Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): Pooled subset analyses from two randomized trials

Background: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. Methods: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. Results: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0–18.2] with dacomitinib and 9.6 months (95% CI 7.4–12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458–1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6–41.5) with dacomitinib versus 23.2 months (95% CI 16.0–31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431–1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. Conclusions: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). Clinical trials number: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067).

Growth and Convergence: The case of China

Growth and Convergence: The Case of China Since the initiation of economic reforms in 1978, China has become one of the world’s fast-growing economies. The rapid growth, however, has not been shared equally across the different regions in China. The prominent feature of substantial differences in incomes and growth rates across the different Chinese regions has attracted the attention of many researchers. This book focuses on issues related to economic growth and convergence across the Chinese regions over the past three decades. The book has eight chapters. Apart from an introduction chapter and a concluding chapter, all the other chapters each deal with some certain aspects of the central issue of regional growth and convergence across China over the past three decades. The whole book is organized as follows. Chapter 1 provides an introduction to the basic issues involved in this book. Chapter 2 tests economic growth and convergence across 31 Chinese provinces during 1981-2005, based on the theoretical framework of the Solow growth model. Chapter 3 investigates the relationship between openness to foreign economic activities, such as foreign trade and foreign direct investment, and the regional economic growth in the case of China during 1981-2005. Chapter 4, based on data of 31 Chinese provinces over the period 1980-2004, presents new evidence on the effects of structural shocks and structural transformation on growth and convergence among the Chinese regions. Chapter 5, by building up an empirical model that takes account of different potential effects of foreign direct investment, focuses on the impacts of foreign direct investment on China’s regional economic performance and growth. Chapter 6 reconsiders the growth and convergence problem of the Chinese regions in an alternative theoretical framework with endogenous saving behavior and capital mobility across regions. Chapter 7, by building up a theoretical model concerning comparative advantage and transaction efficiency, focuses on one of the potential mechanisms through which China achieves its fast economic growth over the past few decades. Chapter 8 concludes the book by summarizing the results from the previous chapters and suggesting directions for further studies.

Growth of and trehalase activity in the thermophilic fungusThermomyces lanuginosus

The thermophilic fungus,Thermomyces lanuginosus, was grown in a glucose-asparagine liquid medium. Optimal mycelial growth occurred at 50°C. The conditions for sporulation were different from those required for vegetative growth. the former being favoured by lower nitrogen level and temperature. Trehalase (α, α-glu coside-l-glucohydrolase, EC 3.2.1.28) was one of the most active glycosidases at 50°C. Non-sporulating mycelium had higher levels of this enzyme than the sporulating mycelium. Trehalase was synthesized constitutively and its activity appears to be controlled by catabolite repression.

The link between foreign aid, public investment and economic growth

Länsimaat ovat rahoittaneet kehitysyhteistyöhankkeita jo lähes kuuden vuosikymmenen ajan, mutta kehitysavun tehokkuudesta ei olla edelleenkään päästy yksimielisyyteen. Yksi avunantajamaiden tapa vaikuttaa kehitysavun tehokkuuteen, eli avun vaikutukseen vastaanottajamaan taloudellisen kasvun kiihdyttäjänä, on sitoa ne julkisen sektorin infrastruktuurihankkeisiin. Joissain tapauksissa tämä vaikuttaa avun vastaanottajan käytökseen ja asenteisiin kehitysapua kohtaan. Tutkielmassa käsitellään kehitysavun tehokkuutta tilanteessa, jossa se on sidottu julkisen sektorin investointeihin kehitysmaassa. Tutkimus pohjaa Kalaitzidakisin ja Kalyvitisin (2008) malliin, jossa osa kehitysmaan julkisen talouden investoinneista rahoitetaan kehitysavulla. Seuraavaksi tarkastellaan ylijäämää tavoittelevan käyttäytymisen (rent- seeking) vaikutusta kehitysavun tehokkuuteen pohjaten Economidesin, Kalyvitisin ja Philippopoulosin (2008) malliin. Tutkielmassa referoidaan lisäksi tutkimuskysymystä sivuavia empiirisiä tutkimuksia, esitellään aluksi tavallisimmat kehitysyhteistyön muodot, sekä esitellään talousteoreettisia näkökulmia kehitysyhteistyön tehokkuuden määrittelylle. Tutkielma perustuu puhtaasti teoreettisiin malleihin ja niissä sovelletut menetelmät ovat matemaattisia. Tutkielmassa käsitellään ensin tapaus, jossa kehitysyhteistyöllä rahoitetaan julkisen sektorin investointihankkeita. Jossain tapauksissa kehitysavun kasvu lasku siirtää vastaanottajamaan kulutusta julkisista investoinneista kulutukseen, jolloin kehitysyhteistyövaroin osittain rahoitettujen hankkeiden koko pienenee, ja suhteellinen tehokkuus laskee. Seuraavaksi tarkastellaan tilannetta, jossa kehitysyhteistyövaroista vain osa päätyy hankkeen rahoittamiseen, ja todetaan, että kehitysavun tehokkuus ja vaikutus maan kansantulon kasvuun vähenee talouden toimijoiden ylijäämää tavoittelevan käyttäytymisen (mukaan lukien korruptio) myötä entisestään. Tämän tutkimuksen perusteella voidaan todeta, että kehitysapu vaikuttaa kehittyvän maan talouden kasvuun tapauksessa, jossa julkisia infrastruktuurihankkeita rahoitetaan osittain maan omin verovaroin ja osittain kehitysyhteistyövaroin. Ylijäämää tavoitteleva käyttäytyminen vaikuttaa kehitysavun tehokkuuteen negatiivistesti vähentäen kehitysavun positiivisia kasvuvaikutuksia.

Study on the Growth of Nb3Sn Superconductor in Cu(Sn)/Nb Diffusion Couple

Nb3Sn growth following the bronze technique, (i.e. by interdiffusion between Cu(Sn) alloy (bronze) and Nb) is one of the important methodologies to produce this superconductor. In this study, we have addressed the confusion over the growth rate of the Nb3Sn phase. Furthermore, a possible explanation for the corrugated layer in the multifilamentary structure is discussed. Kirkendall marker experiments were conducted to study the relative mobilities of the species, which also explained the reason for finding pores in the product phase layer. Based on the parabolic growth constant at different temperatures, the activation energy for the growth is determined. We have further explained the dramatic increase in the growth rate of the prod

On formation, growth and concentrations of air ions

Aerosol particles have effect on climate, visibility, air quality and human health. However, the strength of which aerosol particles affect our everyday life is not well described or entirely understood. Therefore, investigations of different processes and phenomena including e.g. primary particle sources, initial steps of secondary particle formation and growth, significance of charged particles in particle formation, as well as redistribution mechanisms in the atmosphere are required. In this work sources, sinks and concentrations of air ions (charged molecules, cluster and particles) were investigated directly by measuring air molecule ionising components (i.e. radon activity concentrations and external radiation dose rates) and charged particle size distributions, as well as based on literature review. The obtained results gave comprehensive and valuable picture of the spatial and temporal variation of the air ion sources, sinks and concentrations to use as input parameters in local and global scale climate models. Newly developed air ion spectrometers (Airel Ltd.) offered a possibility to investigate atmospheric (charged) particle formation and growth at sub-3 nm sizes. Therefore, new visual classification schemes for charged particle formation events were developed, and a newly developed particle growth rate method was tested with over one year dataset. These data analysis methods have been widely utilised by other researchers since introducing them. This thesis resulted interesting characteristics of atmospheric particle formation and growth: e.g. particle growth may sometimes be suppressed before detection limit (~ 3 nm) of traditional aerosol instruments, particle formation may take place during daytime as well as in the evening, growth rates of sub-3 nm particles were quite constant throughout the year while growth rates of larger particles (3-20 nm in diameter) were higher during summer compared to winter. These observations were thought to be a consequence of availability of condensing vapours. The observations of this thesis offered new understanding of the particle formation in the atmosphere. However, the role of ions in particle formation, which is not well understood with current knowledge, requires further research in future.

Functional Identification of Regulatory Elements within the Promoter Region of Platelet-Derived Growth Factor 2

Human platelet-derived growth factor (PDGF) is composed of two polypeptide chains, PDGF-1 and PDGF-2,the human homolog of the v-sis oncogene. Deregulation of PDGF-2 expression can confer a growth advantage to cells possessing the cognate receptor and, thus, may contribute to the malignant phenotype. We investigated the regulation of PDGF-2 mRNA expression during megakaryocytic differentiation of K562 cells. Induction by 12-O-tetradecanoylphorbol-13-acetate (TPA) led to a greater than 200-fold increase in PDGF-2 transcript levels in these cells. Induction was dependent on protein synthesis and was not enhanced by cycloheximide exposure.In our initial investigation of the PDGF-2 promoter, a minimal promoter region, which included sequences extending only 42 base pairs upstream of the TATA signal, was found to be as efficient as 4 kilobase pairs upstream of the TATA signal in driving expression of a reporter gene in uninduced K562 cells. We also functionally identified different regulatory sequence elements of the PDGF-2 promoter in TPA-induced K562 cells. One region acted as a transcriptional silencer, while another region was necessary for maximal activity of the promoter in megakaryoblasts. This region was shown to bind nuclear factors and was the target for trans-activation in normal and tumor cells. In one tumor cell line, which expressed high PDGF-2 mRNA levels, the presence of the positive regulatory region resulted in a 30-fold increase in promoter activity. However, the ability of the minimal PDGF-2 promoter to drive reporter gene expression in uninduced K562 cells and normal fibroblasts, which contained no detectable PDGF-2 transcripts, implies the existence of other negative control mechanisms beyond the regulation of promoter activity.

Stand growth and management scenarios for Paraserianthes falcataria smallholder plantations in Indonesia

Paraserianthes falcataria is a very fast growing, light wood tree species, that has recently gained wide interest in Indonesia for industrial wood processing. At the moment the P. falcataria plantations managed by smallholders are lacking predefined management programmes for commercial wood production. The general objective of this study was to model the growth and yield of Paraserianthes falcataria stands managed by smallholders in Ciamis, West Java, Indonesia and to develop management scenarios for different production objectives. In total 106 circular sample plots with over 2300 P. falcataria trees were assessed on smallholder plantation inventory. In addition, information on market prices of P. falcataria wood was collected through rapid appraisals among industries. A tree growth model based on Chapman-Richards function was developed on three different site qualities and the stand management scenarios were developed under three management objectives: (1) low initial stand density with low intensity stand management, (2) high initial stand density with medium intensity of intervention, (3) high initial stand density and strong intensity of silvicultural interventions, repeated more than once. In general, the 9 recommended scenarios have rotation ages varying from 4 to 12 years, planting densities from 4x4 meters (625 trees ha-1) to 3x2 meters (1666 trees ha-1) and thinnings at intensities of removing 30 to 60 % of the standing trees. The highest annual income would be generated on high-quality with a scenario with initial planting density 3x2 m (1666 trees ha-1) one thinning at intensity of removing 55 % of the standing trees at the age of 2 years and clear cut at the age of 4 years.

Cationic Amino Acid Transporters and Salmonella Typhimurium ArgT Collectively Regulate Arginine Availability towards Intracellular Salmonella Growth

Cationic amino acid transporters (mCAT1 and mCAT2B) regulate the arginine availability in macrophages. How in the infected cell a pathogen can alter the arginine metabolism of the host remains to be understood. We reveal here a novel mechanism by which Salmonella exploit mCAT1 and mCAT2B to acquire host arginine towards its own intracellular growth within antigen presenting cells. We demonstrate that Salmonella infected bone marrow derived macrophages and dendritic cells show enhanced arginine uptake and increased expression of mCAT1 and mCAT2B. We show that the mCAT1 transporter is in close proximity to Salmonella containing vacuole (SCV) specifically by live intracellular Salmonella in order to access the macrophage cytosolic arginine pool. Further, Lysosome associated membrane protein 1, a marker of SCV, also was found to colocalize with mCAT1 in the Salmonella infected cell. The intra vacuolar Salmonella then acquire the host arginine via its own arginine transporter, ArgT for growth. The argT knockout strain was unable to acquire host arginine and was attenuated in growth in both macrophages and in mice model of infection. Together, these data reveal survival strategies by which virulent Salmonella adapt to the harsh conditions prevailing in the infected host cells.

Dynamic growth of tensile cracks by ductile and brittle fracture mechanisms in a viscoplastic material

In this paper, a finite element analysis of steady-state dynamic crack growth under Mode I, plane strain, small-scale yielding conditions is performed in a rate dependent plastic material characterized by the over-stress model. The main objective of the paper is to obtain theoretically the dependence of dynamic fracture toughness on crack speed. Crack propagation due to a ductile (micro-void) mechanism or a brittle (cleavage) mechanism, as well as transition from one mode to another are considered. The conversion from ductile to brittle has been observed experimentally but has received very little attention using analytical methods. Local fracture criteria based on strains and stresses are used to describe ductile and brittle fracture mechanisms. The results obtained in this paper are in general agreement with micro-structural observations of mode conversion during fracture initiation. Finally, the particular roles played by material rate sensitivity and inertia are examined in some detail.

The impact of ultra thin silicon nitride buffer layer on GaN growth on Si (1 1 1) by RF-MBE

Ultra thin films of pure silicon nitride were grown on a Si (1 1 1) surface by exposing the surface to radio-frequency (RF) nitrogen plasma with a high content of nitrogen atoms. The effect of annealing of silicon nitride surface was investigated with core-level photoelectron spectroscopy. The Si 2p photoelectron spectra reveals a characteristic series of components for the Si species, not only in stoichiometric Si3N4 (Si4+) but also in the intermediate nitridation states with one (Si1+) or three (Si3+) nitrogen nearest neighbors. The Si 2p core-level shifts for the Si1+, Si3+, and Si4+ components are determined to be 0.64, 2.20, and 3.05 eV, respectively. In annealed sample it has been observed that the Si4+ component in the Si 2p spectra is significantly improved, which clearly indicates the crystalline nature of silicon nitride. The high resolution X-ray diffraction (HRXRD), scanning electron microscopy (SEM) and photoluminescence (PL) studies showed a significant improvement of the crystalline qualities and enhancement of the optical properties of GaN grown on the stoichiometric Si3N4 by molecular beam epitaxy (MBE). (C) 2010 Elsevier B.V. All rights reserved.

Electrochemical phase formation involving multicomponents: hemispherical overlap models for varied nucleation and growth conditions

The phenomenological theory of hemispherical growth in the context of phase formation with more than one component is presented. The model discusses in a unified manner both instantaneous and progressive nucleation (at the substrate) as well as arbitrary growth rates (e.g. constant and diffusion controlled growth rates). A generalized version of Avrami ansatz (a mean field description) is used to tackle the ''overlap'' aspects arising from the growing multicentres of the many components involved, observing that the nucleation is confined to the substrate plane only. The time evolution of the total extent of macrogrowth as well as those of the individual components are discussed explicitly for the case of two phases. The asymptotic expressions for macrogrowth are derived. Such analysis depicts a saturation limit (i.e. the maximum extent of growth possible) for the slower growing component and its dependence on the kinetic parameters which, in the electrochemical context, can be controlled through potential. The significance of this model in the context of multicomponent alloy deposition and possible future directions for further development are pointed out.

Perturbative growth of cosmological clustering .2. The two-point correlation

We use the BBGKY hierarchy equations to calculate, perturbatively, the lowest order nonlinear correction to the two-point correlation and the pair velocity for Gaussian initial conditions in a critical density matter-dominated cosmological model. We compare our results with the results obtained using the hydrodynamic equations that neglect pressure and find that the two match, indicating that there are no effects of multistreaming at this order of perturbation. We analytically study the effect of small scales on the large scales by calculating the nonlinear correction for a Dirac delta function initial two-point correlation. We find that the induced two-point correlation has a x(-6) behavior at large separations. We have considered a class of initial conditions where the initial power spectrum at small k has the form k(n) with 0 < n less than or equal to 3 and have numerically calculated the nonlinear correction to the two-point correlation, its average over a sphere and the pair velocity over a large dynamical range. We find that at small separations the effect of the nonlinear term is to enhance the clustering, whereas at intermediate scales it can act to either increase or decrease the clustering. At large scales we find a simple formula that gives a very good fit for the nonlinear correction in terms of the initial function. This formula explicitly exhibits the influence of small scales on large scales and because of this coupling the perturbative treatment breaks down at large scales much before one would expect it to if the nonlinearity were local in real space. We physically interpret this formula in terms of a simple diffusion process. We have also investigated the case n = 0, and we find that it differs from the other cases in certain respects. We investigate a recently proposed scaling property of gravitational clustering, and we find that the lowest order nonlinear terms cause deviations from the scaling relations that are strictly valid in the linear regime. The approximate validity of these relations in the nonlinear regime in l(T)-body simulations cannot be understood at this order of evolution.

Role of elasto-plastic analysis under cyclic loading in fatigue crack growth studies

Linear Elastic Fracture Mechanics (LEFM) has been widely used in the past for fatigue crack growth studies, but this is acceptable only in situations which are within small scale yielding (SSY). In many practical structural components, conditions of SSY could be violated and one has to look for fracture criteria based on elasto-plastic analysis. Crack closure phenomenon, one of the most striking discoveries based on inelastic deformations during crack growth, has significant effect on fatigue crack growth rate. Numerical simulation of this phenomenon is computationally intensive and involved but has been successfully implemented. Stress intensity factors and strain energy release rates lose their meaning, J-integral (or its incremental) values are applicable only in specific situations, whereas alternate path independent integrals have been proposed in the literature for use with elasto-plastic fracture mechanics (EPFM) based criteria. This paper presents certain salient features of two independent finite element (numerical) studies of relevance to fatigue crack growth, where elasto-plastic analysis becomes significant. These problems can only be handled in the current day computational environment, and would have been only a dream just a few years ago.

Instability, intermittency, and multiscaling in discrete growth models of kinetic roughening

We show by numerical simulations that discretized versions of commonly studied continuum nonlinear growth equations (such as the Kardar-Parisi-Zhangequation and the Lai-Das Sarma-Villain equation) and related atomistic models of epitaxial growth have a generic instability in which isolated pillars (or grooves) on an otherwise flat interface grow in time when their height (or depth) exceeds a critical value. Depending on the details of the model, the instability found in the discretized version may or may not be present in the truly continuum growth equation, indicating that the behavior of discretized nonlinear growth equations may be very different from that of their continuum counterparts. This instability can be controlled either by the introduction of higher-order nonlinear terms with appropriate coefficients or by restricting the growth of pillars (or grooves) by other means. A number of such ''controlled instability'' models are studied by simulation. For appropriate choice of the parameters used for controlling the instability, these models exhibit intermittent behavior, characterized by multiexponent scaling of height fluctuations, over the time interval during which the instability is active. The behavior found in this regime is very similar to the ''turbulent'' behavior observed in recent simulations of several one- and two-dimensional atomistic models of epitaxial growth.