New angiogenic regulators produced by TAMs: perspective for targeting tumor angiogenesis

Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs

Influence of Factors of Production on Efficiency of Production Systems

In the course of functioning of firms the uncountable set of variants of use of factors in various combinations is supposed. Diversification of combinations is caused by scientific and technical progress and a condition of the market of factors of production. Scientific and technical progress and technical revolutions lead to occurrence new (interchanged) factors and a new product. Possibility by means of the factor as a result increases to produce a product so much, how many it is necessary for compensation of the factor and an additional product which is not necessary for factor compensation. This additional stock of a product, as a matter of fact, is an additional product. With its production probably further increase in production. The conclusion from here follows: the best use of incomes of production is a condition of the further increase in its scales, a condition of expansion of reproduction. Thus, as a result of connection of factors of production work products, set of material benefits are created. The quantitative relation of volume (weight) of the received product to the work spent for its production, characterises labour productivity. Important problem at studying of factors of production of their influence on efficiency of production systems is the problem of an optimum combination of factors of production DOI: 10.5901/mjss.2015.v6n3s7p41

A multi-wavelength polarimetric study of the blazar CTA 102 during a Gamma-ray flare in 2012

We perform a multi-wavelength polarimetric study of the quasar CTA 102 during an extraordinarily bright $\gamma$-ray outburst detected by the {\it Fermi} Large Area Telescope in September-October 2012 when the source reached a flux of F$_{>100~\mathrm{MeV}} =5.2\pm0.4\times10^{-6}$ photons cm$^{-2}$ s$^{-1}$. At the same time the source displayed an unprecedented optical and NIR outburst. We study the evolution of the parsec scale jet with ultra-high angular resolution through a sequence of 80 total and polarized intensity Very Long Baseline Array images at 43 GHz, covering the observing period from June 2007 to June 2014. We find that the $\gamma$-ray outburst is coincident with flares at all the other frequencies and is related to the passage of a new superluminal knot through the radio core. The powerful $\gamma$-ray emission is associated with a change in direction of the jet, which became oriented more closely to our line of sight ($\theta\sim$1.2$^{\circ}$) during the ejection of the knot and the $\gamma$-ray outburst. During the flare, the optical polarized emission displays intra-day variability and a clear clockwise rotation of EVPAs, which we associate with the path followed by the knot as it moves along helical magnetic field lines, although a random walk of the EVPA caused by a turbulent magnetic field cannot be ruled out. We locate the $\gamma$-ray outburst a short distance downstream of the radio core, parsecs from the black hole. This suggests that synchrotron self-Compton scattering of near-infrared to ultraviolet photons is the probable mechanism for the $\gamma$-ray production.Comment: Accepted for publication in The Astrophysical Journa

Probing the Inner Jet of the Quasar PKS 1510-089 with Multi-waveband Monitoring during Strong Gamma-ray Activity

We present results from monitoring the multi-waveband flux, linear polarization, and parsec-scale structure of the quasar PKS 1510-089, concentrating on eight major gamma-ray flares that occurred during the interval 2009.0-2009.5. The gamma-ray peaks were essentially simultaneous with maxima at optical wavelengths, although the flux ratio of the two wavebands varied by an order of magnitude. The optical polarization vector rotated by 720 degrees during a 5-day period encompassing six of these flares. This culminated in a very bright, roughly 1 day, optical and gamma-ray flare as a bright knot of emission passed through the highest-intensity, stationary feature (the "core") seen in 43 GHz Very Long Baseline Array images. The knot continued to propagate down the jet at an apparent speed of 22c and emit strongly at gamma-ray energies as a months-long X-ray/radio outburst intensified. We interpret these events as the result of the knot following a spiral path through a mainly toroidal magnetic field pattern in the acceleration and collimation zone of the jet, after which it passes through a standing shock in the 43 GHz core and then continues downstream. In this picture, the rapid gamma-ray flares result from scattering of infrared seed photons from a relatively slow sheath of the jet as well as from optical synchrotron radiation in the faster spine. The 2006-2009.7 radio and X-ray flux variations are correlated at very high significance; we conclude that the X-rays are mainly from inverse Compton scattering of infrared seed photons by 20-40 MeV electrons.Comment: 10 pages of text + 5 figures, to be published in Astrophysical Journal Letters in 201

Flaring Behavior of the Quasar 3C~454.3 across the Electromagnetic Spectrum

We analyze the behavior of the parsec-scale jet of the quasar 3C~454.3 during pronounced flaring activity in 2005-2008. Three major disturbances propagated down the jet along different trajectories with Lorentz factors $\Gamma>$10. The disturbances show a clear connection with millimeter-wave outbursts, in 2005 May/June, 2007 July, and 2007 December. High-amplitude optical events in the $R$-band light curve precede peaks of the millimeter-wave outbursts by 15-50 days. Each optical outburst is accompanied by an increase in X-ray activity. We associate the optical outbursts with propagation of the superluminal knots and derive the location of sites of energy dissipation in the form of radiation. The most prominent and long-lasting of these, in 2005 May, occurred closer to the black hole, while the outbursts with a shorter duration in 2005 Autumn and in 2007 might be connected with the passage of a disturbance through the millimeter-wave core of the jet. The optical outbursts, which coincide with the passage of superluminal radio knots through the core, are accompanied by systematic rotation of the position angle of optical linear polarization. Such rotation appears to be a common feature during the early stages of flares in blazars. We find correlations between optical variations and those at X-ray and $\gamma$-ray energies. We conclude that the emergence of a superluminal knot from the core yields a series of optical and high-energy outbursts, and that the mm-wave core lies at the end of the jet's acceleration and collimation zone.Comment: 57 pages, 23 figures, 8 tables (submitted to ApJ

PFKFB3 overexpression in monocytes of patients with colon but not rectal cancer programs pro-tumor macrophages and is indicative for higher risk of tumor relapse

Introduction: Circulating monocytes are main source for tumor-associated macrophages (TAMs) that control tumor growth, angiogenesis, metastasis and therapy resistance. We raised the questions how monocyte programming is affected by growing tumors localized in colon and rectal sections, and how treatment onsets affect monocyte programming in the circulation. Methods: Patients with rectal cancer and colon cancer were enrolled in the study. Peripheral blood monocytes were characterized by phenotypic analysis using flow cytometry, by transcriptomic analysis using RNA sequencing and by gene expression analysis using real-time RT-PCR. Phenotypic analysis was performed with IF/confocal microscopy. Spatial transcriptomic analysis was applied using GeoMX DSP-NGS. Results: In patients with rectal cancer, increased amount of CCR2+ monocytes was indicative for the absence of both lymphatic and hematogenous metastasis. In contrast, in patients with colon cancer CD163+ monocytes were indicative for LN metastasis. NGS analysis identified tumor-specific transcriptional programming of monocytes in all CRC patients compared to healthy individuals. The key transcriptional difference between monocytes of patients with colon and rectal cancer was increased expression of PFKFB3, activator of glycolysis that is currently considered as therapy target for major solid cancers. PFKFB3-expressing monocyte-derived macrophages massively infiltrated tumor in colon. Nanostring technology identified correlation of PFKFB3 with amount and tumor-promoting properties of TAMs in colon but not in rectal cancer. PFKFB3 was indicative for tumor relapse specifically in colon cancer. Discussion: Our findings provide essential argument towards CRC definition to cover two clinically distinct cancers – colon cancer and rectal cancer, that differentially interact with innate immunity

Predictive risk factors before the onset of familial rheumatoid arthritis: the Tatarstan cohort study

BackgroundA familial history of rheumatoid arthritis (RA) predisposes an individual to develop RA. This study aimed at investigating factors associated with this conversion from the Tatarstan cohort.MethodsA total of 144 individuals, referred to as pre-RA and at risk for familial RA, were selected 2 years (range: 2–21 years) before conversion to RA and compared to non-converted 328 first-degree relatives (FDR) from RA as assessed after ≥2 years follow-up, and 355 healthy controls were also selected (HC). Preclinical parameters and socio-demographic/individual/HLA genetic factors were analyzed when data were available at the time of enrollment.ResultsAs compared to FDR and HC groups, pre-RA individuals were characterized before conversion to RA by the presence of arthralgia, severe morning symptoms, a lower educational level, and rural location. An association with the HLA-DRB1 SE risk factor was also retrieved with symmetrical arthralgia and passive smoking. On the contrary, alcohol consumption and childlessness in women were protective and associated with the HLA-DRB1*07:01 locus.ConclusionBefore RA onset, a combination of individual and genetic factors characterized those who are at risk of progressing to RA among those with familial RA relatives