Scientific Rationale Supporting the Clinical Development Strategy for the Investigational Aurora A Kinase Inhibitor Alisertib in Cancer

Alisertib (MLN8237) is a selective small molecule inhibitor of Aurora A kinase that is being developed in multiple cancer indications as a single agent and in combination with other therapies. A significant amount of research has elucidated a role for Aurora A in orchestrating numerous activities of cells transiting through mitosis and has begun to shed light on potential non-mitotic roles for Aurora A as well. These biological insights laid the foundation for multiple clinical trials evaluating the antitumor activity of alisertib in both solid cancers and heme-lymphatic malignancies. Several key facets of Aurora A biology as well as empirical data collected in experimental systems and early clinical trials have directed the development of alisertib towards certain cancer types, including neuroblastoma, small cell lung cancer, neuroendocrine prostate cancer, atypical teratoid / rhabdoid tumors and breast cancer among others. In addition, these scientific insights provided the rationale for combining alisertib with other therapies, including microtubule perturbing agents such as taxanes, EGFR inhibitors, hormonal therapies, platinums, and HDAC inhibitors among others. Here we link the key aspects of the current clinical development of alisertib to the originating scientific rationale and provide an overview of the alisertib clinical experience to date

Computer simulation of random and non-random second-phase particle distributions for both constant and varying particle size

Mechanical properties of two phase materials, such as strength, ductility and toughness, depend on the size and distribution of the second phase. However, no methods are presently available to accurately quantify the homogeneity of the distribution of the second phase. Random and non-random second phase particle distribution have been simulated by computer and analyzed for various area fractions. Distribution of particles with a lognormal size distribution have been analyzed as well. Statistically sufficient number of particles for use in the model was determined and used for all simulations. Average first nearer neighbor spacing values for dilute arrays of particles approach those of Poisson distributions of infinitesimal points. As the particle density increases, the average spacing values approach those of hexagonal arrays. For low area fractions there is little distinction between random and non-random distributions, both from statistical and visual perspectives. For higher area fractions there is a discernible difference between the statistical data for random and non-random distributions, but the visual differences are more obvious. These observation hold for both constant size particles and particle with a lognormal size distribution.http://archive.org/details/computersimulati00manfLieutenant, United States NavyApproved for public release; distribution is unlimited

Managing the Systemic Impact of Periodontitis

Periodontitis is a microbially driven host-mediated disease that leads to loss of periodontal attachment and bone. It is associated with elevation of systemic inflammatory markers and with the presence of systemic co-morbidities. Furthermore, periodontal treatment leads to a 24-48 h-long acute local and systemic inflammatory response. This systemic response might increase the burden of patients with compromised medical history and/or uncontrolled systemic diseases. The correlation between periodontitis and systemic diseases, the impact of periodontitis on the quality of life and public health, the effects of periodontal treatment on systemic health and disease, and the available methods to manage systemic inflammation after periodontal therapy are discussed. The main focus then shifts to a description of the existing evidence regarding the impact of periodontitis and periodontal treatment on systemic health and to the identification of approaches aiming to reduce the effect of periodontitis on systemic inflammation

The fifth leaf and spike organs of barley (Hordeum vulgare L.) display different physiological and metabolic responses to drought stress

Background: Photosynthetic organs of the cereal spike (ear) provide assimilate for grain filling, but their response to drought is poorly understood. In this study, we characterized the drought response of individual organs of the barley spike (awn, lemma, and palea) and compared them with a vegetative organ (fifth leaf). Understanding differences in physiological and metabolic responses between the leaf and spike organs during drought can help us develop high yielding cultivars for environments where terminal drought is prevalent. Results: We exposed barley plants to drought by withholding water for 4 days at the grain filling stage and compared changes in: (1) relative water content (RWC), (2) osmotic potential (Ψs), (3) osmotic adjustment (OA), (4) gas exchange, and (5) metabolite content between organs. Drought reduced RWC and Ψs in all four organs, but the decrease in RWC was greater and there was a smaller change in Ψs in the fifth leaf than the spike organs. We detected evidence of OA in the awn, lemma, and palea, but not in the fifth leaf. Rates of gas exchange declined more rapidly in the fifth leaf than awn during drought. We identified 18 metabolites but, only ten metabolites accumulated significantly during drought in one or more organs. Among these, proline accumulated in all organs during drought while accumulation of the other metabolites varied between organs. This may suggest that each organ in the same plant uses a different set of osmolytes for drought resistance. Conclusions: Our results suggest that photosynthetic organs of the barley spike maintain higher water content, greater osmotic adjustment, and higher rates of gas exchange than the leaf during drought. Keywords: Barley, Awn, Leaf, Lemma, Palea, Drought, Water status, Gas exchange, Metabolite

A New Comorbidity in Periodontitis: Fusobacterium nucleatum and Colorectal Cancer

There is very recent and strong evidence relating Fusobacterium nucleatum to colorectal cancer. In this narrative review, we update the knowledge about gingival dysbiosis and the characteristics of Fusobacterium nucleatum as one of the main bacteria related to periodontitis. We provide data on microbiome, epidemiology, risk factors, prognosis, and treatment of colorectal cancer, one of the most frequent tumours diagnosed and whose incidence increases every year. We describe, from its recent origin, the relationship between this bacterium and this type of cancer and the knowledge and emerging mechanisms that scientific evidence reveals in an updated way. A diagram provided synthesizes the pathogenic mechanisms of this relationship in a comprehensive manner. Finally, the main questions and further research perspectives are presented

Winds at the Mars 2020 Landing Site. 2. Wind Variability and Turbulence

Wind speeds measured by the Mars 2020 Perseverance rover in Jezero crater were fitted as a Weibull distribution. InSight wind data acquired in Elysium Planitia were also used to contextualize observations. Jezero winds were found to be much calmer on average than in previous landing sites, despite the intense aeolian activity observed. However, a great influence of turbulence and wave activity was observed in the wind speed variations, thus driving the probability of reaching the highest wind speeds at Jezero, instead of sustained winds driven by local, regional, or large-scale circulation. The power spectral density of wind speed fluctuations follows a power-law, whose slope deviates depending on the time of day from that predicted considering homogeneous and isotropic turbulence. Daytime wave activity is related to convection cells and smaller eddies in the boundary layer, advected over the crater. The signature of convection cells was also found during dust storm conditions, when prevailing winds were consistent with a tidal drive. Nighttime fluctuations were also intense, suggesting strong mechanical turbulence. Convective vortices were usually involved in rapid wind fluctuations and extreme winds, with variations peaking at 9.2 times the background winds. Transient high wind events by vortex-passages, turbulence, and wave activity could be driving aeolian activity at Jezero. We report the detection of a strong dust cloud of 0.75–1.5 km in length passing over the rover. The observed aeolian activity had major implications for instrumentation, with the wind sensor suffering damage throughout the mission, probably due to flying debris advected by winds.The authors acknowledge and thank the Mars 2020 team. The authors would like to thank Editors and two anonymous reviewers for their constructive reviews, which greatly improved this manuscript. This work is supported by the Spanish Ministry of Science and Innovation, under project RTI2018-098728-B-C31. The derived data presented in this work were processed in the DPS24PA system, which is supported by project no. DV2020-ATM-A01. Part of the research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). The UPV/EHU team is supported by Grant PID2019-109467GB-I00 funded by 1042 MCIN/AEI/10.13039/501100011033/ and by Grupos Gobierno Vasco IT1742-22

The diverse meteorology of Jezero crater over the first 250 sols of Perseverance on Mars

NASA’s Perseverance rover’s Mars Environmental Dynamics Analyzer is collecting data at Jezero crater, characterizing the physical processes in the lowest layer of the Martian atmosphere. Here we present measurements from the instrument’s first 250 sols of operation, revealing a spatially and temporally variable meteorology at Jezero. We find that temperature measurements at four heights capture the response of the atmospheric surface layer to multiple phenomena. We observe the transition from a stable night-time thermal inversion to a daytime, highly turbulent convective regime, with large vertical thermal gradients. Measurement of multiple daily optical depths suggests aerosol concentrations are higher in the morning than in the afternoon. Measured wind patterns are driven mainly by local topography, with a small contribution from regional winds. Daily and seasonal variability of relative humidity shows a complex hydrologic cycle. These observations suggest that changes in some local surface properties, such as surface albedo and thermal inertia, play an influential role. On a larger scale, surface pressure measurements show typical signatures of gravity waves and baroclinic eddies in a part of the seasonal cycle previously characterized as low wave activity. These observations, both combined and simultaneous, unveil the diversity of processes driving change on today’s Martian surface at Jezero crater.This work has been funded by the Spanish Ministry of Economy and Competitiveness, through the projects no. ESP2014-54256-C4- 1-R (also -2-R, -3-R and -4-R); Ministry of Science, Innovation and Universities, projects no. ESP2016-79612-C3-1-R (also -2-R and -3-R); Ministry of Science and Innovation/State Agency of Research (10.13039/501100011033), projects no. ESP2016-80320-C2-1-R, RTI2018-098728-B-C31 (also -C32 and -C33), RTI2018-099825-B-C31, PID2019-109467GB-I00 and PRE2020-092562; Instituto Nacional de Técnica Aeroespacial; Ministry of Science and Innovation’s Centre for the Development of Industrial Technology; Spanish State Research Agency (AEI) Project MDM-2017-0737 Unidad de Excelencia “María de Maeztu”—Centro de Astrobiología; Grupos Gobierno Vasco IT1366- 19; and European Research Council Consolidator Grant no 818602. The US co-authors performed their work under sponsorship from NASA’s Mars 2020 project, from the Game Changing Development programme within the Space Technology Mission Directorate and from the Human Exploration and Operations Directorate. Part of this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). G.M. acknowledges JPL funding from USRA Contract Number 1638782. A.G.F. is supported by the European Research Council, Consolidator Grant no. 818602.Peer ReviewedPostprint (published version

Nocturnal Turbulence at Jezero Crater as Determined From MEDA Measurements and Modeling

Mars 2020 Mars Environmental Dynamics Analyzer (MEDA) instrument data acquired during half of a Martian year (Ls 13°–180°), and modeling efforts with the Mars Regional Atmospheric Modeling System (MRAMS) and the Mars Climate Database (MCD) enable the study of the seasonal evolution and variability of nocturnal atmospheric turbulence at Jezero crater. Nighttime conditions in Mars's Planetary Boundary Layer are highly stable because of strong radiative cooling that efficiently inhibits convection. However, MEDA nighttime observations of simultaneous rapid fluctuations in horizontal wind speed and air temperatures suggest the development of nighttime turbulence in Jezero crater. Mesoscale modeling with MRAMS also shows a similar pattern and enables us to investigate the origins of this turbulence and the mechanisms at play. As opposed to Gale crater, less evidence of turbulence from breaking mountain wave activity was found in Jezero during the period studied with MRAMS. On the contrary, the model suggests that nighttime turbulence at Jezero crater is explained by increasingly strong wind shear produced by the development of an atmospheric bore-like disturbance at the nocturnal inversion interface. These atmospheric bores are produced by downslope winds from the west rim undercutting a strong low-level jet aloft from ∼19:00 to 01:00 LTST and from ∼01:00 LTST to dawn when undercutting weak winds aloft. The enhanced wind shear leads to a reduction in the Richardson number and an onset of mechanical turbulence. Once the critical Richardson Number is reached (Ri ∼ <0.25), shear instabilities can mix warmer air aloft down to the surface.This research was funded by Grant RTI2018-098728-B-C31 and PN2021-PID2021-126719OB-C41 by the Spanish Ministry of Science and Innovation/State Agency of Research MCIN/AEI/10.13039/501100011033. AM, ASL, TR, and RH were supported by Grant PID2019-109467GB-I00 funded by MCIN/AEI/10.13039/501100011033/and by Grupos Gobierno Vasco IT1366-19. Part of this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). The JPL co-authors acknowledge funding from NASA's Space Technology Mission Directorate and the Science Mission Directorate. CEN was supported by funding from the Mars 2020 mission, part of the NASA Mars Exploration Program