High-precision measurement of the half-life of 62^{62}Ga

The beta-decay half-life of 62Ga has been studied with high precision using on-line mass separated samples. The decay of 62Ga which is dominated by a 0+ to 0+ transition to the ground state of 62Zn yields a half-life of T_{1/2} = 116.19(4) ms. This result is more precise than any previous measurement by about a factor of four or more. The present value is in agreement with older literature values, but slightly disagrees with a recent measurement. We determine an error weighted average value of all experimental half-lives of 116.18(4) ms.Comment: 9 pages, 5 figures, accepted for publication in PR

NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers.

Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice, where its precise role is yet unclear. We investigated this in an in vitro model, in which naive pluripotent embryonic stem (ES) cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate. Consequently, bone morphogenetic protein 4 (BMP4), or ectopic expression of key germline transcription factors Prdm1, Prdm14 and Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ES cells. Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs, the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG-binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nature1648

New μs isomers in Tz=1 nuclei produced in the 112Sn(63A MeV)+natNi reaction

Expérience GANIL, équipement SISSI/LISE

Altering Chemosensitivity by Modulating Translation Elongation

BACKGROUND: The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Emu-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents. METHODOLOGY/PRINCIPAL FINDINGS: Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Emu-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor. CONCLUSION/SIGNIFICANCE: Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations

Sparsomycin and its analogues: a preclinical study on novel anticancer drugs

Contains fulltext : mmubn000001_065390628.pdf (publisher's version ) (Open Access)Promotores : D. Wagener, E. van der Kleijn en H. Ottenheijm193 p

ORAL OPIOIDS IN THE TREATMENT OF CANCER PAIN

Persistent severe cancer pain should be treated with opioid drugs, principally morphine. It can be administered orally, rectally and parenterally. Morphine is metabolised in the liver mainly to glucuronides, of which morphine-6-glucuronide is a powerful analgesic. Oral morphine should be administered regularly and in individualized doses. The use of morphine is frequently accompanied by adverse effects such as constipation, nausea, vomiting and sedation. Management of these is critical for successful pain treatment. Although alternatives are available none has any clear advantage over morphine in cancer pain, and should be reserved for special situations. Oral morphine is successful in more than 90% of cancer pain patients. Slow release morphine sulphate tablets (MS Contin) are often the best choice. For the few patients who need parenteral medication, continuous subcutaneous morphine sulphate infusion is generally the most suitable. Some pains are morphine resistant, especially those due to nerve injury. In these cases pain is best treated with tricyclic antidepressants and/or anticonvulsants