Perivascular tumor-associated macrophages and their role in cancer progression

Perivascular (Pv) tumor-associated macrophages (TAMs) are a highly specialized stromal subset within the tumor microenvironment (TME) that are defined by their spatial proximity, within one cell thickness, to blood vasculature. PvTAMs have been demonstrated to support a variety of pro-tumoral functions including angiogenesis, metastasis, and modulating the immune and stromal landscape. Furthermore, PvTAMs can also limit the response of anti-cancer and anti-angiogenic therapies and support tumor recurrence post-treatment. However, their role may not exclusively be pro-tumoral as PvTAMs can also have immune-stimulatory capabilities. PvTAMs are derived from a monocyte progenitor that develop and localize to the Pv niche as part of a multistep process which relies on a series of signals from tumor, endothelial and Pv mesenchymal cell populations. These cellular communications and signals create a highly specialized TAM subset that can also form CCR5-dependent multicellular ‘nest’ structures in the Pv niche. This review considers our current understanding of the role of PvTAMs, their markers for identification, development, and function in cancer. The role of PvTAMs in supporting disease progression and modulating the outcome from anti-cancer therapies highlight these cells as a therapeutic target. However, their resistance to pan-TAM targeting therapies, such as those targeting the colony stimulating factor-1 (CSF1)-CSF1 receptor axis, prompts the need for more targeted therapeutic approaches to be considered for this subset. This review highlights potential therapeutic strategies to target and modulate PvTAM development and function in the TME

Impaired health-related quality of life in children and adolescents with chronic conditions: a comparative analysis of 10 disease clusters and 33 disease categories/severities utilizing the PedsQL™ 4.0 Generic Core Scales

<p>Abstract</p> <p>Background</p> <p>Advances in biomedical science and technology have resulted in dramatic improvements in the healthcare of pediatric chronic conditions. With enhanced survival, health-related quality of life (HRQOL) issues have become more salient. The objectives of this study were to compare generic HRQOL across ten chronic disease clusters and 33 disease categories/severities from the perspectives of patients and parents. Comparisons were also benchmarked with healthy children data.</p> <p>Methods</p> <p>The analyses were based on over 2,500 pediatric patients from 10 physician-diagnosed disease clusters and 33 disease categories/severities and over 9,500 healthy children utilizing the PedsQL™ 4.0 Generic Core Scales. Patients were recruited from general pediatric clinics, subspecialty clinics, and hospitals.</p> <p>Results</p> <p>Pediatric patients with diabetes, gastrointestinal conditions, cardiac conditions, asthma, obesity, end stage renal disease, psychiatric disorders, cancer, rheumatologic conditions, and cerebral palsy self-reported progressively more impaired overall HRQOL than healthy children, respectively, with medium to large effect sizes. Patients with cerebral palsy self-reported the most impaired HRQOL, while patients with diabetes self-reported the best HRQOL. Parent proxy-reports generally paralleled patient self-report, with several notable differences.</p> <p>Conclusion</p> <p>The results demonstrate differential effects of pediatric chronic conditions on patient HRQOL across diseases clusters, categories, and severities utilizing the PedsQL™ 4.0 Generic Core Scales from the perspectives of pediatric patients and parents. The data contained within this study represents a larger and more diverse population of pediatric patients with chronic conditions than previously reported in the extant literature. The findings contribute important information on the differential effects of pediatric chronic conditions on generic HRQOL from the perspectives of children and parents utilizing the PedsQL™ 4.0 Generic Core Scales. These findings with the PedsQL™ have clinical implications for the healthcare services provided for children with chronic health conditions. Given the degree of reported impairment based on PedsQL™ scores across different pediatric chronic conditions, the need for more efficacious targeted treatments for those pediatric patients with more severely impaired HRQOL is clearly and urgently indicated.</p

Solving random boundary heat model using the finite difference method under mean square convergence

"This is the peer reviewed version of the following article: Cortés, J. C., Romero, J. V., Roselló, M. D., Sohaly, MA. Solving random boundary heat model using the finite difference method under mean square convergence. Comp and Math Methods. 2019; 1:e1026. https://doi.org/10.1002/cmm4.1026 , which has been published in final form at https://doi.org/10.1002/cmm4.1026. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] This contribution is devoted to construct numerical approximations to the solution of the one-dimensional boundary value problem for the heat model with uncertainty in the diffusion coefficient. Approximations are constructed via random numerical schemes. This approach permits discussing the effect of the random diffusion coefficient, which is assumed a random variable. We establish results about the consistency and stability of the random difference scheme using mean square convergence. Finally, an illustrative example is presented.Spanish Ministerio de Economía y Competitividad. Grant Number: MTM2017-89664-PCortés, J.; Romero, J.; Roselló, M.; Sohaly, M. (2019). Solving random boundary heat model using the finite difference method under mean square convergence. Computational and Mathematical Methods. 1(3):1-15. https://doi.org/10.1002/cmm4.1026S11513Han, X., & Kloeden, P. E. (2017). Random Ordinary Differential Equations and Their Numerical Solution. Probability Theory and Stochastic Modelling. doi:10.1007/978-981-10-6265-0Villafuerte, L., Braumann, C. A., Cortés, J.-C., & Jódar, L. (2010). Random differential operational calculus: Theory and applications. Computers & Mathematics with Applications, 59(1), 115-125. doi:10.1016/j.camwa.2009.08.061Logan, J. D. (2004). Partial Differential Equations on Bounded Domains. Undergraduate Texts in Mathematics, 121-171. doi:10.1007/978-1-4419-8879-9_4Cannon, J. R. (1964). A Cauchy problem for the heat equation. Annali di Matematica Pura ed Applicata, 66(1), 155-165. doi:10.1007/bf02412441LinPPY.On The Numerical Solution of The Heat Equation in Unbounded Domains[PhD thesis].New York NY:New York University;1993.Li, J.-R., & Greengard, L. (2007). On the numerical solution of the heat equation I: Fast solvers in free space. Journal of Computational Physics, 226(2), 1891-1901. doi:10.1016/j.jcp.2007.06.021Han, H., & Huang, Z. (2002). Exact and approximating boundary conditions for the parabolic problems on unbounded domains. Computers & Mathematics with Applications, 44(5-6), 655-666. doi:10.1016/s0898-1221(02)00180-3Han, H., & Huang, Z. (2002). A class of artificial boundary conditions for heat equation in unbounded domains. Computers & Mathematics with Applications, 43(6-7), 889-900. doi:10.1016/s0898-1221(01)00329-7Strikwerda, J. C. (2004). Finite Difference Schemes and Partial Differential Equations, Second Edition. doi:10.1137/1.9780898717938Kloeden, P. E., & Platen, E. (1992). Numerical Solution of Stochastic Differential Equations. doi:10.1007/978-3-662-12616-5Øksendal, B. (2003). Stochastic Differential Equations. Universitext. doi:10.1007/978-3-642-14394-6Holden, H., Øksendal, B., Ubøe, J., & Zhang, T. (2010). Stochastic Partial Differential Equations. doi:10.1007/978-0-387-89488-1El-Tawil, M. A., & Sohaly, M. A. (2012). Mean square convergent three points finite difference scheme for random partial differential equations. Journal of the Egyptian Mathematical Society, 20(3), 188-204. doi:10.1016/j.joems.2012.08.017Cortés, J.-C., Navarro-Quiles, A., Romero, J.-V., Roselló, M.-D., & Sohaly, M. A. (2018). Solving the random Cauchy one-dimensional advection–diffusion equation: Numerical analysis and computing. Journal of Computational and Applied Mathematics, 330, 920-936. doi:10.1016/j.cam.2017.02.001Cortés, J. C., Jódar, L., Villafuerte, L., & Villanueva, R. J. (2007). Computing mean square approximations of random diffusion models with source term. Mathematics and Computers in Simulation, 76(1-3), 44-48. doi:10.1016/j.matcom.2007.01.020Cortés, J. C., Jódar, L., & Villafuerte, L. (2009). Random linear-quadratic mathematical models: Computing explicit solutions and applications. Mathematics and Computers in Simulation, 79(7), 2076-2090. doi:10.1016/j.matcom.2008.11.008Henderson, D., & Plaschko, P. (2006). Stochastic Differential Equations in Science and Engineering. doi:10.1142/580

Temporal trends and lesion sets for persistent atrial fibrillation ablation: a meta-analysis with trial sequential analysis and meta-regression

BACKGROUND: Ablation for persistent atrial fibrillation (PsAF) has been performed for over 20 years, although success rates have remained modest. Several adjunctive lesion sets have been studied but none have become standard of practice. We sought to describe how the efficacy of ablation for PsAF has evolved in this time period with a focus on the effect of adjunctive ablation strategies. METHODS: Databases were searched for prospective studies of PsAF ablation. We performed meta-regression and trial sequential analysis. RESULTS: A total of 99 studies (15 424 patients) were included. Ablation for PsAF achieved the primary outcome (freedom of atrial fibrillation/atrial tachycardia rate at 12 months follow-up) in 48.2% (5% CI, 44.0-52.3). Meta-regression showed freedom from atrial arrhythmia at 12 months has improved over time, while procedure time and fluoroscopy time have significantly reduced. Through the use of cumulative meta-analyses and trial sequential analysis, we show that some ablation strategies may initially seem promising, but after several randomized controlled trials may be found to be ineffective. Trial sequential analysis showed that complex fractionated atrial electrogram ablation is ineffective and further study of this treatment would be futile, while posterior wall isolation currently does not have sufficient evidence for routine use in PsAF ablation. CONCLUSIONS: Overall success rates from PsAF ablation and procedure/fluoroscopy times have improved over time. However, no adjunctive lesion set, in addition to pulmonary vein isolation, has been conclusively demonstrated to be beneficial. Through the use of trial sequential analysis, we highlight the importance of adequately powered randomized controlled trials, to avoid reaching premature conclusions, before widespread adoption of novel therapies

Random attractors for degenerate stochastic partial differential equations

We prove the existence of random attractors for a large class of degenerate stochastic partial differential equations (SPDE) perturbed by joint additive Wiener noise and real, linear multiplicative Brownian noise, assuming only the standard assumptions of the variational approach to SPDE with compact embeddings in the associated Gelfand triple. This allows spatially much rougher noise than in known results. The approach is based on a construction of strictly stationary solutions to related strongly monotone SPDE. Applications include stochastic generalized porous media equations, stochastic generalized degenerate p-Laplace equations and stochastic reaction diffusion equations. For perturbed, degenerate p-Laplace equations we prove that the deterministic, infinite dimensional attractor collapses to a single random point if enough noise is added.Comment: 34 pages; The final publication is available at http://link.springer.com/article/10.1007%2Fs10884-013-9294-

The stealth episome: suppression of gene expression on the excised genomic island PPHGI-1 from Pseudomonas syringae pv. phaseolicola

Pseudomonas syringae pv. phaseolicola is the causative agent of halo blight in the common bean, Phaseolus vulgaris. P. syringae pv. phaseolicola race 4 strain 1302A contains the avirulence gene avrPphB (syn. hopAR1), which resides on PPHGI-1, a 106 kb genomic island. Loss of PPHGI-1 from P. syringae pv. phaseolicola 1302A following exposure to the hypersensitive resistance response (HR) leads to the evolution of strains with altered virulence. Here we have used fluorescent protein reporter systems to gain insight into the mobility of PPHGI-1. Confocal imaging of dual-labelled P. syringae pv. phaseolicola 1302A strain, F532 (dsRFP in chromosome and eGFP in PPHGI-1), revealed loss of PPHGI-1::eGFP encoded fluorescence during plant infection and when grown in vitro on extracted leaf apoplastic fluids. Fluorescence-activated cell sorting (FACS) of fluorescent and non-fluorescent PPHGI-1::eGFP F532 populations showed that cells lost fluorescence not only when the GI was deleted, but also when it had excised and was present as a circular episome. In addition to reduced expression of eGFP, quantitative PCR on sub-populations separated by FACS showed that transcription of other genes on PPHGI-1 (avrPphB and xerC) was also greatly reduced in F532 cells harbouring the excised PPHGI-1::eGFP episome. Our results show how virulence determinants located on mobile pathogenicity islands may be hidden from detection by host surveillance systems through the suppression of gene expression in the episomal state

In situ evidence for the structure of the magnetic null in a 3D reconnection event in the Earth's magnetotail

Magnetic reconnection is one of the most important processes in astrophysical, space and laboratory plasmas. Identifying the structure around the point at which the magnetic field lines break and subsequently reform, known as the magnetic null point, is crucial to improving our understanding reconnection. But owing to the inherently three-dimensional nature of this process, magnetic nulls are only detectable through measurements obtained simultaneously from at least four points in space. Using data collected by the four spacecraft of the Cluster constellation as they traversed a diffusion region in the Earth's magnetotail on 15 September, 2001, we report here the first in situ evidence for the structure of an isolated magnetic null. The results indicate that it has a positive-spiral structure whose spatial extent is of the same order as the local ion inertial length scale, suggesting that the Hall effect could play an important role in 3D reconnection dynamics.Comment: 14 pages, 4 figure

Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

On the geometry of the set of symmetric matrices with repeated eigenvalues

We investigate some geometric properties of the real algebraic variety \u394 of symmetric matrices with repeated eigenvalues. We explicitly compute the volume of its intersection with the sphere and prove a Eckart\u2013Young\u2013Mirsky-type theorem for the distance function from a generic matrix to points in \u394. We exhibit connections of our study to real algebraic geometry (computing the Euclidean distance degree of \u394) and random matrix theory

The origin of human chromosome 2 analyzed by comparative chromosome mapping with a DNA microlibrary

Fluorescencein situ hybridization (FISH) of microlibraries established from distinct chromosome subregions can test the evolutionary conservation of chromosome bands as well as chromosomal rearrangements that occurred during primate evolution and will help to clarify phylogenetic relationships. We used a DNA library established by microdissection and microcloning from the entire long arm of human chromosome 2 for fluorescencein situ hybridization and comparative mapping of the chromosomes of human, great apes (Pan troglodytes, Pan paniscus, Gorilla gorilla, Pongo pygmaeus) and Old World monkeys (Macaca fuscata andCercopithecus aethiops). Inversions were found in the pericentric region of the primate chromosome 2p homologs in great apes, and the hybridization pattern demonstrates the known phylogenetically derived telomere fusion in the line that leads to human chromosome 2. The hybridization of the 2q microlibrary to chromosomes of Old World monkeys gave a different pattern from that in the gorilla and the orang-utan, but a pattern similar to that of chimpanzees. This suggests convergence of chromosomal rearrangements in different phylogenetic lines