834 research outputs found
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A Potent and Effective Suicidal Listeria Vaccine Platform.
Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection
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Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment.
Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L- CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206- M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells
CP and related phenomena in the context of Stellar Evolution
We review the interaction in intermediate and high mass stars between their
evolution and magnetic and chemical properties. We describe the theory of
Ap-star `fossil' fields, before touching on the expected secular diffusive
processes which give rise to evolution of the field. We then present recent
results from a spectropolarimetric survey of Herbig Ae/Be stars, showing that
magnetic fields of the kind seen on the main-sequence already exist during the
pre-main sequence phase, in agreement with fossil field theory, and that the
origin of the slow rotation of Ap/Bp stars also lies early in the pre-main
sequence evolution; we also present results confirming a lack of stars with
fields below a few hundred gauss. We then seek which macroscopic motions
compete with atomic diffusion in determining the surface abundances of AmFm
stars. While turbulent transport and mass loss, in competition with atomic
diffusion, are both able to explain observed surface abundances, the interior
abundance distribution is different enough to potentially lead to a test using
asterosismology. Finally we review progress on the turbulence-driving and
mixing processes in stellar radiative zones.Comment: Proceedings of IAU GA in Rio, JD4 on Ap stars; 10 pages, 7 figure
Does mating behaviour affect connectivity in marine fishes? Comparative population genetics of two protogynous groupers (Family Serranidae)
Abstract Pelagic larval duration (PLD) has been hypothesized to be the primary predictor of connectivity in marine fishes; however, few studies have examined the effects that adult reproductive behaviour may have on realized dispersal. We assessed gene flow (connectivity) by documenting variation in microsatellites and mitochondrial DNA sequences in two protogynous species of groupers, the aggregate spawning red hind, Epinephelus guttatus, and the single-male, harem-spawning coney, Cephalopholis fulva, to ask whether reproductive strategy affects connectivity. Samples of both species were obtained from waters off three islands (Puerto Rico, St. Thomas and St. Croix) in the Caribbean Sea. Despite the notion that aggregate spawning of red hind may facilitate larval retention, stronger signals of population structure were detected in the haremspawning coney. Heterogeneity and/or inferred barriers, based on microsatellites, involved St. Croix (red hind and coney) and the west coast of Puerto Rico (coney). Heterogeneity and/or inferred barriers, based on mitochondrial DNA, involved St. Croix (coney only). Genetic divergence in both species was stronger for microsatellites than for mitochondrial DNA, suggesting sex-biased dispersal in both species. Longterm migration rates, based on microsatellites, indicated asymmetric gene flow for both species in the same direction as mean surface currents in the region. Red hind had higher levels of variation in microsatellites and lower levels of variation in mitochondrial DNA. Long-term effective size and effective number of breeders were greater for red hind; estimates of h f , a proxy for long-term effective female size, were the same in both species. Patterns of gene flow in both species appear to stem in part from shared aspects of larval and adult biology, local bathymetry and surface current patterns. Differences in connectivity and levels of genetic variation between the species, however, likely stem from differences in behaviour related to reproductive strategy
Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes.
Listeria monocytogenes is an important cause of maternal-fetal infections and serves as a model organism to study these important but poorly understood events. L. monocytogenes can infect non-phagocytic cells by two means: direct invasion and cell-to-cell spread. The relative contribution of each method to placental infection is controversial, as is the anatomical site of invasion. Here, we report for the first time the use of first trimester placental organ cultures to quantitatively analyze L. monocytogenes infection of the human placenta. Contrary to previous reports, we found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection by either internalin-mediated invasion or cell-to-cell spread. Instead, extravillous cytotrophoblasts-which anchor the placenta in the decidua (uterine lining) and abundantly express E-cadherin-served as the primary portal of entry for L. monocytogenes from both extracellular and intracellular compartments. Subsequent bacterial dissemination to the villous stroma, where fetal capillaries are found, was hampered by further cellular and histological barriers. Our study suggests the placenta has evolved multiple mechanisms to resist pathogen infection, especially from maternal blood. These findings provide a novel explanation why almost all placental pathogens have intracellular life cycles: they may need maternal cells to reach the decidua and infect the placenta
Environmental variables, habitat discontinuity and life history shaping the genetic structure of Pomatoschistus marmoratus
Coastal lagoons are semi-isolated ecosystems
exposed to wide fluctuations of environmental conditions
and showing habitat fragmentation. These features may
play an important role in separating species into different
populations, even at small spatial scales. In this study, we
evaluate the concordance between mitochondrial (previous
published data) and nuclear data analyzing the genetic
variability of Pomatoschistus marmoratus in five localities,
inside and outside the Mar Menor coastal lagoon (SE
Spain) using eight microsatellites. High genetic diversity
and similar levels of allele richness were observed across
all loci and localities, although significant genic and
genotypic differentiation was found between populations
inside and outside the lagoon. In contrast to the FST values
obtained from previous mitochondrial DNA analyses
(control region), the microsatellite data exhibited significant
differentiation among samples inside the Mar Menor
and between lagoonal and marine samples. This pattern
was corroborated using Cavalli-Sforza genetic distances.
The habitat fragmentation inside the coastal lagoon and
among lagoon and marine localities could be acting as a
barrier to gene flow and contributing to the observed
genetic structure. Our results from generalized additive
models point a significant link between extreme lagoonal
environmental conditions (mainly maximum salinity) and
P. marmoratus genetic composition. Thereby, these environmental
features could be also acting on genetic structure
of coastal lagoon populations of P. marmoratus favoring
their genetic divergence. The mating strategy of P. marmoratus
could be also influencing our results obtained from
mitochondrial and nuclear DNA. Therefore, a special
consideration must be done in the selection of the DNA
markers depending on the reproductive strategy of the
species
Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study
The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. NCT01183780
The complete genome sequence and comparative genome analysis of the high pathogenicity Yersinia enterocolitica strain 8081
The human enteropathogen, Yersinia enterocolitica, is a significant link in the range of Yersinia pathologies extending
from mild gastroenteritis to bubonic plague. Comparison at the genomic level is a key step in our understanding of the
genetic basis for this pathogenicity spectrum. Here we report the genome of Y. enterocolitica strain 8081 (serotype 0:8;
biotype 1B) and extensive microarray data relating to the genetic diversity of the Y. enterocolitica species. Our analysis
reveals that the genome of Y. enterocolitica strain 8081 is a patchwork of horizontally acquired genetic loci, including a
plasticity zone of 199 kb containing an extraordinarily high density of virulence genes. Microarray analysis has
provided insights into species-specific Y. enterocolitica gene functions and the intraspecies differences between the
high, low, and nonpathogenic Y. enterocolitica biotypes. Through comparative genome sequence analysis we provide
new information on the evolution of the Yersinia. We identify numerous loci that represent ancestral clusters of genes
potentially important in enteric survival and pathogenesis, which have been lost or are in the process of being lost, in
the other sequenced Yersinia lineages. Our analysis also highlights large metabolic operons in Y. enterocolitica that are
absent in the related enteropathogen, Yersinia pseudotuberculosis, indicating major differences in niche and nutrients
used within the mammalian gut. These include clusters directing, the production of hydrogenases, tetrathionate
respiration, cobalamin synthesis, and propanediol utilisation. Along with ancestral gene clusters, the genome of Y.
enterocolitica has revealed species-specific and enteropathogen-specific loci. This has provided important insights into
the pathology of this bacterium and, more broadly, into the evolution of the genus. Moreover, wider investigations
looking at the patterns of gene loss and gain in the Yersinia have highlighted common themes in the genome evolution
of other human enteropathogens
A meta-analytic review of stand-alone interventions to improve body image
Objective
Numerous stand-alone interventions to improve body image have been developed. The
present review used meta-analysis to estimate the effectiveness of such interventions, and
to identify the specific change techniques that lead to improvement in body image.
Methods
The inclusion criteria were that (a) the intervention was stand-alone (i.e., solely focused on
improving body image), (b) a control group was used, (c) participants were randomly
assigned to conditions, and (d) at least one pretest and one posttest measure of body
image was taken. Effect sizes were meta-analysed and moderator analyses were conducted.
A taxonomy of 48 change techniques used in interventions targeted at body image
was developed; all interventions were coded using this taxonomy.
Results
The literature search identified 62 tests of interventions (N = 3,846). Interventions produced
a small-to-medium improvement in body image (d+ = 0.38), a small-to-medium reduction in
beauty ideal internalisation (d+ = -0.37), and a large reduction in social comparison tendencies
(d+ = -0.72). However, the effect size for body image was inflated by bias both within
and across studies, and was reliable but of small magnitude once corrections for bias were
applied. Effect sizes for the other outcomes were no longer reliable once corrections for
bias were applied. Several features of the sample, intervention, and methodology moderated
intervention effects. Twelve change techniques were associated with improvements in
body image, and three techniques were contra-indicated.
Conclusions
The findings show that interventions engender only small improvements in body image, and
underline the need for large-scale, high-quality trials in this area. The review identifies effective
techniques that could be deployed in future interventions
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