Human mesenchymal stem cells stimulate EaHy926 endothelial cell migration:combined proteomic and in vitro analysis of the influence of donor-donor variability

Mesenchymal stem cells (MSCs) stimulate angiogenesis within a wound environment and this effect is mediated through paracrine interactions with the endothelial cells present. Here we report that human MSC-conditioned medium (n=3 donors) significantly increased EaHy-926 endothelial cell adhesion and cell migration, but that this stimulatory effect was markedly donor-dependent. MALDI-TOF/TOF mass spectrometry demonstrated that whilst collagen type I and fibronectin were secreted by all of the MSC cultures, the small leucine rich proteoglycan, decorin was secreted only by the MSC culture that was least effective upon EaHy-926 cells. These individual extracellular matrix components were then tested as culture substrata. EaHy-926 cell adherence was greatest on fibronectin-coated surfaces with least adherence on decorin-coated surfaces. Scratch wound assays were used to examine cell migration. EaHy-926 cell scratch wound closure was quickest on substrates of fibronectin and slowest on decorin. However, EaHy-926 cell migration was stimulated by the addition of MSC-conditioned medium irrespective of the types of culture substrates. These data suggest that whilst the MSC secretome may generally be considered angiogenic, the composition of the secretome is variable and this variation probably contributes to donor-donor differences in activity. Hence, screening and optimizing MSC secretomes will improve the clinical effectiveness of pro-angiogenic MSC-based therapies

Young and Eccentric: The Quadruple System HD 86588

High-resolution spectroscopy and speckle interferometry reveal the young star HD 86588 as a quadruple system with a three-tier hierarchy. The 0.″3 resolved binary A,B with an estimated period around 300 years contains the 8-yr pair Aa,Abc (also potentially resolvable), where Ab,Ac is a double-lined binary with equal components, for which we compute the spectroscopic orbit. Despite the short period of 2.4058 days, the orbit of Ab,Ac is eccentric (e = 0.086 ±0.003). It has a large inclination, but there are no eclipses; only a 4.4 mmag light modulation apparently caused by star spots on the components of this binary is detected with Evryscope. Assuming a moderate extinction of A V = 0.5 mag and a parallax of 5.2 mas, we find that the stars are on or close to the main sequence (age >10 Myr) and their masses are from 1 to 1.3 solar. We measure the strength of the lithium line in the visual secondary B which, together with rotation, suggests that the system is younger than 150 Myr. This object is located behind the extension of the Chamaeleon I dark cloud (which explains extinction and interstellar sodium absorption), but apparently does not belong to it. We propose a scenario where the inner orbit has recently acquired its high eccentricity through dynamical interaction with the outer two components; it is now undergoing rapid tidal circularization on a timescale of ∼1 Myr. Alternatively, the eccentricity could be excited quasi-stationary by the outer component Aa

Chlorine adsorption on the Cu(111) surface

We investigate the adsorption of chlorine on the Cu(111) surface with full potential all-electron density functional calculations. Chlorine adsorption at the fcc hollow sites is slightly preferred over that at the hcp hollow. The adsorption geometry is in excellent agreement with electron diffraction and ion scattering data. Adsorption energies and surface diffusion barriers are close to those deduced from experiment.Comment: to appear in Chem. Phys. Let

News from the Muon (g-2) Experiment at BNL

The magnetic moment anomaly a_mu = (g_mu - 2) / 2 of the positive muon has been measured at the Brookhaven Alternating Gradient Synchrotron with an uncertainty of 0.7 ppm. The new result, based on data taken in 2000, agrees well with previous measurements. Standard Model evaluations currently differ from the experimental result by 1.6 to 3.0 standard deviations.Comment: Talk presented at RADCOR - Loops and Legs 2002, Kloster Banz, Germany, September 8-13 2002, to be published in Nuclear Physics B (Proc. Suppl.); 5 pages, 3 figure

The LABOCA survey of the extended Chandra Deep Field South : two modes of star formation in active galactic nucleus hosts?

We study the co-existence of star formation and active galactic nucleus (AGN) activity in Chandra X-ray-selected AGN by analyzing stacked 870 μm submillimeter emission from a deep and wide map of the Extended Chandra Deep Field South (ECDFS), obtained with the LABOCA instrument at the APEX telescope. The total X-ray sample of 895 sources with median redshift z ~ 1 drawn from the combined (E)CDFS X-ray catalogs is detected at >11σ significance at a mean submillimeter flux of 0.49 ± 0.04 mJy, corresponding to a typical star formation rate (SFR) around 30 M sun yr-1 for a T = 35 K, β = 1.5 graybody far-infrared spectral energy distribution. The good signal-to-noise ratio permits stacking analyses for major subgroups, splitting the sample by redshift, intrinsic luminosity, and AGN obscuration properties. We observe a trend of SFR increasing with redshift. An increase of SFR with AGN luminosity is indicated at the highest L 2-10 keV >~ 1044 erg s-1 luminosities only. Increasing trends with X-ray obscuration as expected in some AGN evolutionary scenarios are not observed for the bulk of the X-ray AGN sample but may be present for the highest intrinsic luminosity objects with L 2-10 keV >~ 1044 erg s-1. This behavior suggests a transition between two modes in the co-existence of AGN activity and star formation. For the bulk of the sample, the X-ray luminosity and obscuration of the AGN are not intimately linked to the global SFR of their hosts. The hosts are likely massive and forming stars secularly, at rates similar to the pervasive star formation seen in massive galaxies without an AGN at similar redshifts. In these systems, star formation is not linked to a specific state of the AGN and the period of moderately luminous AGN activity may not highlight a major evolutionary transition of the galaxy. The change indicated toward more intense star formation, and a more pronounced increase in SFRs between unobscured and obscured AGN reported in the literature at highest (L 2-10 keV >~ 1044 erg s-1) luminosities suggests that these luminous AGNs follow an evolutionary path on which obscured AGN activity and intense star formation are linked, possibly via merging. Comparison to local hard X-ray-selected AGN supports this interpretation. SFRs in the hosts of moderate luminosity AGN at z ~ 1 are an order of magnitude higher than at z ~ 0, following the increase in the non-AGN massive galaxy population. At high AGN luminosities, hosts on the evolutionary link/merger path emerge from this secular level of star formation

Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol

Background: High dose unilobar radioembolization (also termed ‘radiation lobectomy’)—the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy—has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant. Methods: The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose–response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank. Discussion: This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice. Trial registration: Netherlands Trial Register NL8902 , registered on 2020–09-15

Adaptive preconditioning in neurological diseases -­ therapeutic insights from proteostatic perturbations

International audienceIn neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson´s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses - and the molecular pathways they recruit - might be exploited for therapeutic gai

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine