Polyphenon E enhances the antitumor immune response in neuroblastoma by inactivating myeloid suppressor cells

This is the author's accepted manuscript. The final published article is available from the link below. Note: In this manuscript as well as in the original published version of this article the word "Polyphenon" was incorrectly spelled in the title as "Polyphenol."Purpose: Neuroblastoma is a rare childhood cancer whose high risk, metastatic form has a dismal outcome in spite of aggressive therapeutic interventions. The toxicity of drug treatments is a major problem in this pediatric setting. In this study, we investigated whether Polyphenon E, a clinical grade mixture of green tea catechins under evaluation in multiple clinical cancer trials run by the National Cancer Institute (Bethesda, MD), has anticancer activity in mouse models of neuroblastoma. Experimental Design: We used three neuroblastoma models: (i) transgenic TH-MYCN mouse developing spontaneous neuroblastomas; (ii) nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenotransplanted with human SHSY5Y cells; and (iii) A/J mice transplanted with syngeneic Neuro 2A cells. Mice were randomized in control and Polyphenon E–drinking groups. Blood from patients with neuroblastoma and normal controls was used to assess the phenotype and function of myeloid cells. Results: Polyphenon E reduced the number of tumor-infiltrating myeloid cells, and inhibited the development of spontaneous neuroblastomas in TH-MYCN transgenic mice. In therapeutic models of neuroblastoma in A/J, but not in immunodeficient NOD/SCID mice, Polyphenon E inhibited tumor growth by acting on myeloid-derived suppressor cells (MDSC) and CD8 T cells. In vitro, Polyphenon E impaired the development and motility of MDSCs and promoted differentiation to more neutrophilic forms through the 67 kDa laminin receptor signaling and induction of granulocyte colony-stimulating factor. The proliferation of T cells infiltrating a patient metastasis was reactivated by Polyphenon E. Conclusions: These findings suggest that the neuroblastoma-promoting activity of MDSCs can be manipulated pharmacologically in vivo and that green tea catechins operate, at least in part, through this mechanism.SPARKS, Research in Childhood Cancer, the CGD Research Trust, and the Wellcome Trust

Extended investigation of superdeformed bands in 151,152^{151,152}Tb nuclei

A detailed study of known and new SD bands in Tb isotopes has been performed with the use of the EUROBALL IV -ray array. The high-statistics data set has allowed for the extension of known SD bands at low and high spins by new -ray transitions. These transitions, as it turns out, correspond to the rotational frequencies where the principal superdeformed gaps (Z=66,N=86) close giving rise to up- or down-bending mechanisms. This enables to attribute the underlying theoretical configurations with much higher confidence as compared to the previous identifications. Five new SD bands have been discovered, three of them assigned to the 152Tb and the two others to the 151Tb nuclei. Nuclear mean-field calculations have been used to interpret the structure of known SD bands as well as of the new ones in terms of nucleonic configurations

LEGU-MED: Developing Biodiversity-Based Agriculture with Legume Cropping Systems in the Mediterranean Basin

Environmental degradation and the decrease of ecosystem service provision are currently of major concern, with current agricultural systems being a major driver. To meet our future environmental and sustainability targets a transformation of the agro-food systems and current agricultural value chain are crucial. One approach to redesign farming systems is the concept of biodiversity-based agriculture (BBA) which relies on sustainable diversification of biological components and their natural interactions in farming systems to maximize fertility, productivity, and resilience to external perturbations. Despite minimizing anthropogenic inputs, BBA is not yet able to meet all beneficial environmental objectives. BBA applied in the Mediterranean basin requires urgent innovation in approaches, methodologies, and models for small-holder traditional farming systems to ensure a stable provision of ecosystem services and better resilience to environmental stresses linked to climate change. Legumes are the backbone of the Mediterranean agro-ecosystems from ancient times, but their unique and wide biodiversity was not sufficiently valorized, especially by North-African countries. Here, we present LEGU-MED, a three-year international project funded by PRIMA initiative 2019. An international consortium was established involving five universities, 5 research institutes, and one private company from 8 countries: Italy, Germany, Spain, Algeria, Tunisia, Turkey, Lebanon, and Croatia. The main objective of this project is to put forward an international and well-integrated plan to valorize the legume agrobiodiversity of the Mediterranean in biodiversity-based farming systems and consequently enhance agro-ecosystem functions and services in the Mediterranean basin. The successful completion of LEGU-MED will have the following impacts on Mediterranean legume-based farming systems: (1) improve water use efficiency, (2) reduce the use of anthropogenic inputs through the maintenance of soil fertility, (3) enhance pollination and improve ecological connectivity with flora and fauna, (4) protect close-by wildland ecosystems, (5) enhance other ecosystem services (e.g., pest, disease, and weed suppression), and (6) provide healthier and safer protein-rich food. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Noncanonical DNA Motifs as Transactivation Targets by Wild Type and Mutant p53

Sequence-specific binding by the human p53 master regulator is critical to its tumor suppressor activity in response to environmental stresses. p53 binds as a tetramer to two decameric half-sites separated by 0–13 nucleotides (nt), originally defined by the consensus RRRCWWGYYY (n = 0–13) RRRCWWGYYY. To better understand the role of sequence, organization, and level of p53 on transactivation at target response elements (REs) by wild type (WT) and mutant p53, we deconstructed the functional p53 canonical consensus sequence using budding yeast and human cell systems. Contrary to early reports on binding in vitro, small increases in distance between decamer half-sites greatly reduces p53 transactivation, as demonstrated for the natural TIGER RE. This was confirmed with human cell extracts using a newly developed, semi–in vitro microsphere binding assay. These results contrast with the synergistic increase in transactivation from a pair of weak, full-site REs in the MDM2 promoter that are separated by an evolutionary conserved 17 bp spacer. Surprisingly, there can be substantial transactivation at noncanonical ½-(a single decamer) and ¾-sites, some of which were originally classified as biologically relevant canonical consensus sequences including PIDD and Apaf-1. p53 family members p63 and p73 yielded similar results. Efficient transactivation from noncanonical elements requires tetrameric p53, and the presence of the carboxy terminal, non-specific DNA binding domain enhanced transactivation from noncanonical sequences. Our findings demonstrate that RE sequence, organization, and level of p53 can strongly impact p53-mediated transactivation, thereby changing the view of what constitutes a functional p53 target. Importantly, inclusion of ½- and ¾-site REs greatly expands the p53 master regulatory network

A New Fracture Criterion under Multiaxial Monotonic Loading for Rubbers

International audienc

Experimental and numerical study on the temperature-dependent behavior of a fluoro-elastomer

International audienc

Time resistance of industrial steel portal frames with haunches under fire

To protect human lives and prevent against failure of structures, the collapse of industrial buildings under fire should always occur inward with a minimum failure time. The objective of this paper is to investigate the behaviour of industrial steel portal frames with haunches in fire situation. The structure is studied using finite element software ANSYS with an uncoupled thermal and mechanical analysis. The inclination angle of the rafter and the haunch’s length for the portal frame are taken as variables. A comparative study of the numerical simulations and the simplified method (R15) show a close agreement between the two analyses according to the failure time.info:eu-repo/semantics/publishedVersio