Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells

PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKCδ and inhibiting PKCα. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC50 of PEP005 ranged from 0.01–140 μM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 μM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKCδ and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

LINE BROADENING OF NE-LIKE XENON AS A DIAGNOSTIC FOR HIGH-DENSITY IMPLOSION EXPERIMENTS

8TH TOPICAL CONF ON HIGH TEMPERATURE PLASMA DIAGNOSTICS, HYANNIS, MA, MAY 06-10, 1990International audienc

A study of picosecond laser-solid interactions up to 10(19) W cm(-2)

The interaction of a 1053 nm picosecond laser pulse with a solid target has been studied for focused intensities of up to 1019 W cm-2. The maximum ion energy cutoff Emax (which is related to the hot electron temperature) is in the range 1.0-12.0 MeV and is shown to scale as Emax≈I1/3. The hot electron temperatures were in the range 70-400 keV for intensities up to 5 × 1018 W cm-2 with an indication of a high absorption of laser energy. Measurements of x-ray/y-ray bremsstrahlung emission suggest the existence of at least two electron temperatures. Collimation of the plasma flow has been observed by optical probing techniques. ©7997 American Institute of Physics

Competing effects of collisional ionization and radiative cooling in inertially confined plasmas

International audienceWe describe an experimental investigation, a detailed analysis of the Ar XVII 1s(2 1)S-1s3p P-1 (He beta) line shape formed in a high-energy-density implosion, and report on one-dimensional radiation-hydrodynamics simulation of the implosion. In this experiment trace quantities of argon are doped into a lower-Z gas-filled core of a plastic microsphere. The dopant level is controlled to ensure that the He beta transition is optically thin and easily observable. Then the observed line shape is used to derive electron temperatures (T-e) and electron densities (n(e)). The high-energy density plasma, with T-e approaching 1 keV and n(e) = 10(24) cm(-3), is created by placing the microsphere in a gold cylindrical enclosure, the interior of which is directly irradiated by a high-energy laser; the x rays produced by this laser-gold interaction indirectly implode the microsphere. Central to the interpretation of the hydrodynamics of the implosions is the characterization and understanding of the formation of these plasmas. To develop an understanding of the plasma and its temporal evolution, time-resolved T-e and n(e) measurements are extracted using techniques that are independent of the plasma hydrodynamics. Comparing spectroscopic diagnostics with measurements derived from other diagnostic methods, we find the spectroscopic measurements to be reliable and further we find that the experiment-to-experiment comparison shows that these implosions are reproducible

Evolution of electron temperature and electron density in indirectly driven spherical implosions

International audienceUsing spectroscopic measurements to extract electron density and temperature, we construct simulation-independent time histories of the assembly and disassembly phase of an imploding core, To achieve this, we show the hot dense plasma produced by indirectly imploding gas-filled microsphere is a reproducible and reliable plasma source. We further show that this plasma is suitable for detailed hydrodynamic and spectroscopic studies, and that the plasma provides a useful testbed for nonlocal thermodynamic equilibrium plasma studies at extreme conditions

Structural basis for AcrVA4 inhibition of specific CRISPR-Cas12a.

CRISPR-Cas systems provide bacteria and archaea with programmable immunity against mobile genetic elements. Evolutionary pressure by CRISPR-Cas has driven bacteriophage to evolve small protein inhibitors, anti-CRISPRs (Acrs), that block Cas enzyme function by wide-ranging mechanisms. We show here that the inhibitor AcrVA4 uses a previously undescribed strategy to recognize the L. bacterium Cas12a (LbCas12a) pre-crRNA processing nuclease, forming a Cas12a dimer, and allosterically inhibiting DNA binding. The Ac. species Cas12a (AsCas12a) enzyme, widely used for genome editing applications, contains an ancestral helical bundle that blocks AcrVA4 binding and allows it to escape anti-CRISPR recognition. Using biochemical, microbiological, and human cell editing experiments, we show that Cas12a orthologs can be rendered either sensitive or resistant to AcrVA4 through rational structural engineering informed by evolution. Together, these findings explain a new mode of CRISPR-Cas inhibition and illustrate how structural variability in Cas effectors can drive opportunistic co-evolution of inhibitors by bacteriophage

CASTILLO SÁNCHEZ, POLO DEL [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201