Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF

© 2016 BMJ Publishing Group Ltd & British Thoracic Society.Rationale Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal of all fibrotic conditions with no curative therapies. Common pathomechanisms between IPF and cancer are increasingly recognised, including dysfunctional pan-PI3 kinase (PI3K) signalling as a driver of aberrant proliferative responses. GSK2126458 is a novel, potent, PI3K/mammalian target of rapamycin (mTOR) inhibitor which has recently completed phase I trials in the oncology setting. Our aim was to establish a scientific and dosing framework for PI3K inhibition with this agent in IPF at a clinically developable dose. Methods We explored evidence for pathway signalling in IPF lung tissue and examined the potency of GSK2126458 in fibroblast functional assays and precision-cut IPF lung tissue. We further explored the potential of IPF patient-derived bronchoalveolar lavage (BAL) cells to serve as pharmacodynamic biosensors to monitor GSK2126458 target engagement within the lung. Results We provide evidence for PI3K pathway activation in fibrotic foci, the cardinal lesions in IPF. GSK2126458 inhibited PI3K signalling and functional responses in IPF-derived lung fibroblasts, inhibiting Akt phosphorylation in IPF lung tissue and BAL derived cells with comparable potency. Integration of these data with GSK2126458 pharmacokinetic data from clinical trials in cancer enabled modelling of an optimal dosing regimen for patients with IPF. Conclusions Our data define PI3K as a promising therapeutic target in IPF and provide a scientific and dosing framework for progressing GSK2126458 to clinical testing in this disease setting. A proof-ofmechanism trial of this agent is currently underway. Trial registration number NCT01725139, pre-clinical

Responsiveness differences in outcome instruments after revision hip arthroplasty: What are the implications?

Responsiveness to change is an important psychometric property of an outcome instrument. Assessment of health-related quality of life (HRQoL) is critical to outcome assessment after total joint replacement, a surgery aimed at improving pain, function and HRQoL of the patients undergoing these procedures. In a recent study, Shi et al. examined the responsiveness to change of various subscales of two instruments, physician-administered Harris Hip Score and patient self-administered Short Form-36 (SF-36), 6 months after revision total hip arthroplasty. The responsiveness statistics for both scales were reasonable, higher for Harris Hip Score than SF-36. This is the first study to examine responsiveness of these instruments in revision THA patients in a systematic fashion

Changes in microphytobenthos fluorescence over a tidal cycle: implications for sampling designs

Intertidal microphytobenthos (MPB) are important primary producers and provide food for herbivores in soft sediments and on rocky shores. Methods of measuring MPB biomass that do not depend on the time of collection relative to the time of day or tidal conditions are important in any studies that need to compare temporal or spatial variation, effects of abiotic factors or activity of grazers. Pulse amplitude modulated (PAM) fluorometry is often used to estimate biomass of MPB because it is a rapid, non-destructive method, but it is not known how measures of fluorescence are altered by changing conditions during a period of low tide. We investigated this experimentally using in situ changes in minimal fluorescence (F) on a rocky shore and on an estuarine mudflat around Sydney (Australia), during low tides. On rocky shores, the time when samples are taken during low tide had little direct influence on measures of fluorescence as long as the substratum is dry. Wetness from wave-splash, seepage from rock pools, run-off, rainfall, etc., had large consequences for any comparisons. On soft sediments, fluorescence was decreased if the sediment dried out, as happens during low-spring tides on particularly hot and dry days. Surface water affected the response of PAM and therefore measurements used to estimate MPB, emphasising the need for care to ensure that representative sampling is done during low tide

The Eyes Have It: Sex and Sexual Orientation Differences in Pupil Dilation Patterns

Recent research suggests profound sex and sexual orientation differences in sexual response. These results, however, are based on measures of genital arousal, which have potential limitations such as volunteer bias and differential measures for the sexes. The present study introduces a measure less affected by these limitations. We assessed the pupil dilation of 325 men and women of various sexual orientations to male and female erotic stimuli. Results supported hypotheses. In general, self-reported sexual orientation corresponded with pupil dilation to men and women. Among men, substantial dilation to both sexes was most common in bisexual-identified men. In contrast, among women, substantial dilation to both sexes was most common in heterosexual-identified women. Possible reasons for these differences are discussed. Because the measure of pupil dilation is less invasive than previous measures of sexual response, it allows for studying diverse age and cultural populations, usually not included in sexuality research

Ex vivo micro-computed tomography analysis of bleomycin-induced lung fibrosis for preclinical drug evaluation.

Research into the pathogenesis underlying the development of idiopathic pulmonary fibrosis is hampered by a repertoire of animal models that fail to recapitulate all the features of the human disease. Better use and understanding of what the animal models represent may improve clinical predictability. We interrogated ex vivo micro-computed tomography (CT) as a novel end-point measure in the mouse model of bleomycin-induced lung fibrosis (BILF), and to evaluate a therapeutic dosing regimen for preclinical drug evaluation. A detailed characterisation of BILF was performed using standard end-point measures (lung hydroxyproline and histology). High resolution micro-CT (∼13.7 μm voxel size) was evaluated for quantifying the extent and severity of lung fibrosis. The period from 14 to 28 days following bleomycin instillation represents progression of established fibrosis. A therapeutic dosing regimen during this period was validated using a transforming growth factor-β receptor-1 kinase inhibitor, and micro-CT provided a highly sensitive and quantitative measure of fibrosis. Moreover, fibrotic lesions did not completely resolve, but instead persisted for ≥6 months following a single insult with bleomycin. Ex vivo micro-CT analysis of BILF allows robust evaluation of therapeutic dosing once fibrosis is already well established, requiring fewer mice than conventional biochemical end-points

Advancing the defensive explanation for anxiety disorders: lorazepam effects on human defense are systematically modulated by personality and threat-type

Clinically effective drugs against human anxiety and fear systematically alter the innate defensive behavior of rodents, suggesting that in humans these emotions reflect defensive adaptations. Compelling experimental human evidence for this theory is yet to be obtained. We report the clearest test to date by investigating the effects of 1 and 2mg of the anti-anxiety drug lorazepam on the intensity of threat-avoidance behavior in 40 healthy adult volunteers (20 females). We found lorazepam modulated the intensity of participants’ threat-avoidance behavior in a dose-dependent manner. However, the pattern of effects depended upon two factors: type of threat-avoidance behavior and theoretically relevant measures of personality. In the case of flight behavior (one-way active avoidance), lorazepam increased intensity in low scorers on the Fear Survey Schedule tissuedamage fear but reduced it in high scorers. Conversely, in the case of risk-assessment behavior (two-way active avoidance), lorazepam reduced intensity in low scorers on the Spielberger trait anxiety but increased it in high scorers. Anti-anxiety drugs do not systematically affect rodent flight behavior; therefore, we interpret this new finding as suggesting that lorazepam has a broader effect on defense in humans than in rodents, perhaps by modulating general perceptions of threat intensity. The different patterning of lorazepam effects on the two behaviors implies that human perceptions of threat intensity are nevertheless distributed across two different neural streams, which influence effects observed on one-way or two-way active avoidance demanded by the situation

CMMSE2017: On two classes of fourth- and seventh-order vectorial methods with stable behavior

[EN] A family of fourth-order iterative methods without memory, for solving nonlinear systems, and its seventh-order extension, are analyzed. By using complex dynamics tools, their stability and reliability are studied by means of the properties of the rational function obtained when they are applied on quadratic polynomials. The stability of their fixed points, in terms of the value of the parameter, its critical points and their associated parameter planes, etc. give us important information about which members of the family have good properties of stability and whether in any of them appear chaos in the iterative process. The conclusions obtained in this dynamical analysis are used in the numerical section, where an academical problem and also the chemical problem of predicting the diffusion and reaction in a porous catalyst pellet are solved.This research was partially supported by Ministerio de Economia y Competitividad MTM2014-52016-C02-2-P and Generalitat Valenciana PROMETEO/2016/089.Cordero Barbero, A.; Guasp, L.; Torregrosa Sánchez, JR. (2018). CMMSE2017: On two classes of fourth- and seventh-order vectorial methods with stable behavior. Journal of Mathematical Chemistry. 56(7):1902-1923. https://doi.org/10.1007/s10910-017-0814-0S19021923567S. Amat, S. Busquier, Advances in Iterative Methods for Nonlinear Equations (Springer, Berlin, 2016)S. Amat, S. Busquier, S. Plaza, Review of some iterative root-finding methods from a dynamical point of view. Sci. Ser. A Math. Sci. 10, 3–35 (2004)S. Amat, S. Busquier, S. Plaza, A construction of attracting periodic orbits for some classical third-order iterative methods. Comput. Appl. Math. 189, 22–33 (2006)I.K. Argyros, Á.A. Magreñn, On the convergence of an optimal fourth-order family of methods and its dynamics. Appl. Math. Comput. 252, 336–346 (2015)D.K.R. Babajee, A. Cordero, J.R. Torregrosa, Study of multipoint iterative methods through the Cayley quadratic test. Comput. Appl. Math. 291, 358–369 (2016). doi: 10.1016/J.CAM.2014.09.020P. Blanchard, The dynamics of Newton’s method. Proc. Symp. Appl. Math. 49, 139–154 (1994)F.I. Chicharro, A. Cordero, J.R. Torregrosa, Drawing dynamical and parameters planes of iterative families and methods. Sci. World J. 2013, Article ID 780153 (2013)C. Chun, M.Y. Lee, B. Neta, J. Džunić, On optimal fourth-order iterative methods free from second derivative and their dynamics. Appl. Math. Comput. 218, 6427–6438 (2012)A. Cordero, E. Gómez, J.R. Torregrosa, Efficient high-order iterative methods for solving nonlinear systems and their application on heat conduction problems. Complexity 2017, Article ID 6457532 (2017)A. Cordero, J.R. Torregrosa, Variants of Newton’s method using fifth-order quadrature formulas. Appl. Math. Comput. 190, 686–698 (2007)R.L. Devaney, An Introduction to Chaotic Dynamical Systems (Addison-Wesley Publishing Company, Reading, 1989)P.G. Logrado, J.D.M. Vianna, Partitioning technique procedure revisited: formalism and first application to atomic problems. Math. Chem. 22, 107–116 (1997)C.G. Jesudason, I. Numerical nonlinear analysis: differential methods and optimization applied to chemical reaction rate determination. Math. Chem. 49, 1384–1415 (2011)Á.A. Magreñán, Different anomalies in a Jarratt family of iterative root-finding methods. Appl. Math. Comput. 233, 29–38 (2014)M. Mahalakshmi, G. Hariharan, K. Kannan, The wavelet methods to linear and nonlinear reaction-diffusion model arising in mathematical chemistry. Math. Chem. 51(9), 2361–2385 (2013)K. Maleknejad, M. Alizadeh, An efficient numerical scheme for solving Hammerstein integral equation arisen in chemical phenomenon. Proc. Comput. Sci. 3, 361–364 (2011)B. Neta, C. Chun, M. Scott, Basins of attraction for optimal eighth-order methods to find simple roots of nonlinear equations. Appl. Math. Comput. 227, 567–592 (2014)M.S. Petković, B. Neta, L.D. Petković, J. Džunić, Multipoint Methods for Solving Nonlinear Equations (Elsevier, Amsterdam, 2013)R.C. Rach, J.S. Duan, A.M. Wazwaz, Solving coupled Lane–Emden boundary value problems in catalytic diffusion reactions by the Adomian decomposition method. Math. Chem. 52(1), 255–267 (2014)R. Singh, G. Nelakanti, J. Kumar, A new effcient technique for solving two-point boundary value problems for integro-differential equations. Math. Chem. 52, 2030–2051 (2014

Presence of Mycoplasma fermentans in the bloodstream of Mexican patients with rheumatoid arthritis and IgM and IgG antibodies against whole microorganism

<p>Abstract</p> <p>Background</p> <p>Increasing evidence incriminates bacteria, especially <it>Mycoplasma fermentans</it>, as possible arthritogenic agents in humans. The purpose of this study was to investigate <it>M. fermentans </it>in the bloodstream of patients with rheumatoid arthritis.</p> <p>Methods</p> <p>Two hundred and nineteen blood samples from patients with rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, and healthy individuals were screened by bacterial culture and direct PCR in order to detect mycoplasmas; IgM and IgG against <it>M. fermentans </it>PG18 were also detected by ELISA and Immunoblotting assays in patients with rheumatoid arthritis and healthy individuals.</p> <p>Results</p> <p>Blood samples from patients with antiphospholipid syndrome and healthy individuals were negative for mycoplasma by culture or direct PCR. In blood samples from patients with systemic lupus erythematosus were detected by direct PCR <it>M. fermentans </it>in 2/50 (2%), <it>M. hominis </it>in 2/50 (2%) and <it>U. urealyticum </it>in 1/50 (0.5%). In patients with RA <it>M. fermentans </it>was detected by culture in 13/87 blood samples and in 13/87 by direct PCR, however, there was only concordance between culture and direct PCR in six samples, so <it>M. fermentans </it>was detected in 20/87(23%) of the blood samples from patients with RA by either culture or PCR. Antibody-specific ELISA assay to <it>M. fermentans </it>PG18 was done, IgM was detected in sera from 40/87 patients with RA and in sera of 7/67 control individuals, IgG was detected in sera from 48/87 RA patients and in sera from 7/67 healthy individuals. Antibody-specific immunoblotting to <it>M. fermentans </it>PG18 showed IgM in sera from 35/87 patients with RA and in sera from 4/67 healthy individuals, IgG was detected in sera from 34/87 patients and in sera from 5/67 healthy individuals.</p> <p>Conclusion</p> <p>Our findings show that only <it>M. fermentans </it>produce bacteremia in a high percentage of patients with RA. This finding is similar to those reported in the literature. IgM and IgG against <it>M. fermentans </it>PG18 were more frequent in patients with RA than healthy individuals.</p

Genoviz Software Development Kit: Java tool kit for building genomics visualization applications

<p>Abstract</p> <p>Background</p> <p>Visualization software can expose previously undiscovered patterns in genomic data and advance biological science.</p> <p>Results</p> <p>The Genoviz Software Development Kit (SDK) is an open source, Java-based framework designed for rapid assembly of visualization software applications for genomics. The Genoviz SDK framework provides a mechanism for incorporating adaptive, dynamic zooming into applications, a desirable feature of genome viewers. Visualization capabilities of the Genoviz SDK include automated layout of features along genetic or genomic axes; support for user interactions with graphical elements (Glyphs) in a map; a variety of Glyph sub-classes that promote experimentation with new ways of representing data in graphical formats; and support for adaptive, semantic zooming, whereby objects change their appearance depending on zoom level and zooming rate adapts to the current scale. Freely available demonstration and production quality applications, including the Integrated Genome Browser, illustrate Genoviz SDK capabilities.</p> <p>Conclusion</p> <p>Separation between graphics components and genomic data models makes it easy for developers to add visualization capability to pre-existing applications or build new applications using third-party data models. Source code, documentation, sample applications, and tutorials are available at <url>http://genoviz.sourceforge.net/</url>.</p

The Mechanisms of Codon Reassignments in Mitochondrial Genetic Codes

Many cases of non-standard genetic codes are known in mitochondrial genomes. We carry out analysis of phylogeny and codon usage of organisms for which the complete mitochondrial genome is available, and we determine the most likely mechanism for codon reassignment in each case. Reassignment events can be classified according to the gain-loss framework. The gain represents the appearance of a new tRNA for the reassigned codon or the change of an existing tRNA such that it gains the ability to pair with the codon. The loss represents the deletion of a tRNA or the change in a tRNA so that it no longer translates the codon. One possible mechanism is Codon Disappearance, where the codon disappears from the genome prior to the gain and loss events. In the alternative mechanisms the codon does not disappear. In the Unassigned Codon mechanism, the loss occurs first, whereas in the Ambiguous Intermediate mechanism, the gain occurs first. Codon usage analysis gives clear evidence of cases where the codon disappeared at the point of the reassignment and also cases where it did not disappear. Codon disappearance is the probable explanation for stop to sense reassignments and a small number of reassignments of sense codons. However, the majority of sense to sense reassignments cannot be explained by codon disappearance. In the latter cases, by analysis of the presence or absence of tRNAs in the genome and of the changes in tRNA sequences, it is sometimes possible to distinguish between the Unassigned Codon and Ambiguous Intermediate mechanisms. We emphasize that not all reassignments follow the same scenario and that it is necessary to consider the details of each case carefully.Comment: 53 pages (45 pages, including 4 figures + 8 pages of supplementary information). To appear in J.Mol.Evo