A phase II trial of brivanib in recurrent or persistent endometrial cancer: An NRG oncology/gynecologic oncology group study

PURPOSE Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). PATIENTS AND METHODS Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed. RESULTS Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1-24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6%-31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9%-43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS. CONCLUSION Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.

Sex differences in the human connectome: 4-Tesla high angular resolution diffusion imaging (HARDI) tractography in 234 young adult twins

Cortical connectivity is associated with cognitive and behavioral traits that are thought to vary between sexes. Using high-angular resolution diffusion imaging at 4 Tesla, we scanned 234 young adult twins and siblings (mean age: 23.4 2.0 SD years) with 94 diffusion-encoding directions. We applied a novel Hough transform method to extract fiber tracts throughout the entire brain, based on fields of constant solid angle orientation distribution functions (ODFs). Cortical surfaces were generated from each subject's 3D T1-weighted structural MRI scan, and tracts were aligned to the anatomy. Network analysis revealed the proportions of fibers interconnecting 5 key subregions of the frontal cortex, including connections between hemispheres. We found significant sex differences (147 women/87 men) in the proportions of fibers connecting contralateral superior frontal cortices. Interhemispheric connectivity was greater in women, in line with long-standing theories of hemispheric specialization. These findings may be relevant for ongoing studies of the human connectome.

The Effect of Intrauterine Growth Restriction on Long-Term Outcome in Very or Extremely Low Birth Weight Infants

The project consisted of two long-term follow-up studies of preterm children addressing the question whether intrauterine growth restriction affects the outcome. Assessment at 5 years of age of 203 children with a birth weight less than 1000 g born in Finland in 1996-1997 showed that 9% of the children had cognitive impairment, 14% cerebral palsy, and 4% needed a hearing aid. The intelligence quotient was lower (p<0.05) than the reference value. Thus, 20% exhibited major, 19% minor disabilities, and 61% had no functional abnormalities. Being small for gestational age (SGA) was associated with sub-optimal growth later. In children born before 27 gestational weeks, the SGA had more neuropsychological disabilities than those appropriate for gestational age (AGA). In another cohort with birth weight less than 1500 g assessed at 5 years of age, echocardiography showed a thickened interventricular septum and a decreased left ventricular end-diastolic diameter in both SGA and AGA born children. They also had a higher systolic blood pressure than the reference. Laser-Doppler flowmetry showed different endothelium-dependent and -independent vasodilation responses in the AGA children compared to those of the controls. SGA was not associated with cardio-vascular abnormalities. Auditory event-related potentials (AERPs) were recorded using an oddball paradigm with frequency deviants (standard tone 500 Hz and deviant 750-Hz with 10% probability). At term, the P350 was smaller in SGA and AGA infants than in controls. At 12 months, the automatic change detection peak (mismatch negativity, MMN) was observed in the controls. However, the pre-term infants had a difference positivity that correlated with their neurodevelopment scores. At 5 years of age, the P1-deflection, which reflects primary auditory processing, was smaller, and the MMN larger in the preterm than in the control children. Even with a challenging paradigm or a distraction paradigm, P1 was smaller in the preterm than in the control children. The SGA and AGA children showed similar AERP responses. Prematurity is a major risk factor for abnormal brain development. Preterm children showed signs of cardiovascular abnormality suggesting that prematurity per se may carry a risk for later morbidity. The small positive amplitudes in AERPs suggest persisting altered auditory processing in the preterm in-fants.

Non-periodic tilings in 2-dimensions with 4, 6, 8, 10 and 12-fold symmetries

The two dimensional plane can be filled with rhombuses, so as to generate non-periodic tilings with 4, 6, 8, 10 and 12-fold symmetries. Some representative tilings constructed using the rule of inflation are shown. The numerically computed diffraction patterns for the corresponding tilings are also shown to facilitate a comparison with possible X-ray or electron diffraction pictures.

Darcian mixed convection plumes along vertical adiabatic surfaces in a saturated porous medium

The mixed convection flow due to a line thermal source embedded at the leading edge of an adiabatic vertical plane surface immersed in a saturated porous medium has been studied. Both weakly and strongly buoyant plume regimes have been considered. The cases of buoyancy assisting and buoyancy opposing flow conditions have been incorporated in the analysis. The results are presented for the entire range of buoyancy parameter from the pure forced convection (xgr=0) to the pure free convection (xgr rarr infin@#@) regimes. For buoyancy-assisting flow, the wall temperature and the velocity at the wall increase as the plume strength increases. However, they all decrease as the free-stream velocity increases. For buoyancyopposing flow, the temperature at the wall increases as the strength of the plume increases but velocity at the wall decreases.

Monitoring urbanization and its implications in a mega city from space: Spatiotemporal patterns and its indicators

Rapid and invasive urbanization has been associated with depletion of natural resources (vegetation and water resources), which in turn deteriorates the landscape structure and conditions in the local environment. Rapid increase in population due to the migration from rural areas is one of the critical issues of the urban growth. Urbanisation in India is drastically changing the land cover and often resulting in the sprawl. The sprawl regions often lack basic amenities such as treated water supply, sanitation, etc. This necessitates regular monitoring and understanding of the rate of urban development in order to ensure the sustenance of natural resources. Urban sprawl is the extent of urbanization which leads to the development of urban forms with the destruction of ecology and natural landforms. The rate of change of land use and extent of urban sprawl can be efficiently visualized and modelled with the help of geo-informatics. The knowledge of urban area, especially the growth magnitude, shape geometry, and spatial pattern is essential to understand the growth and characteristics of urbanization process. Urban pattern, shape and growth can be quantified using spatial metrics. This communication quantifies the urbanisation and associated growth pattern in Delhi. Spatial data of four decades were analysed to understand land over and land use dynamics. Further the region was divided into 4 zones and into circles of 1 km incrementing radius to understand and quantify the local spatial changes. Results of the landscape metrics indicate that the urban center was highly aggregated and the outskirts and the buffer regions were in the verge of aggregating urban patches. Shannon's Entropy index clearly depicted the outgrowth of sprawl areas in different zones of Delhi. (C) 2014 Elsevier Ltd. All rights reserved.

The effects of capillary force in micro or nano-indentation

Models describing wet adhesion between indenters and substrates joined by liquid bridges are investigated. The influences of indenter shapes and various parameters of structures on capillary force are focused. In the former, we consider several shapes, such as conical, spherical and truncated conical indenter with a spherical end. In the latter, the effects of the contact angle, the environmental humidity, the gap between the indenter and the substrate, etc. are included. Different dependences of the capillary force on the indenter shapes and the geometric parameters are observed. Most interesting finding is that applying the present results to micro- and nano-indentation experiments shows the size effect in indentation hardness not produced but underestimated by the effects of capillary force.(4 refs)

Ab initio study of anharmonicity in high pressure Cmca-4 metallic hydrogen

Hydrogen is the only atom for which the Schr odinger equation is solvable. Consisting only of a proton and an electron, hydrogen is the lightest element and, nevertheless, is far from being simple. Under ambient conditions, it forms diatomic molecules H2 in gas phase, but di erent temperature and pressures lead to a complex phase diagram, which is not completely known yet. Solid hydrogen was rst documented in 1899 [1] and was found to be isolating. At higher pressures, however, hydrogen can be metallized. In 1935 Wigner and Huntington predicted that the metallization pressure would be 25 GPa [2], where molecules would disociate to form a monoatomic metal, as alkali metals that lie below hydrogen in the periodic table. The prediction of the metallization pressure turned out to be wrong: metallic hydrogen has not been found yet, even under a pressure as high as 320 GPa. Nevertheless, extrapolations based on optical measurements suggest that a metallic phase may be attained at 450 GPa [3]. The interest of material scientist in metallic hydrogen can be attributed, at least to a great extent, to Ashcroft, who in 1968 suggested that such a system could be a hightemperature superconductor [4]. The temperature at which this material would exhibit a transition from a superconducting to a non-superconducting state (Tc) was estimated to be around room temperature. The implications of such a statement are very interesting in the eld of astrophysics: in planets that contain a big quantity of hydrogen and whose temperature is below Tc, superconducting hydrogen may be found, specially at the center, where the gravitational pressure is high. This might be the case of Jupiter, whose proportion of hydrogen is about 90%. There are also speculations suggesting that the high magnetic eld of Jupiter is due to persistent currents related to the superconducting phase [5]. Metallization and superconductivity of hydrogen has puzzled scientists for decades, and the community is trying to answer several questions. For instance, what is the structure of hydrogen at very high pressures? Or a more general one: what is the maximum Tc a phonon-mediated superconductor can have [6]? A great experimental e ort has been carried out pursuing metallic hydrogen and trying to answer the questions above; however, the characterization of solid phases of hydrogen is a hard task. Achieving the high pressures needed to get the sought phases requires advanced technologies. Diamond anvil cells (DAC) are commonly used devices. These devices consist of two diamonds with a tip of small area; for this reason, when a force is applied, the pressure exerted is very big. This pressure is uniaxial, but it can be turned into hydrostatic pressure using transmitting media. Nowadays, this method makes it possible to reach pressures higher than 300 GPa, but even at this pressure hydrogen does not show metallic properties. A recently developed technique that is an improvement of DAC can reach pressures as high as 600 GPa [7], so it is a promising step forward in high pressure physics. Another drawback is that the electronic density of the structures is so low that X-ray di raction patterns have low resolution. For these reasons, ab initio studies are an important source of knowledge in this eld, within their limitations. When treating hydrogen, there are many subtleties in the calculations: as the atoms are so light, the ions forming the crystalline lattice have signi cant displacements even when temperatures are very low, and even at T=0 K, due to Heisenberg's uncertainty principle. Thus, the energy corresponding to this zero-point (ZP) motion is signi cant and has to be included in an accurate determination of the most stable phase. This has been done including ZP vibrational energies within the harmonic approximation for a range of pressures and at T=0 K, giving rise to a series of structures that are stable in their respective pressure ranges [8]. Very recently, a treatment of the phases of hydrogen that includes anharmonicity in ZP energies has suggested that relative stability of the phases may change with respect to the calculations within the harmonic approximation [9]. Many of the proposed structures for solid hydrogen have been investigated. Particularly, the Cmca-4 structure, which was found to be the stable one from 385-490 GPa [8], is metallic. Calculations for this structure, within the harmonic approximation for the ionic motion, predict a Tc up to 242 K at 450 GPa [10]. Nonetheless, due to the big ionic displacements, the harmonic approximation may not su ce to describe correctly the system. The aim of this work is to apply a recently developed method to treat anharmonicity, the stochastic self-consistent harmonic approximation (SSCHA) [11], to Cmca-4 metallic hydrogen. This way, we will be able to study the e ects of anharmonicity in the phonon spectrum and to try to understand the changes it may provoque in the value of Tc. The work is structured as follows. First we present the theoretical basis of the calculations: Density Functional Theory (DFT) for the electronic calculations, phonons in the harmonic approximation and the SSCHA. Then we apply these methods to Cmca-4 hydrogen and we discuss the results obtained. In the last chapter we draw some conclusions and propose possible future work.

The role of the surfaces in the photon absorption in Ge nanoclusters embedded in silica.

The usage of semiconductor nanostructures is highly promising for boosting the energy conversion efficiency in photovoltaics technology, but still some of the underlying mechanisms are not well understood at the nanoscale length. Ge quantum dots (QDs) should have a larger absorption and a more efficient quantum confinement effect than Si ones, thus they are good candidate for third-generation solar cells. In this work, Ge QDs embedded in silica matrix have been synthesized through magnetron sputtering deposition and annealing up to 800°C. The thermal evolution of the QD size (2 to 10 nm) has been followed by transmission electron microscopy and X-ray diffraction techniques, evidencing an Ostwald ripening mechanism with a concomitant amorphous-crystalline transition. The optical absorption of Ge nanoclusters has been measured by spectrophotometry analyses, evidencing an optical bandgap of 1.6 eV, unexpectedly independent of the QDs size or of the solid phase (amorphous or crystalline). A simple modeling, based on the Tauc law, shows that the photon absorption has a much larger extent in smaller Ge QDs, being related to the surface extent rather than to the volume. These data are presented and discussed also considering the outcomes for application of Ge nanostructures in photovoltaics.PACS: 81.07.Ta; 78.67.Hc; 68.65.-k.

Lean product development in practice: Insights from 4 companies

This paper aims to elucidate practitioners' understanding and implementation of Lean in Product Development (LPD). We report on a workshop held in the UK during 2012. Managers and engineers from four organizations discussed their understanding of LPD and their ideas and practice regarding management and assessment of value and waste. The study resulted in a set of insights into current practice and lean thinking from the industry perspective. Building on this, the paper introduces a balanced value and waste model that can be used by practitioners as a checklist to identify issues that need to be considered when applying LPD. The main results indicate that organizations tend to focus on waste elimination rather than value enhancement in LPD. Moreover, the lean metrics that were discussed by the workshop participants do not link the strategic level with the operational one, and poorly reflect the value and waste generated in the process. Future directions for research are explored, and include the importance of a balanced approach considering both value and waste when applying LPD, and the need to link lean metrics with value and waste levels.

Characteristics of sulfide corrosion products on 316L stainless steel surfaces in the presence of sulfate-reducing bacteria

It has been found that microbial communities play a significant role in the corrosion process of steels exposed in aquatic and soil environments. Biomineralization influenced by microorganisms is believed to be responsible for the formation of corrosion products via complicated pathways of electron transfer between microbial cells and the metal. In this study, sulfide corrosion products were investigated for 316L stainless steel exposed to media with sulfate-reducing bacteria media for 7 weeks. The species of inorganic and organic sulfides in the passive film on the stainless steel were observed by epifluorescence microscope, environmental scanning electron microscope combined with energy dispersive spectroscopy and X-ray photoelectron spectroscopy. The transformation from metal oxides to metal sulfides influenced by sulfate-reducing bacteria is emphasized in this paper. (c) 2005 Elsevier B.V. All rights reserved.

Region-wide changes in marine ecosystem dynamics: state-space models to distinguish trends from step changes

Regime shifts are sudden changes in ecosystem structure that can be detected across several ecosystem components. The concept that regime shifts are common in marine ecosystems has gained popularity in recent years. Many studies have searched for the step-like changes in ecosystem state expected under a simple interpretation of this idea. However, other kinds of change, such as pervasive trends, have often been ignored. We assembled over 300 ecological time series from seven UK marine regions, covering two to three decades. We developed state-space models for the first principal component of the time series in each region, a common measure of ecosystem state. Our models allowed both trends and step changes, possibly in combination. We found trends in three of seven regions and step changes in two of seven regions. Gradual and sudden changes are therefore important trajectories to consider in marine ecosystems.

Determination of ammonia based on the electro-oxidation of hydroquinone in dimethylformamide or in the room temperature ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide

The results detail a novel methodology for the electrochemical determination of ammonia based on its interaction with hydroquinone in DMF. It has been shown that ammonia reversibly removes protons from the hydroquinone molecules, thus facilitating the oxidative process with the emergence of a new wave at less positive potentials. The analytical utility of the proposed methodology has been examined with a linear range from 10 to 95 ppm and corresponding limit-of-detection of 4.2 ppm achievable. Finally, the response of hydroquinone in the presence of ammonia has been examined in the room temperature ionic liquid 1-ethyl-3-methylimidazolium bis(trifluormethylsulfonyl)imide, [EMIM][N(Tf)(2)]. Analogous voltammetric waveshapes to that observed in DMF were obtained, thereby confirming the viability of the method in either DMF or [EMIM][N(Tf)(2)] as solvent. (C) 2003 Elsevier B.V. All rights reserved.