Receptor tyrosine kinase inhibitors negatively impact on pro-reparative characteristics of human cardiac progenitor cells

Receptor tyrosine kinase inhibitors improve cancer survival but their cardiotoxicity requires investigation. We investigated these inhibitors' effects on human cardiac progenitor cells in vitro and rat heart in vivo. We applied imatinib, sunitinib or sorafenib to human cardiac progenitor cells, assessing cell viability, proliferation, stemness, differentiation, growth factor production and second messengers. Alongside, sunitinib effects were assessed in vivo. Inhibitors decreased (\u1d631 < 0.05) cell viability, at levels equivalent to 'peak' (24 h; imatinib: 91.5 ± 0.9%; sunitinib: 83.9 ± 1.8%; sorafenib: 75.0 ± 1.6%) and 'trough' (7 days; imatinib: 62.3 ± 6.2%; sunitinib: 86.2 ± 3.5%) clinical plasma levels, compared to control (100% viability). Reduced (\u1d631 < 0.05) cell cycle activity was seen with imatinib (29.3 ± 4.3% cells in S/G2/M-phases; 50.3 ± 5.1% in control). Expression of PECAM-1, Nkx2.5, Wnt2, linked with cell differentiation, were decreased (\u1d631 < 0.05) 2, 2 and 6-fold, respectively. Expression of HGF, p38 and Akt1 in cells was reduced (\u1d631 < 0.05) by sunitinib. Second messenger (p38 and Akt1) blockade affected progenitor cell phenotype, reducing c-kit and growth factor (HGF, EGF) expression. Sunitinib for 9 days (40 mg/kg, i.p.) in adult rats reduced (\u1d631 < 0.05) cardiac ejection fraction (68 ± 2% \u1d637\u1d634. baseline (83 ± 1%) and control (84 ± 4%)) and reduced progenitor cell numbers. Receptor tyrosine kinase inhibitors reduce cardiac progenitor cell survival, proliferation, differentiation and reparative growth factor expression

Transplantation of Skeletal Muscle-Derived Sca-1⁺/PW1⁺/Pax7⁻ Interstitial Cells (PICs) Improves Cardiac Function and Attenuates Remodeling in Mice Subjected to Myocardial Infarction

We have previously shown that skeletal muscle-derived Sca-1⁺/PW1⁺/Pax7⁻ interstitial cells (PICs) are multi-potent and enhance endogenous repair and regeneration. Here, we investigated the regenerative potential of PICs following intramyocardial transplantation in mice subjected to an acute myocardial infarction (MI). MI was induced through the ligation of the left anterior descending coronary artery in 8-week old male C57BL/6 mice. 5 × 10⁵ eGFP-labelled PICs (MI + PICs; n = 7) or PBS (MI-PBS; n = 7) were injected intramyocardially into the border zone. Sham mice (n = 8) were not subjected to MI, or the transplantation of PICs or PBS. BrdU was administered via osmotic mini-pump for 14 days. Echocardiography was performed prior to surgery (baseline), and 1-, 3- and 6-weeks post-MI and PICs transplantation. Mice were sacrificed at 6 weeks post-MI + PICs transplantation, and heart sections were analysed for fibrosis, hypertrophy, engraftment, proliferation, and differentiation of PICs. A significant (\u1d631 < 0.05) improvement in ejection fraction (EF) and fractional shortening was observed in the MI-PICs group, compared to MI + PBS group at 6-weeks post MI + PICs transplantation. Infarct size/fibrosis of the left ventricle significantly (\u1d631 < 0.05) decreased in the MI-PICs group (14.0 ± 2.5%), compared to the MI-PBS group (32.8 ± 2.2%). Cardiomyocyte hypertrophy in the border zone significantly (\u1d631 < 0.05) decreased in the MI-PICs group compared to the MI-PBS group (330.0 ± 28.5 µM2 vs. 543.5 ± 26.6 µm2), as did cardiomyocyte apoptosis (0.6 ± 0.9% MI-PICs vs. 2.8 ± 0.8% MI-PBS). The number of BrdU+ cardiomyocytes was significantly (\u1d631 < 0.05) increased in the infarct/border zone of the MI-PICs group (7.0 ± 3.3%), compared to the MI-PBS group (1.7 ± 0.5%). The proliferation index (total BrdU+ cells) was significantly increased in the MI-PICs group compared to the MI-PBS group (27.0 ± 3.4% vs. 7.6 ± 1.0%). PICs expressed and secreted pro-survival and reparative growth factors, supporting a paracrine effect of PICs during recovery/remodeling. Skeletal muscle-derived PICs show significant reparative potential, attenuating cardiac remodelling following transplantation into the infarcted myocardium. PICs can be easily sourced from skeletal muscle and therefore show promise as a potential cell candidate for supporting the reparative and regenerative effects of cell therapie

Aged-senescent cells contribute to impaired heart regeneration

Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32-86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16INK4A , SA-β-gal, DNA damage γH2AX, telomere length, senescence-associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wild-type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67-, EdU-positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart

Thoracoscopic resection of a paraaortic bronchogenic cyst

Bronchogenic mediastinal cysts (BMC) represent 18% of primitive mediastinal tumors and the most frequent cystic lesions in this area. Nowadays, BMC are usually treated by VATS. However, the presence of major adhesions to vital structures is often considered as an unfavourable condition for thoracoscopic treatment. The authors report the thoracoscopic treatment of a BMC having dense adhesions to the aortic arch. Diagnosis and surgical treatment is described. Review of the literature and surgical options on this topic are discussed

Tipping the Balance: Robustness of Tip Cell Selection, Migration and Fusion in Angiogenesis

Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, ‘stabilised’ tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer

Alexithymia in juvenile primary headache sufferers: a pilot study

Starting in the 1990s, there has been accumulating evidence of alexithymic characteristics in adult patients with primary headache. Little research has been conducted, however, on the relationship between alexithymia and primary headache in developmental age. In their research on alexithymia in the formative years, the authors identified one of the most promising prospects for research, as discussed here. The aim of this study was to verify whether there is: (a) a link between tension-type headache and alexithymia in childhood and early adolescence; and (b) a correlation between alexithymia in children/preadolescents and their mothers. This study was based on an experimental group of 32 patients (26 females and 6 males, aged from 8 to 15 years, mean 11.2 ± 2.0) suffering from tension-type headache and 32 control subjects (26 females and 6 males, aged from 8 to 15 years, mean 11.8 ± 1.6). Tension-type headache was diagnosed by applying the International Headache Classification (ICHD-II, 2004). The alexithymic construct was measured using an Italian version of the Alexithymia Questionnaire for Children in the case of the juvenile patients and the Toronto Alexithymia Scale (TAS-20) for their mothers. Higher rates of alexithymia were observed in the children/preadolescents in the experimental group (EG) than in the control group; in the EG there was no significant correlation between the alexithymia rates in the children/preadolescents and in their mothers

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

n/

A search for the dimuon decay of the Standard Model Higgs boson with the ATLAS detector

A search for the dimuon decay of the Standard Model (SM) Higgs boson is performed using data corresponding to an integrated luminosity of 139 fb(-1) collected with the ATLAS detector in Run 2 pp collisions at root s = 13 TeV at the Large Hadron Collider. The observed (expected) significance over the background-only hypothesis for a Higgs boson with a mass of 125.09 GeV is 2.0 sigma (1.7 sigma). The observed upper limit on the cross section times branching ratio for pp -&gt; H -&gt; mu mu is 2.2 times the SM prediction at 95% confidence level, while the expected limit on a H -&gt; mu mu signal assuming the absence (presence) of a SM signal is 1.1(2.0). The best-fit value of the signal strength parameter, defined as the ratio of the observed signal yield to the one expected in the SM, is mu = 1.2 +/- 0.6. (C) 2020 The Author(s). Published by Elsevier B.V

Alignment of the ATLAS Inner Detector in Run 2

The performance of the ATLAS Inner Detector alignment has been studied using pp collision data at v s = 13 TeV collected by the ATLAS experiment during Run 2 (2015-2018) of the Large Hadron Collider (LHC). The goal of the detector alignment is to determine the detector geometry as accurately as possible and correct for time-dependent movements. The Inner Detector alignment is based on the minimization of track-hit residuals in a sequence of hierarchical levels, from global mechanical assembly structures to local sensors. Subsequent levels have increasing numbers of degrees of freedom; in total there are almost 750,000. The alignment determines detector geometry on both short and long timescales, where short timescales describe movementswithin anLHCfill. The performance and possible track parameter biases originating from systematic detector deformations are evaluated. Momentum biases are studied using resonances decaying to muons or to electrons. The residual sagitta bias and momentum scale bias after alignment are reduced to less than similar to 0.1 TeV-1 and 0.9 x 10(-3), respectively. Impact parameter biases are also evaluated using tracks within jets