Vaccines : A rapidly evolving technology - Are the hurdles being addressed?

AbstractVaccination usually works in infectious disease, why not in Cancer? Differences in the potency of microbial and cancer antigens, poor initiation of an immune response due to inadequate expression of tumour associated antigens, weak antigens or tolerance induction and local immune suppression were considered. There is a big difference between a therapeutic and a prophylactic vaccine.The opinion of the expert group was that an improved therapeutic efficacy can hardly be expected by further variation of types of vaccines, schedules, routes of administration and adjuvants alone. A major hurdle for developing therapeutic cancer vaccines is the need to effectively monitor the immune response and to be able to use this in an adaptive trial approach.End-points of assessment should be different from standard treatments as complete response or partial responses are usually low, unless combined with other therapies.In order to focus resources to overcome the hurdles of enhancing the therapeutic efficacy of cancer vaccines the Cancer Vaccine Clinical Trial Working Group, representing academia and the pharmaceutical and biotechnology industries has in a consensus process defined 'A clinical development paradigm for cancer vaccines and related biologics'

Two-Loop Polarization Contributions to Radiative-Recoil Corrections to Hyperfine Splitting in Muonium

We calculate radiative-recoil corrections of order $\alpha^2(Z\alpha)(m/M)E_F$ to hyperfine splitting in muonium generated by the diagrams with electron and muon polarization loops. These corrections are enhanced by the large logarithm of the electron-muon mass ratio. The leading logarithm cubed and logarithm squared contributions were obtained a long time ago. The single-logarithmic and nonlogarithmic contributions calculated here improve the theory of hyperfine splitting, and affect the value of the electron-muon mass ratio extracted from the experimental data on the muonium hyperfine splitting.Comment: 15 pages, 11 figure

Single-Spin Observables and Orbital Structures in Hadronic Distributions

Within the light-quark sector of the standard model, P-odd observables are generated from point-like electroweak processes while A_t- odd observables (neglecting quark mass parameters) come from dynamic spin-orbit correlations within hadrons or within larger composite systems, such as nuclei. The effects of A_t-odd dynamics can be inserted into transverse-momentum dependent constituent distribution functions and, in this paper, we construct the contribution from an orbital quark to the A_t odd quark parton distribution. Using this distribution, we examine the crucial role of initial- and final-state interactions in the observation of the scattering asymmetries in different hard-scattering processes. This construction provides a geometrical and dynamical interpretation of the Collins conjugation relation between single-spin asymmetries in semi-inclusive deep inelastic scattering and the asymmetries in Drell-Yan production. Finally, our construction allows us to display a significant difference between the calculation of a spin asymmetry generated by a hard scattering mechanism involving color-singlet exchange (such as a photon) and a calculation of an asymmetry with a hard-scattering exchange involving gluons. This leads to an appreciation of the process dependence inherent in measurements of single-spin observables.Comment: 35 pages, 6 figure

Producing valid statistics when legislation, culture, and medical practices differ for births at or before the threshold of survival: Report of a European workshop

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The compositional and evolutionary logic of metabolism

Metabolism displays striking and robust regularities in the forms of modularity and hierarchy, whose composition may be compactly described. This renders metabolic architecture comprehensible as a system, and suggests the order in which layers of that system emerged. Metabolism also serves as the foundation in other hierarchies, at least up to cellular integration including bioenergetics and molecular replication, and trophic ecology. The recapitulation of patterns first seen in metabolism, in these higher levels, suggests metabolism as a source of causation or constraint on many forms of organization in the biosphere. We identify as modules widely reused subsets of chemicals, reactions, or functions, each with a conserved internal structure. At the small molecule substrate level, module boundaries are generally associated with the most complex reaction mechanisms and the most conserved enzymes. Cofactors form a structurally and functionally distinctive control layer over the small-molecule substrate. Complex cofactors are often used at module boundaries of the substrate level, while simpler ones participate in widely used reactions. Cofactor functions thus act as "keys" that incorporate classes of organic reactions within biochemistry. The same modules that organize the compositional diversity of metabolism are argued to have governed long-term evolution. Early evolution of core metabolism, especially carbon-fixation, appears to have required few innovations among a small number of conserved modules, to produce adaptations to simple biogeochemical changes of environment. We demonstrate these features of metabolism at several levels of hierarchy, beginning with the small-molecule substrate and network architecture, continuing with cofactors and key conserved reactions, and culminating in the aggregation of multiple diverse physical and biochemical processes in cells.Comment: 56 pages, 28 figure

Twistors, Harmonics and Holomorphic Chern-Simons

We show that the off-shell N=3 action of N=4 super Yang-Mills can be written as a holomorphic Chern-Simons action whose Dolbeault operator is constructed from a complex-real (CR) structure of harmonic space. We also show that the local space-time operators can be written as a Penrose transform on the coset SU(3)/(U(1) \times U(1)). We observe a strong similarity to ambitwistor space constructions.Comment: 34 pages, 3 figures, v2: replaced with published version, v3: Added referenc

5-dim Superconformal Index with Enhanced En Global Symmetry

The five-dimensional $\mathcal{N}=1$ supersymmetric gauge theory with Sp(N) gauge group and SO(2N_f) flavor symmetry describes the physics on N D4-branes with $N_f$ D8-branes on top of a single O8 orientifold plane in Type I' theory. This theory is known to be superconformal at the strong coupling limit with the enhanced global symmetry $E_{N_f+1}$ for $N_f\le 7$. In this work we calculate the superconformal index on $S^1\times S^4$ for the Sp(1) gauge theory by the localization method and confirm such enhancement of the global symmetry at the superconformal limit for $N_f\le 5$ to a few leading orders in the chemical potential. Both perturbative and (anti)instanton contributions are present in this calculation. For $N_f=6,7$ cases some issues related the pole structure of the instanton calculation could not be resolved and here we could provide only some suggestive answer for the leading contributions to the index. For the Sp(N) case, similar issues related to the pole structure appear.Comment: 70 pages, references added, published versio

Learning through social spaces: migrant women and lifelong learning in post-colonial London

This article shows how migrant women engage in learning through social spaces. It argues that such spaces are little recognised, and that there are multiple ways in which migrant women construct and negotiate their informal learning through socialising with other women in different informal modes. Additionally, the article shows how learning is shaped by the socio-political, geographical and multicultural context of living in London, outlining ways in which gendered and racialised identities shape, construct and constrain participation in lifelong learning. The article shows that one way in which migrant women resist (post)colonial constructions of difference is by engaging in informal and non-formal lifelong learning, arguing that the benefits are (at least) two-fold. The women develop skills (including language skills) but also use their informal learning to develop what is referred to in this article as 'relational capital'. The article concludes that informal lifelong learning developed through social spaces can enhance a sense of belonging for migrant women

Transient increase in CSF GAP-43 concentration after ischemic stroke

Background: Cerebrospinal fluid (CSF) biomarkers reflect ongoing processes in the brain. Growth-associated protein 43 (GAP-43) is highly upregulated in brain tissue shortly after experimental ischemia suggesting the CSF GAP-43 concentration may be altered in ischemic brain disorders. CSF GAP-43 concentration is elevated in Alzheimer’s disease patients; however, patients suffering from stroke have not been studied previously. Methods: The concentration of GAP-43 was measured in longitudinal CSF samples from 28 stroke patients prospectively collected on days 0–1, 2–4, 7–9, 3 weeks, and 3–5 months after ischemia and cross-sectionally in 19 controls. The stroke patients were clinically evaluated using a stroke severity score system. The extent of the brain lesion, including injury size and degrees of white matter lesions and atrophy were evaluated by CT and magnetic resonance imaging. Results: Increased GAP-43 concentration was detected from day 7–9 to 3 weeks after stroke, compared to day 1–4 and to levels in the control group (P = 0.02 and P = 0.007). At 3–5 months after stroke GAP-43 returned to admission levels. The initial increase in GAP-43 during the nine first days was associated to stroke severity, the degree of white matter lesions and atrophy and correlated positively with infarct size (rs = 0.65, P = 0.001). Conclusions: The transient increase of CSF GAP-43 is important to take into account when used as a biomarker for other neurodegenerative diseases such as Alzheimer’s disease. Furthermore, GAP-43 may be a marker of neuronal responses after stroke and additional studies confirming the potential of CSF GAP-43 to reflect severity and outcome of stroke in larger cohorts are warranted

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314