Management of androgen-ablation refractory prostate cancer. Role for somatostatin analogues?

Patients with metastasised prostate cancer survive longer with anti-androgen therapy but eventually all progress into the androgen-ablation refractory (AAR) stage and die. There are only few effective strategies to treat patients with AAR cancers and they include even more effective androgen blockade by for example glucocorticoids or ketoconazole. Some of the tumours differentiate into neuroendocrine tumours and become completely independent of androgen stimulation. It is believed that these tumours over-express somatostatin receptors which may be a new target for the anti-tumour treatment. In this article we present a patient with advanced AAR prostate cancer and intractable retching and vomiting. As the last resort, he was treated with octreotide SC which resulted rapid amelioration of the symptoms and in significantly decreased PSA which could be translated into longer survival. In this article we review rationale for the use of somatostatin analogues in the treatment of patients with hormone-refractory prostate cancer. Adv. Pall. Med. 2010; 9, 4: 145–150Patients with metastasised prostate cancer survive longer with anti-androgen therapy but eventually all progress into the androgen-ablation refractory (AAR) stage and die. There are only few effective strategies to treat patients with AAR cancers and they include even more effective androgen blockade by for example glucocorticoids or ketoconazole. Some of the tumours differentiate into neuroendocrine tumours and become completely independent of androgen stimulation. It is believed that these tumours over-express somatostatin receptors which may be a new target for the anti-tumour treatment. In this article we present a patient with advanced AAR prostate cancer and intractable retching and vomiting. As the last resort, he was treated with octreotide SC which resulted rapid amelioration of the symptoms and in significantly decreased PSA which could be translated into longer survival. In this article we review rationale for the use of somatostatin analogues in the treatment of patients with hormone-refractory prostate cancer. Adv. Pall. Med. 2010; 9, 4: 145–15

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

Chromatin dynamics and the role of G9a in gene regulation and enhancer silencing during early mouse development.

Early mouse development is accompanied by dynamic changes in chromatin modifications, including G9a-mediated histone H3 lysine 9 dimethylation (H3K9me2), which is essential for embryonic development. Here we show that genome-wide accumulation of H3K9me2 is crucial for postimplantation development, and coincides with redistribution of enhancer of zeste homolog 2 (EZH2)-dependent histone H3 lysine 27 trimethylation (H3K27me3). Loss of G9a or EZH2 results in upregulation of distinct gene sets involved in cell cycle regulation, germline development and embryogenesis. Notably, the H3K9me2 modification extends to active enhancer elements where it promotes developmentally-linked gene silencing and directly marks promoters and gene bodies. This epigenetic mechanism is important for priming gene regulatory networks for critical cell fate decisions in rapidly proliferating postimplantation epiblast cells.Wellcome Trust: Jan J Zylicz, Ufuk Günesdogan, Jamie A Hackett, Delphine Cougot, Caroline Lee, MA Surani, WT096738; European Commission (EC): Ufuk Günesdogan; Wellcome Trust: Jan J Zylicz, RG44593This is the final version of the article. It was first available from eLife via http://dx.doi.org/10.7554/eLife.0957

G9a regulates temporal preimplantation developmental program and lineage segregation in blastocyst

Early mouse development is regulated and accompanied by dynamic changes in chromatin modifications, including G9a-mediated histone H3 lysine 9 dimethylation (H3K9me2). Previously, we provided insights into its role in post-implantation development (Zylicz et al., 2015). Here we explore the impact of depleting the maternally inherited G9a in oocytes on development shortly after fertilisation. We show that G9a accumulates typically at 4 to 8-cell stage to promote timely repression of a subset of 4-cell stage-specific genes. Loss of maternal inheritance of G9a disrupts the gene regulatory network resulting in developmental delay and destabilisation of inner cell mass lineages by the late blastocyst stage. Our results indicate a vital role of this maternally inherited epigenetic regulator in creating conducive conditions for developmental progression and on cell fate choices.Wellcome Trust/CRUK Gurdon Institute, University of Cambridge Wellcome Trust/Medical Research Council, Stem Cell Institute, University of Cambridg

PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos.

Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which includes comprehensive DNA demethylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs causes complete male and female sterility, preceded by the upregulation of LINE1 and IAP transposons as well as activation of a DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation. PRMT5 is necessary for the repressive H2A/H4R3me2s chromatin modification on LINE1 and IAP transposons in PGCs, directly implicating this modification in transposon silencing during DNA hypomethylation. PRMT5 translocates back to the cytoplasm subsequently, to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA remethylation. Thus, PRMT5 is directly involved in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation.U.G. was supported by a Marie Sk1odowska Curie Intra-European Fellowship. J.J.Z. was a recipient of a Wellcome Trust PhD Studentship (RG44593). This research was supported by grants from the Wellcome Trust to M.A.S. (WT096738).This is the final published version. It first appeared at http://www.cell.com/molecular-cell/abstract/S1097-2765%2814%2900787-4

Valuing the commons : an international study on the recreational benefits of the Baltic Sea

The Baltic Sea provides benefits to all of the nine nations along its coastline, with some 85 million people living within the catchment area. Achieving improvements in water quality requires international cooperation. The likelihood of effective cooperation is known to depend on the distribution across countries of the benefits and costs of actions needed to improve water quality. In this paper, we estimate the benefits associated with recreational use of the Baltic Sea in current environmental conditions using a travel cost approach, based on data from a large, standardized survey of households in each of the 9 Baltic Sea states. Both the probability of engaging in recreation (participation) and the number of visits people make are modeled. A large variation in the number of trips and the extent of participation is found, along with large differences in current annual economic benefits from Baltic Sea recreation. The total annual recreation benefits are close to 15 billion EUR. Under a water quality improvement scenario, the proportional increases in benefits range from 7 to 18% of the current annual benefits across countries. Depending on how the costs of actions are distributed, this could imply difficulties in achieving more international cooperation to achieve such improvements.PostprintPeer reviewe

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

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Contains fulltext : 169681.pdf (publisher's version ) (Open Access)Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/- heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/- knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/- and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/- mice in the Visual Discrimination &Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/- mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/- mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability