Effect of food on the pharmacokinetics of oral MMI270B (CGS 27023A), a novel matrix metalloproteinase inhibitor

MMI270B is a matrix metalloproteinase inhibitor (MMPI) with in vitro and in vivo activity. To exert optimal target inhibition, MMPI must be given chronically, and therefore, oral bioavailability is important. We analyzed the effect of food intake on AUC0-8 h, Cmax, and Tmax. Seventeen patients were entered into the study. Doses of MMI270B were 150, 400, and 600 mg. The first day, patients ingested the drug in a fasted state and were not allowed to eat for 2 h. The second day, patients ingested the drug 30 min after a light breakfast. Mean AUC0-8 h was not significantly influenced by food intake. Plasma concentrations were well above the IC50 of several MMPs at all doses tested. Mean Cmax was significantly decreased after food intake. Mean Tmax was significantly delayed after food intake. Food intake did not result in a significant change in exposure to MMI270B (AUC0-8 h) but did result in a significant, although not clinically relevant, decrease in peak plasma levels and time to reach peak plasma levels. No specific guidelines concerning the ingestion of MMI270B in either a fed or a fasted state are recommended

State of the climate in 2015

In 2015, the dominant greenhouse gases released into Earth\u2019s atmosphere\u2014carbon dioxide, methane, and nitrous oxide\u2014all continued to reach new high levels. At Mauna Loa, Hawaii, the annual CO2 concentration increased by a record 3.1 ppm, exceeding 400 ppm for the first time on record. The 2015 global CO2 average neared this threshold, at 399.4 ppm. Additionally, one of the strongest El Ni\uf1o events since at least 1950 developed in spring 2015 and continued to evolve through the year. The phenomenon was far reaching, impacting many regions across the globe and affecting most aspects of the climate system. Owing to the combination of El Ni\uf1o and a long-term upward trend, Earth observed record warmth for the second consecutive year, with the 2015 annual global surface temperature surpassing the previous record by more than 0.1\ub0C and exceeding the average for the mid- to late 19th century\u2014commonly considered representative of preindustrial conditions\u2014by more than 1\ub0C for the first time. Above Earth\u2019s surface, lower troposphere temperatures were near-record high. Across land surfaces, record to near-record warmth was reported across every inhabited continent. Twelve countries, including Russia and China, reported record high annual temperatures. In June, one of the most severe heat waves since 1980 affected Karachi, Pakistan, claiming over 1000 lives. On 27 October, Vredendal, South Africa, reached 48.4\ub0C, a new global high temperature record for this month. In the Arctic, the 2015 land surface temperature was 1.2\ub0C above the 1981\u20132010 average, tying 2007 and 2011 for the highest annual temperature and representing a 2.8\ub0C increase since the record began in 1900. Increasing temperatures have led to decreasing Arctic sea ice extent and thickness. On 25 February 2015, the lowest maximum sea ice extent in the 37-year satellite record was observed, 7% below the 1981\u20132010 average. Mean sea surface temperatures across the Arctic Ocean during August in ice-free regions, representative of Arctic Ocean summer anomalies, ranged from ~0\ub0C to 8\ub0C above average. As a consequence of sea ice retreat and warming oceans, vast walrus herds in the Pacific Arctic are hauling out on land rather than on sea ice, raising concern about the energetics of females and young animals. Increasing temperatures in the Barents Sea are linked to a community-wide shift in fish populations: boreal communities are now farther north, and long-standing Arctic species have been almost pushed out of the area. Above average sea surface temperatures are not confined to the Arctic. Sea surface temperature for 2015 was record high at the global scale; however, the North Atlantic southeast of Greenland remained colder than average and colder than 2014. Global annual ocean heat content and mean sea level also reached new record highs. The Greenland Ice Sheet, with the capacity to contribute ~7 m to sea level rise, experienced melting over more than 50% of its surface for the first time since the record melt of 2012. Other aspects of the cryosphere were remarkable. Alpine glacier retreat continued, and preliminary data indicate that 2015 is the 36th consecutive year of negative annual mass balance. Across the Northern Hemisphere, late-spring snow cover extent continued its trend of decline, with June the second lowest in the 49-year satellite record. Below the surface, record high temperatures at 20-m depth were measured at all permafrost observatories on the North Slope of Alaska, increasing by up to 0.66\ub0C decade\u20131 since 2000. In the Antarctic, surface pressure and temperatures were lower than the 1981\u20132010 average for most of the year, consistent with the primarily positive southern annular mode, which saw a record high index value of +4.92 in February. Antarctic sea ice extent and area had large intra-annual variability, with a shift from record high levels in May to record low levels in August. Springtime ozone depletion resulted in one of the largest and most persistent Antarctic ozone holes observed since the 1990s. Closer to the equator, 101 named tropical storms were observed in 2015, well above the 1981\u20132010 average of 82. The eastern/central Pacific had 26 named storms, the most since 1992. The western north Pacific and north and south Indian Ocean basins also saw high activity. Globally, eight tropical cyclones reached the Saffir\u2013Simpson Category 5 intensity level. Overlaying a general increase in the hydrologic cycle, the strong El Ni\uf1o enhanced precipitation variability around the world. An above-normal rainy season led to major floods in Paraguay, Bolivia, and southern Brazil. In May, the United States recorded its all-time wettest month in its 121-year national record. Denmark and Norway reported their second and third wettest year on record, respectively, but globally soil moisture was below average, terrestrial groundwater storage was the lowest in the 14-year record, and areas in \u201csevere\u201d drought rose from 8% in 2014 to 14% in 2015. Drought conditions prevailed across many Caribbean island nations, Colombia, Venezuela, and northeast Brazil for most of the year. Several South Pacific countries also experienced drought. Lack of rainfall across Ethiopia led to its worst drought in decades and affected millions of people, while prolonged drought in South Africa severely affected agricultural production. Indian summer monsoon rainfall was just 86% of average. Extremely dry conditions in Indonesia resulted in intense and widespread fires during August\u2013November that produced abundant carbonaceous aerosols, carbon monoxide, and ozone. Overall, emissions from tropical Asian biomass burning in 2015 were almost three times the 2001\u201314 average

Direct observation of the dead-cone effect in quantum chromodynamics

At particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD) [1]. The vacuum is not transparent to the partons and induces gluon radiation and quark pair production in a process that can be described as a parton shower [2]. Studying the pattern of the parton shower is one of the key experimental tools in understanding the properties of QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass m and energy E, within a cone of angular size m/E around the emitter [3]. A direct observation of the dead-cone effect in QCD has not been possible until now, due to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible bound hadronic states. Here we show the first direct observation of the QCD dead-cone by using new iterative declustering techniques [4, 5] to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD, which is derived more generally from its origin as a gauge quantum field theory. Furthermore, the measurement of a dead-cone angle constitutes the first direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics.The direct measurement of the QCD dead cone in charm quark fragmentation is reported, using iterative declustering of jets tagged with a fully reconstructed charmed hadron.In particle collider experiments, elementary particle interactions with large momentum transfer produce quarks and gluons (known as partons) whose evolution is governed by the strong force, as described by the theory of quantum chromodynamics (QCD). These partons subsequently emit further partons in a process that can be described as a parton shower which culminates in the formation of detectable hadrons. Studying the pattern of the parton shower is one of the key experimental tools for testing QCD. This pattern is expected to depend on the mass of the initiating parton, through a phenomenon known as the dead-cone effect, which predicts a suppression of the gluon spectrum emitted by a heavy quark of mass $m_{\rm{Q}}$ and energy $E$, within a cone of angular size $m_{\rm{Q}}$/$E$ around the emitter. Previously, a direct observation of the dead-cone effect in QCD had not been possible, owing to the challenge of reconstructing the cascading quarks and gluons from the experimentally accessible hadrons. We report the direct observation of the QCD dead cone by using new iterative declustering techniques to reconstruct the parton shower of charm quarks. This result confirms a fundamental feature of QCD. Furthermore, the measurement of a dead-cone angle constitutes a direct experimental observation of the non-zero mass of the charm quark, which is a fundamental constant in the standard model of particle physics