ZBTB18 restricts chromatin accessibility and prevents transcriptional adaptations that drive metastasis.

Metastases arise from rare cancer cells that successfully adapt to the diverse microenvironments encountered during dissemination through the bloodstream and colonization of distant tissues. How cancer cells acquire the ability to appropriately respond to microenvironmental stimuli remains largely unexplored. Here, we report an epigenetic pliancy mechanism that allows cancer cells to successfully metastasize. We find that a decline in the activity of the transcriptional repressor ZBTB18 defines metastasis-competent cancer cells in mouse models. Restoration of ZBTB18 activity reduces chromatin accessibility at the promoters of genes that drive metastasis, such as Tgfbr2, and this prevents TGFß1 pathway activation and consequently reduces cell migration and invasion. Besides repressing the expression of metastatic genes, ZBTB18 also induces widespread chromatin closing, a global epigenetic adaptation previously linked to reduced phenotypic flexibility. Thus, ZBTB18 is a potent chromatin regulator, and the loss of its activity enhances chromatin accessibility and transcriptional adaptations that promote the phenotypic changes required for metastasis.

Cation Ordering and Exsolution in Copper-Containing Forms of the Flexible Zeolite Rho (Cu,M-Rho; M=H, Na) and Their Consequences for CO2 Adsorption.

The flexibility of the zeolite Rho framework offers great potential for tunable molecular sieving. The fully copper-exchanged form of Rho and mixed Cu,H- and Cu,Na-forms have been prepared. EPR spectroscopy reveals that Cu2+ ions are present in the dehydrated forms and Rietveld refinement shows these prefer S6R sites, away from the d8r windows that control diffusion. Fully exchanged Cu-Rho remains in an open form upon dehydration, the d8r windows remain nearly circular and the occupancy of window sites is low, so that it adsorbs CO2 rapidly at room temperature. Breakthrough tests with 10 % CO2 /40 % CH4 mixtures show that Cu4.9 -Rho is able to produce pure methane, albeit with a relatively low capacity at this pCO2 due to the weak interaction of CO2 with Cu cations. This is in strong contrast to Na-Rho, where cations in narrow elliptical window sites enable CO2 to be adsorbed with high selectivity and uptake but too slowly to enable the production of pure methane in similar breakthrough experiments. A series of Cu,Na-Rho materials was prepared to improve uptake and selectivity compared to Cu-Rho, and kinetics compared to Na-Rho. Remarkably, Cu,Na-Rho with >2 Cu cations per unit cell exhibited exsolution, due to the preference of Na cations for narrow S8R sites in distorted Rho and of Cu cations for S6R sites in the centric, open form of Rho. The exsolved Cu,Na-Rho showed improved performance in CO2 /CH4 breakthrough tests, producing pure CH4 with improved uptake and CO2 /CH4 selectivity compared to that of Cu4.9 -Rho.

Safety and Immunogenicity of a Heterologous Prime-Boost Ebola Virus Vaccine Regimen in Healthy Adults in the United Kingdom and Senegal.

BACKGROUND: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. METHODS: We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. RESULTS: The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. CONCLUSIONS: MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control. CLINICAL TRIALS REGISTRATION: NCT02451891; NCT02485912.