Prediction of amikacin dose requirements in neutropenic patients with haematological disease

This study reports on the use of an easily applied Bayesian forecasting programme (OPT; Clyde-soft) to predict amikacin dose requirements in 10 patients with haematological disease and neutropenic fever. OPT-determined dose adjustment achieved therapeutic drug levels for 80% of the peak and 94% of the trough measurements

CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering

CD20 monoclonal antibody therapies have significantly improved the outlook for patients with B-cell malignancies. However, many patients acquire resistance, demonstrating the need for new and improved drugs. We previously demonstrated that the natural process of antibody hexamer formation on targeted cells allows for optimal induction of complement-dependent cytotoxicity. Complement-dependent cytotoxicity can be potentiated by introducing a single point mutation such as E430G in the IgG Fc domain that enhances intermolecular Fc-Fc interactions between cell-bound IgG molecules, thereby facilitating IgG hexamer formation. Antibodies specific for CD37, a target that is abundantly expressed on healthy and malignant B cells, are generally poor inducers of complement-dependent cytotoxicity. Here we demonstrate that introduction of the hexamerization-enhancing mutation E430G in CD37-specific antibodies facilitates highly potent complement-dependent cytotoxicity in chronic lymphocytic leukemia cells ex vivo. Strikingly, we observed that combinations of hexamerization-enhanced CD20 and CD37 antibodies cooperated in C1q binding and induced superior and synergistic complement-dependent cytotoxicity in patient-derived cancer cells compared to the single agents. Furthermore, CD20 and CD37 antibodies colocalized on the cell membrane, an effect that was potentiated by the hexamerization-enhancing mutation. Moreover, upon cell surface binding, CD20 and CD37 antibodies were shown to form mixed hexameric antibody complexes consisting of both antibodies each bound to their own cognate target, so-called hetero-hexamers. These findings provide novel insights into the mechanisms of synergy in antibody-mediated complement-dependent cytotoxicity and provide a rationale to explore Fc-engineering and antibody hetero-hexamerization as a tool to enhance the cooperativity and therapeutic efficacy of antibody combinations.Transplantation and autoimmunit

The Sample Analysis at Mars Investigation and Instrument Suite

International audienceThe Sample Analysis at Mars (SAM) investigation of the Mars Science Laboratory (MSL) addresses the chemical and isotopic composition of the atmosphere and volatiles extracted from solid samples. The SAM investigation is designed to contribute substantially to the mission goal of quantitatively assessing the habitability of Mars as an essential step in the search for past or present life on Mars. SAM is a 40 kg instrument suite located in the interior of MSL's Curiosity rover. The SAM instruments are a quadrupole mass spectrometer, a tunable laser spectrometer, and a 6-column gas chromatograph all coupled through solid and gas processing systems to provide complementary information on the same samples. The SAM suite is able to measure a suite of light isotopes and to analyze volatiles directly from the atmosphere or thermally released from solid samples. In addition to measurements of simple inorganic compounds and noble gases SAM will conduct a sensitive search for organic compounds with either thermal or chemical extraction from sieved samples delivered by the sample processing system on the Curiosity rover's robotic arm

Astrobiology and the possibility of life on Earth and elsewhere…

Astrobiology is an interdisciplinary scientific field not only focused on the search of extraterrestrial life, but also on deciphering the key environmental parameters that have enabled the emergence of life on Earth. Understanding these physical and chemical parameters is fundamental knowledge necessary not only for discovering life or signs of life on other planets, but also for understanding our own terrestrial environment. Therefore, astrobiology pushes us to combine different perspectives such as the conditions on the primitive Earth, the physicochemical limits of life, exploration of habitable environments in the Solar System, and the search for signatures of life in exoplanets. Chemists, biologists, geologists, planetologists and astrophysicists are contributing extensively to this interdisciplinary research field. From 2011 to 2014, the European Space Agency (ESA) had the initiative to gather a Topical Team of interdisciplinary scientists focused on astrobiology to review the profound transformations in the field that have occurred since the beginning of the new century. The present paper is an interdisciplinary review of current research in astrobiology, covering the major advances and main outlooks in the field. The following subjects will be reviewed and most recent discoveries will be highlighted: the new understanding of planetary system formation including the specificity of the Earth among the diversity of planets, the origin of water on Earth and its unique combined properties among solvents for the emergence of life, the idea that the Earth could have been habitable during the Hadean Era, the inventory of endogenous and exogenous sources of organic matter and new concepts about how chemistry could evolve towards biological molecules and biological systems. In addition, many new findings show the remarkable potential life has for adaptation and survival in extreme environments. All those results from different fields of science are guiding our perspectives and strategies to look for life in other Solar System objects as well as beyond, in extrasolar worlds