equilibrium. The results suggest that it may be common for a stable predator population to increase in abundance as its own mortality rate increases in stable systems, provided that the predator has a saturating functional response. Sufficiently strong density dependence in the prey generally reverses this outcome, and results in a decrease in predator population size with increasing predator mortality rate. Stability is decreased when the juvenile stage has a fixed duration, but population increases with increasing mortality are still observed in large areas of stable parameter space. This raises two coupled questions which are as yet unanswered; (1) do such increases in population size with higher mortality actually occur in nature; and (2) if not, what prevents them from occurring? Stage-structured prey and stage-related predation can also reverse the 'paradox of enrichment', leading to stability rather than instability when prey growth is increased.     

Spontaneous conformational changes in the E. coli GroEL subunit from all-atom molecular dynamics simulations

The Escherichia coli chaperonin GroEL is a complex of identical subunit proteins (57 kDa each) arranged in a back-to-back stacking of two heptameric rings. Its hallmarks include nested positive intra-ring and negative inter-ring cooperativity in adenosine trisphosphate (ATP) binding and the ability to mediate the folding of newly transcribed and/or denatured substrate proteins. We performed unbiased molecular dynamics simulations of the GroEL subunit protein in explicit water both with and without the nucleotide KMgATP to understand better the details of the structural transitions that enable these behaviors. Placing KMgATP in the equatorial domain binding pocket of a t state subunit, which corresponds to a low ATP-affinity state, produced a short-lived (6 ns) state that spontaneously transitioned to the high ATP-affinity r state. The important feature of this transition is a large-scale rotation of the intermediate domain's helix M to close the ATP binding pocket. Pivoting of helix M is accompanied by counterclockwise rotation and slight deformation of the apical domain, important for lowering the affinity for substrate protein. Aligning simulation conformations into model heptamer rings demonstrates that the t-->r transition in one subunit is not sterically hindered by t state neighbors, but requires breakage of Arg(197)-Glu(386) intersubunit salt bridges, which are important for inter-ring positive cooperativity. Lowest-frequency quasi-harmonic modes of vibration computed pre- and post-transition clearly show that natural vibrations facilitate the transition. Finally, we propose a novel mechanism for inter-ring cooperativity in ATP binding inspired by the observation of spontaneous insertion of the side chain of Ala(480) into the empty nucleotide pocket.     

A Cost-Utility Analysis of Lung Cancer Screening and the Additional Benefits of Incorporating Smoking Cessation Interventions

Background

A 2011 report from the National Lung Screening Trial indicates that three annual low-dose computed tomography (LDCT) screenings for lung cancer reduced lung cancer mortality by 20% compared to chest X-ray among older individuals at high risk for lung cancer. Discussion has shifted from clinical proof to financial feasibility. The goal of this study was to determine whether LDCT screening for lung cancer in a commercially-insured population (aged 50–64) at high risk for lung cancer is cost-effective and to quantify the additional benefits of incorporating smoking cessation interventions in a lung cancer screening program.

Methods and Findings

The current study builds upon a previous simulation model to estimate the cost-utility of annual, repeated LDCT screenings over 15 years in a high risk hypothetical cohort of 18 million adults between age 50 and 64 with 30+ pack-years of smoking history. In the base case, the lung cancer screening intervention cost $27.8 billion over 15 years and yielded 985,284 quality-adjusted life years (QALYs) gained for a cost-utility ratio of $28,240 per QALY gained. Adding smoking cessation to these annual screenings resulted in increases in both the costs and QALYs saved, reflected in cost-utility ratios ranging from $16,198 per QALY gained to $23,185 per QALY gained. Annual LDCT lung cancer screening in this high risk population remained cost-effective across all sensitivity analyses.

Conclusions

The findings of this study indicate that repeat annual lung cancer screening in a high risk cohort of adults aged 50–64 is highly cost-effective. Offering smoking cessation interventions with the annual screening program improved the cost-effectiveness of lung cancer screening between 20% and 45%. The cost-utility ratios estimated in this study were in line with other accepted cancer screening interventions and support inclusion of annual LDCT screening for lung cancer in a high risk population in clinical recommendations.