Evolutionary dynamics of cancer cell populations under immune selection pressure and optimal control of chemotherapy

Increasing experimental evidence suggests that epigenetic and microenvironmental factors play a key role in cancer progression. In this respect, it is now generally recognized that the immune system can act as an additional selective pressure, which modulates tumor development and leads, through cancer immunoediting, to the selection for resistance to immune effector mechanisms. This may have serious implications for the design of effective anti-cancer protocols. Motivated by these considerations, we present a mathematical model for the dynamics of cancer and immune cells under the effects of chemotherapy and immunity-boosters. Tumor cells are modeled as a population structured by a continuous phenotypic trait, that is related to the level of resistance to receptor-induced cell death triggered by effector lymphocytes. The level of resistance can vary over time due to the effects of epigenetic modifications. In the asymptotic regime of small epimutations, we highlight the ability of the model to reproduce cancer immunoediting. In an optimal control framework, we tackle the problem of designing effective anti-cancer protocols. The results obtained suggest that chemotherapeutic drugs characterized by high cytotoxic effects can be useful for treating tumors of large size. On the other hand, less cytotoxic chemotherapy in combination with immunity-boosters can be effective against tumors of smaller size. Taken together, these results support the development of therapeutic protocols relying on combinations of less cytotoxic agents and immune-boosters to fight cancer in the early stages. © EDP Sciences, 2014

Antibiotics that affect translation can antagonize phage infectivity by interfering with the deployment of counter-defenses

This is the final version. Available on open access from the National Academy of Sciences via the DOI i this recordData, Materials, and Software Availability: All study data are included in the article and/or SI Appendix.It is becoming increasingly clear that antibiotics can both positively and negatively impact the infectivity of bacteriophages (phage), but the underlying mechanisms often remain unclear. Here we demonstrate that antibiotics that target the protein translation machinery can fundamentally alter the outcome of bacteria-phage interactions by interfering with the production of phage-encoded counter-defense proteins. Specifically, using Pseudomonas aeruginosa PA14 and phage DMS3vir as a model, we show that bacteria with Clustered Regularly Interspaced Short Palindromic Repeat, CRISPR associated (CRISPR-Cas) immune systems have elevated levels of immunity against phage that encode anti-CRISPR (acr) genes when translation inhibitors are present in the environment. CRISPR-Cas are highly prevalent defense systems that enable bacteria to detect and destroy phage genomes in a sequence-specific manner. In response, many phages encode acr genes that are expressed immediately following the infection to inhibit key steps of the CRISPR-Cas immune response. Our data show that while phage-carrying acr genes can amplify efficiently on bacteria with CRISPR-Cas immune systems in the absence of antibiotics, the presence of antibiotics that act on protein translation prevents phage amplification, while protecting bacteria from lysis.Biotechnology and Biological Sciences Research Council (BBSRC)Engineering and Physical Sciences Research Council (EPSRC)European Union Horizon 202

Concentric double hollow grid cathode discharges

A new cathode system, consisting of two concentric spherical hollow grids with two aligned orifices, is investigated by space-resolved Langmuir probe measurements and non-linear dynamics analysis. Negative biases of this spherical hollow grids arrangement lead to the formation of two complex space charge structures in the regions of the orifices. The overall dynamics of the current-voltage characteristic (I–V characteristic) of each discharge is characterized by strong oscillatory behaviour with various waveforms correlated with jumps in the static I–V characteristics. Space-resolved measurements through the two aligned orifices of the two grids show a peak increase of the electron temperature and particle density in the regions of the two space-charge structures. The effects of the biases and Ar pressure on the overall spatial distribution of all plasma parameters are investigated. Two important working points of the concentric double hollow grid cathode discharges are revealed which could make this configuration suitable as an electron source

Bacteriostatic antibiotics promote CRISPR-Cas adaptive immunity by enabling increased spacer acquisition

This is the final version. Available on open access from Cell Press via the DOI in this recordData and code availability: Source data are available at Mendeley Data: https://doi.org/10.17632/gbdfwg325y.1 This paper does not report original code. Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request.Phages impose strong selection on bacteria to evolve resistance against viral predation. Bacteria can rapidly evolve phage resistance via receptor mutation or using their CRISPR-Cas adaptive immune systems. Acquisition of CRISPR immunity relies on the insertion of a phage-derived sequence into CRISPR arrays in the bacterial genome. Using Pseudomonas aeruginosa and its phage DMS3vir as a model, we demonstrate that conditions that reduce bacterial growth rates, such as exposure to bacteriostatic antibiotics (which inhibit cell growth without killing), promote the evolution of CRISPR immunity. We demonstrate that this is due to slower phage development under these conditions, which provides more time for cells to acquire phage-derived sequences and mount an immune response. Our data reveal that the speed of phage development is a key determinant of the evolution of CRISPR immunity and suggest that use of bacteriostatic antibiotics can trigger elevated levels of CRISPR immunity in human-associated and natural environments.European Union Horizon 2020Natural Environment Research Council (NERC)Ministry of Science and Higher Education of the Russian FederationNational Institutes of Health (NIH)Russian Science Foundatio

Pattern recognition receptor-mediated cytokine response in infants across 4 continents⋆

Background Susceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination. Objective Determine whether differences in innate immune responses exist among infants from different continents of the world. Methods We determined the innate cytokine response following pattern recognition receptor (PRR) stimulation of whole blood from 2-year-old infants across 4 continents (Africa, North America, South America, and Europe). Results We found that despite the many possible genetic and environmental exposure differences in infants across 4 continents, innate cytokine responses were similar for infants from North America, South America, and Europe. However, cells from South African infants secreted significantly lower levels of cytokines than did cells from infants from the 3 other sites, and did so following stimulation of extracellular and endosomal but not cytosolic PRRs. Conclusions Substantial differences in innate cytokine responses to PRR stimulation exist among different populations of infants that could not have been predicted. Delineating the underlying mechanism(s) for these differences will not only aid in improving vaccine-mediated protection but possibly also provide clues for the susceptibility to infection in different regions of the world

So happy for your loss: Consumer schadenfreude increases choice satisfaction

Consumers often feel schadenfreude, an emotion reflecting an experience of pleasure over misfortunes of another. Schadenfreude has found wide use in advertising, but its actual consequences for consumers have not been thoroughly documented. The present research investigates the effect of schadenfreude on consumers' satisfaction with choices they have made. Building on the feelings‐as‐information theory, the authors posit that consumers take their positive feelings of schadenfreude over another's unrelated bad purchase as positive information about their own choices, and through such misattribution become more satisfied with their own choices. Three experiments show that feeling schadenfreude over another consumer's bad purchase makes consumers more satisfied with their own choices (Study 1), regardless of whether the other's bad purchase is in the same or in a different product category as one's own choice (Study 2), but only so long as consumers are not aware that they are engaging in misattribution (Study 3). The present research contributes to the literature on schadenfreude and feelings‐as‐information theory. Its findings may be used by marketers aiming to exert an unconscious influence on consumer satisfaction

Empirical evaluation of microtremor H/V spectral ratio

The objective of this work is to perform a purely empirical assessment of the actual capabilities of the horizontal-to-vertical (H/V) spectral ratio technique to provide reliable and relevant information concerning site conditions and/or site amplification. This objective has been tackled through the homogeneous (re)processing of a large volume of earthquakes and ambient noise data recorded by different research teams in more than 200 sites located mainly in Europe, but also in the Caribbean and in Tehran. The original recordings were first gathered in a specific database with information on both the sites and recorded events. Then, for all sites close to an instrumented reference, average site-to-reference spectral ratios (“spectral ratio method” (SSR)) were derived in a homogeneous way (window selection, smoothing, signal-to-noise ratio threshold, averaging), as well as H/V ratios (“HVSRE–RF”) on earthquake recordings. H/V ratios were also obtained from noise recordings at each site (either specific measurements, or extracted from pre- or post-event noise windows). The spectral curves resulting from these three techniques were estimated reliable for a subset of 104 sites, and were thus compared in terms of fundamental frequency, amplitude and amplification bandwidth, exhibiting agreements and disagreements, for which interpretations are looked for in relation with characteristics of site conditions. The first important result consists in the very good agreement between fundamental frequencies obtained with either technique, observed for 81% of the analyzed sites. A significant part of the disagreements correspond to thick, low frequency, continental sites where natural noise level is often very low and H/V noise ratios do not exhibit any clear peak. The second important result is the absence of correlation between H/V peak amplitude and the actual site amplification measured on site-to-reference spectral ratios. There are, however, two statistically significant results about the amplitude of the H/V curve: the peak amplitude may be considered as a lower bound estimate of the actual amplification indicated by SSR (it is smaller for 79% of the 104 investigated sites), and, from another point of view, the difference in amplitude exhibits a questioning correlation with the geometrical characteristics of the sediment/basement interface: large SSR/HV differences might thus help to detect the existence of significant 2D or 3D effects.Published75-1084.1. Metodologie sismologiche per l'ingegneria sismicaJCR Journalreserve

Live to cheat another day: bacterial dormancy facilitates the social exploitation of beta-lactamases

The breakdown of antibiotics by β-lactamases may be cooperative, since resistant cells can detoxify their environment and facilitate the growth of susceptible neighbours. However, previous studies of this phenomenon have used artificial bacterial vectors or engineered bacteria to increase the secretion of β-lactamases from cells. Here, we investigated whether a broad-spectrum β-lactamase gene carried by a naturally occurring plasmid (pCT) is cooperative under a range of conditions. In ordinary batch culture on solid media, there was little or no evidence that resistant bacteria could protect susceptible cells from ampicillin, although resistant colonies could locally detoxify this growth medium. However, when susceptible cells were inoculated at high densities, late-appearing phenotypically susceptible bacteria grew in the vicinity of resistant colonies. We infer that persisters, cells that have survived antibiotics by undergoing a period of dormancy, founded these satellite colonies. The number of persister colonies was positively correlated with the density of resistant colonies and increased as antibiotic concentrations decreased. We argue that detoxification can be cooperative under a limited range of conditions: if the toxins are bacteriostatic rather than bacteridical; or if susceptible cells invade communities after resistant bacteria; or if dormancy allows susceptible cells to avoid bactericides. Resistance and tolerance were previously thought to be independent solutions for surviving antibiotics. Here, we show that these are interacting strategies: the presence of bacteria adopting one solution can have substantial effects on the fitness of their neighbours

Coronary atherosclerosis scoring with semiquantitative CCTA risk scores for prediction of major adverse cardiac events: Propensity score-based analysis of diabetic and non-diabetic patients.

AIMS:We aimed to compare semiquantitative coronary computed tomography angiography (CCTA) risk scores - which score presence, extent, composition, stenosis and/or location of coronary artery disease (CAD) - and their prognostic value between patients with and without diabetes mellitus (DM). Risk scores derived from general chest-pain populations are often challenging to apply in DM patients, because of numerous confounders. METHODS:Out of a combined cohort from the Leiden University Medical Center and the CONFIRM registry with 5-year follow-up data, we performed a secondary analysis in diabetic patients with suspected CAD who were clinically referred for CCTA. A total of 732 DM patients was 1:1 propensity-matched with 732 non-DM patients by age, sex and cardiovascular risk factors. A subset of 7 semiquantitative CCTA risk scores was compared between groups: 1) any stenosis ≥50%, 2) any stenosis ≥70%, 3) stenosis-severity component of the coronary artery disease-reporting and data system (CAD-RADS), 4) segment involvement score (SIS), 5) segment stenosis score (SSS), 6) CT-adapted Leaman score (CT-LeSc), and 7) Leiden CCTA risk score. Cox-regression analysis was performed to assess the association between the scores and the primary endpoint of all-cause death and non-fatal myocardial infarction. Also, area under the receiver-operating characteristics curves were compared to evaluate discriminatory ability. RESULTS:A total of 1,464 DM and non-DM patients (mean age 58 ± 12 years, 40% women) underwent CCTA and 155 (11%) events were documented after median follow-up of 5.1 years. In DM patients, the 7 semiquantitative CCTA risk scores were significantly more prevalent or higher as compared to non-DM patients (p ≤ 0.022). All scores were independently associated with the primary endpoint in both patients with and without DM (p ≤ 0.020), with non-significant interaction between the scores and diabetes (interaction p ≥ 0.109). Discriminatory ability of the Leiden CCTA risk score in DM patients was significantly better than any stenosis ≥50% and ≥70% (p = 0.003 and p = 0.007, respectively), but comparable to the CAD-RADS, SIS, SSS and CT-LeSc that also focus on the extent of CAD (p ≥ 0.265). CONCLUSION:Coronary atherosclerosis scoring with semiquantitative CCTA risk scores incorporating the total extent of CAD discriminate major adverse cardiac events well, and might be useful for risk stratification of patients with DM beyond the binary evaluation of obstructive stenosis alone

Influence of Myocardial Ischemia Extent on Left Ventricular Global Longitudinal Strain in Patients After ST-Segment Elevation Myocardial Infarction

Cardiolog