Dynamic Assessment of Cardiovascular Biomarkers

The behaviour of cardiovascular parameters during exercise remains unsettled. Arterial stiffness is one of the most promising and innovative vascular biomarkers; this vessel property is usually evaluated at rest, but, since it aims to describe a stress-strain vessel behaviour, it is not a static parameter. Hence, our aim was to develop a method able to evaluate carotid elasticity dynamically in order to investigate if this analysis can provide information regarding differences between populations (i.e. patients and healthy subjects). We developed an approach based on a contour tracking algorithm applied to ultrasound B-mode image sequences and used it in conjunction with a local pressure estimation to assess carotid distensibility. The method's reproducibility was evaluated by analyzing a group of healthy volunteers during two sessions 3 days apart. Repeatability was expressed as coefficient of variation and satisfactory results were obtained in exercise. After testing the robustness of the technique, the approach was applied during graded bicycle semi-supine exercise session in patients with known or suspected coronary artery disease (CAD) and results were compared with a control group. 36 consecutive patients (20 men, 61±8years), and 18 healthy volunteers (9 men, 34±3 years) were recruited. Right carotid diameter (D) and distension (ΔD) were estimated by the developed ultrasound B-mode image processing method, and central pulse pressure (PPa) by radial tonometry; then, carotid elasticity was expressed as cross-sectional distensibility coefficient (DC). Besides the vascular evaluation we introduced the estimation of left-ventricular elastance (ElvI) by echocardiography, in order to obtain a more integrated dynamic picture including arterial-ventricular coupling. All measurements were performed at rest, peak of age-dependent maximal heart rate and during recovery. At rest, D and PPa were higher in patients than in controls, whereas no significant differences were observed in ΔD and mean blood pressure; DC and ElvI were lower in patients than in healthy volunteers. At peak mean blood pressure increased both in patients and controls; DC significantly decreased and D increased in healthy subjects but not in patients. Finally ElvI highly increased in controls but not in patients. Behaviours of the two populations during recovery were similar. Hence, we can conclude that the developed approach provides a suitable reproducibility for clinical studies and was able to dynamically discriminate between different kind of subjects. In particular, in patients with known or suspected CAD, carotid distensibility, which at rest is lower than in healthy controls, remains unchanged during maximal exercise, despite a similar increase in mean blood pressure in the two populations. This difference is underlined also by the absence of strong cardiac response and carotid vasodilation in the pathologic population. From our preliminary results, the importance of a dynamic assessment of carotid elasticity was confirmed, and there is evidence of a clinical need including a simple and robust device to more easily perform this kind of analysis than by ultrasound. In our lab a first prototype based on vibration approach was designed and might be the suitable solution for implementing low-cost and easy carotid elasticity dynamic evaluation. In the future, the cardiologist ambulatory might provide, besides cardiac and pressure monitoring, additive relevant clinical information from an arterial elasticity 24-hours device

Impact of the PDFs on the Z and W lineshapes at LHC

The parton distribution functions (PDFs) of the proton play a role in determining the lineshape of $Z$ and $W$ bosons produced at the LHC. In particular, the mode of the gauge boson virtuality is shifted with respect to the pole due to the dependence of the partonic luminosity on the boson virtuality. The knowledge of this shift contributes to the systematic uncertainty for a direct measurement of the boson mass. A detailed study of the shift and of its systematic uncertainty due to the limited knowledge of the PDFs is obtained using a tree-level model of $Z$ and $W$ boson production in proton-proton collisions at $\sqrt{s}=13$ TeV. A Monte Carlo simulation is further used to validate the tree-level model and study the dependence of the shift on the transverse momentum of the gauge bosons. The tree-level calculation is found to provide a good description of the shift. The systematic uncertainty on the lineshape due to the PDFs is estimated to be below one MeV in the phase-space relevant for a future high-precision mass measurement of the gauge boson masses at the LHC

The Ultrasound Window Into Vascular Ageing: A Technology Review by the VascAgeNet COST Action

Arteriosclerosis; Ultrasound; Vascular ageingArteriosclerosi; Ecografia; Envelliment vascularArteriosclerosis; Ecografía; Envejecimiento vascularNon-invasive ultrasound (US) imaging enables the assessment of the properties of superficial blood vessels. Various modes can be used for vascular characteristics analysis, ranging from radiofrequency (RF) data, Doppler- and standard B/M-mode imaging, to more recent ultra-high frequency and ultrafast techniques. The aim of the present work was to provide an overview of the current state-of-the-art non-invasive US technologies and corresponding vascular ageing characteristics from a technological perspective. Following an introduction about the basic concepts of the US technique, the characteristics considered in this review are clustered into: 1) vessel wall structure; 2) dynamic elastic properties, and 3) reactive vessel properties. The overview shows that ultrasound is a versatile, non-invasive, and safe imaging technique that can be adopted for obtaining information about function, structure, and reactivity in superficial arteries. The most suitable setting for a specific application must be selected according to spatial and temporal resolution requirements. The usefulness of standardization in the validation process and performance metric adoption emerges. Computer-based techniques should always be preferred to manual measures, as long as the algorithms and learning procedures are transparent and well described, and the performance leads to better results. Identification of a minimal clinically important difference is a crucial point for drawing conclusions regarding robustness of the techniques and for the translation into practice of any biomarker.This article is based upon work from COST Action CA18216 VascAgeNet, supported by COST (European Cooperation in Science and Technology, www.cost.eu). A.G. has received funding from “La Caixa” Foundation (LCF/BQ/PR22/11920008). R.E.C is supported by the National Health and Medical Research Council of Australia (reference: 2009005) and by a National Heart Foundation Future Leader Fellowship (reference: 105636). J.A. acknowledges support from the British Heart Foundation [PG/15/104/31913], the Wellcome EPSRC Centre for Medical Engineering at King's College London [WT 203148/Z/16/Z], and the Cardiovascular MedTech Co-operative at Guy's and St Thomas' NHS Foundation Trust [MIC-2016-019]

HOW DOES IT WORK A QUALITY/PERFORMANCE MANAGEMENT SYSTEM IN A BIOMEDICAL RESEARCH INSTITUTION? LIGHTS AND SHADOWS

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Isolation of an "early" transit amplifying keratinocyte population in human epidermis: a role for the low affinity neurotrophin receptor CD271

In the interfollicular epidermis (IFE), stem cells (KSC) generate transit amplifying (TA) cells that, after symmetric divisions, produce differentiating daughters. Here, we isolated and characterized the highly proliferative interfollicular epidermal basal cell population "early" TA (ETA) cells, based on their capacity to adhere to type IV collagen. Proliferation and colony-forming efficiency in ETA cells are lower than in KSC but higher than in "late" TA (LTA). Stemness, proliferation, and differentiation markers confirmed that ETA cells display a unique phenotype. Skin reconstructs derived from ETA cells present different features (epidermal thickness, Ki67, and Survivin expression), as compared to skin equivalents generated from either KSC or LTA cells. The low-affinity neurotrophin receptor CD271, which regulates the KSC to TA cell transition in the human epidermis through an on/off switch control mechanism, is predominantly expressed in ETA cells. Skin equivalents generated from siRNA CD271 ETA cells display a more proliferative and less differentiated phenotype, as compared to mock-derived reconstructs. Consistently, CD271 overexpression in LTA cells generates a more proliferative skin equivalent than mock LTA cells. Finally, the CD271 level declines with cellular senescence, while it induces a delay in p16INK4 expression. We conclude that ETA cells represent the first KSC progenitor with exclusive features. CD271 identifies and modulates ETA cells, thus participating in the early differentiation and regenerative capacity of the human epidermis

The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer cell phenotype and resistance to therapy.

This Perspective addresses the interactions of cancer stem cells (CSC) with environment which result in the modulation of CSC metabolism, and thereby of CSC phenotype and resistance to therapy. We considered first as a model disease chronic myeloid leukemia (CML), which is triggered by a well-identified oncogenetic protein (BCR/Abl) and brilliantly treated with tyrosine kinase inhibitors (TKi). However, TKi are extremely effective in inducing remission of disease, but unable, in most cases, to prevent relapse. We demonstrated that the interference with cell metabolism (oxygen/glucose shortage) enriches cells exhibiting the leukemia stem cell (LSC) phenotype and, at the same time, suppresses BCR/Abl protein expression. These LSC are therefore refractory to the TKi Imatinib-mesylate, pointing to cell metabolism as an important factor controlling the onset of TKi-resistant minimal residual disease (MRD) of CML and the related relapse. Studies of solid neoplasias brought another player into the control of MRD, low tissue pH, which often parallels cancer growth and progression. Thus, a 3-party scenario emerged for the regulation of CSC/LSC maintenance, MRD induction and disease relapse: the “hypoxic” versus the “ischemic” vs. the “acidic” environment. As these environments are unlikely constrained within rigid borders, we named this model the “metabolically-modulated stem cell niche.

Charting the Galactic acceleration field II. A global mass model of the Milky Way from the STREAMFINDER Atlas of Stellar Streams detected in Gaia DR3

We present an atlas and follow-up spectroscopic observations of 87 thin stream-like structures detected with the STREAMFINDER algorithm in Gaia DR3, of which 29 are new discoveries. Here we focus on using these streams to refine mass models of the Galaxy. Fits with a double power law halo with the outer power law slope set to $-\beta_h=3$ yield an inner power law slope $-\gamma_h=0.97^{+0.17}_{-0.21}$, a scale radius of $r_{0, h}=14.7^{+4.7}_{-1.0}$ kpc, a halo density flattening $q_{m, h}=0.75\pm0.03$, and a local dark matter density of $\rho_{h, \odot}=0.0114\pm0.0007 {\rm M_\odot pc^{-3}}$. Freeing $\beta$ yields $\beta=2.53^{+0.42}_{-0.16}$, but this value is heavily influenced by our chosen virial mass limit. The stellar disks are found to have a combined mass of $4.20^{+0.44}_{-0.53}\times10^{10} {\rm M_\odot}$, with the thick disk contributing $12.4\pm0.7$\% to the local stellar surface density. The scale length of the thin and thick disks are $2.17^{+0.18}_{-0.08}$ kpc and $1.62^{+0.72}_{-0.13}$ kpc, respectively, while their scale heights are $0.347^{+0.007}_{-0.010}$ kpc and $0.86^{+0.03}_{-0.02}$ kpc, respectively. The virial mass of the favored model is $M_{200}=1.09^{+0.19}_{-0.14}\times 10^{12} {\rm M_\odot}$, while the mass inside of 50 kpc is $M_{R<50}=0.46\pm0.03\times 10^{12} {\rm M_\odot}$. We introduce the Large Magellanic Cloud (LMC) into the derived potential models, and fit the "Orphan" stream therein, finding a mass for the LMC that is consistent with recent estimates. Some highlights of the atlas include the nearby trailing arm of $\omega$-Cen, and a nearby very metal-poor stream that was once a satellite of the Sagittarius dwarf galaxy. Finally, we unambiguously detect a hot component around the GD-1 stream, consistent with it having been tidally pre-processed within its own DM subhalo.Comment: 43 pages, 26 figures, submitted to Ap