Persistent DNA damage-induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells

Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, they must be equipped with DNA damage responses able to maintain genomic integrity while ensuring their lifelong persistence. Evaluation of hMSC response to genotoxic insults is of great interest considering both their therapeutic potential and their physiological functions. This study aimed to investigate the response of human bone marrow MSCs to the genotoxic agent Actinomycin D (ActD), a well-known anti-tumour drug. We report that hMSCs react by undergoing premature senescence driven by a persistent DNA damage response activation, as hallmarked by inhibition of DNA synthesis, p21 and p16 protein expression, marked Senescent Associated β-galactosidase activity and enlarged γH2AX foci co-localizing with 53BP1 protein. Senescent hMSCs overexpress several senescence-associated secretory phenotype (SASP) genes and promote motility of lung tumour and osteosarcoma cell lines in vitro. Our findings disclose a multifaceted consequence of ActD treatment on hMSCs that on the one hand helps to preserve this stem cell pool and prevents damaged cells from undergoing neoplastic transformation, and on the other hand alters their functional effects on the surrounding tissue microenvironment in a way that might worsen their tumour-promoting behaviour

Peak nasal inspiratory flow and peak expiratory flow. Upright and sitting values in an adult population

Background: Nasal obstruction is correlated with a decreased quality of life . An easy way to evaluate nasal patency is the peak nasal inspiratory flow (PNIF) measurement. Normal PNIF values have been published by many authors. However, some authors evaluated volunteers in a sitting position, while others have measured PNIF values in standing volunteers. Body position has been shown to influence pulmonary function, with differences between sitting and upright positions. As nasal and pulmonary flows are strictly related, the present pilot study tried to establish whether PNIF/PEF changed with body position in adults. Methodology/Principal: PNIF and PEF were measured in sitting and standing positions with the order of testing randomized in 76 healthy volunteers, 30 male (40 ±16 years). Results: In the group as a whole between sitting and upright position, PEF was significantly different (p=0.009), while PNIF showed a trend towards a significant difference (p=0.10). Conclusions: The present study, although showing a generally positive effect of the standing position on PEF values, does not show a clear effect on PNIF

the event driven software library for yarp with algorithms and icub applications

Event-driven (ED) cameras are an emerging technology that sample the visual signal based on changes in the signal magnitude, rather than at a fixed-rate over time. The change in paradigm results in a camera with a lower latency, that uses less power, has reduced bandwidth, and higher dynamic range. Such cameras offer many potential advantages for on-line, autonomous, robots; however the sensor data does not directly integrate with current "image-based" frameworks and software libraries. The iCub robot uses Yet Another Robot Platform (YARP) as middleware to provide modular processing and connectivity to sensors and actuators. This paper introduces a library that incorporates an event-based framework into the YARP architecture, allowing event cameras to be used with the iCub (and other YARP-based) robots. We describe the philosophy and methods for structuring events to facilitate processing, while maintaining low-latency and real-time operation. We also describe several processing modules made available open-source, and three example demonstrations that can be run on the neuromorphic iCub

Aurora Kinase A expression is associated with lung cancer histological-subtypes and with tumor de-differentiation

<p>Abstract</p> <p>Background</p> <p>Aurora kinase A (<it>AURKA</it>) is a member of serine/threonine kinase family. Several kinases belonging to this family are activated in the G2/M phase of the cell cycle being involved in mitotic chromosomal segregation. <it>AURKA </it>overexpression is significantly associated with neoplastic transformation in several tumors and deregulated <it>Aurora Kinases </it>expression leads to chromosome instability, thus contributing to cancer progression. The purpose of the present study was to investigate the expression of <it>AURKA </it>in non small cell lung cancer (NSCLC) specimens and to correlate its mRNA or protein expression with patients' clinico-pathological features.</p> <p>Materials and methods</p> <p>Quantitative real-time PCR and immunohistochemistry analysis on matched cancer and corresponding normal tissues from surgically resected non-small cell lung cancers (NSCLC) have been performed aiming to explore the expression levels of <it>AURKA </it>gene.</p> <p>Results</p> <p><it>AURKA </it>expression was significantly up-modulated in tumor samples compared to matched lung tissue (p < 0.01, mean log2(FC) = 1.5). Moreover, <it>AURKA </it>was principally up-modulated in moderately and poorly differentiated lung cancers (p < 0.01), as well as in squamous and adenocarcinomas compared to the non-invasive bronchioloalveolar histotype (p = 0.029). No correlation with survival was observed.</p> <p>Conclusion</p> <p>These results indicate that in NSCLC <it>AURKA </it>over-expression is restricted to specific subtypes and poorly differentiated tumors.</p

Dasatinib modulates sensitivity to pemetrexed in malignant pleural mesothelioma cell lines

BACKGROUND: Thymidylate synthase (TS), one of the key enzymes for thymidine synthesis, is a target of pemetrexed (PEM), a key agent for the systemic therapy of malignant pleural mesothelioma (MPM) and its overexpression has been correlated to PEM-resistance. In MPM, experimental data report activation of the c-SRC tyrosine kinase suggesting it as a potential target to be further investigated. RESULTS: MPM cell lines showed different sensitivity, being MSTO the most and REN the least sensitive to PEM. REN cells showed high levels of both TS and SRC: dasatinib inhibited SRC activation and suppressed TS protein expression, starting from 100 nM dose, blocking the PEM-induced up regulation of TS protein levels. Dasatinib treatment impaired cells migration, and both sequential and co-administration with PEM significantly increased apoptosis. Dasatinib pretreatment improved sensitivity to PEM, downregulated TS promoter activity and, in association with PEM, modulated the downstream PI3K-Akt-mTOR signaling. CELL LINES AND METHODS: In three MPM cell lines (MPP89, REN and MSTO), the effects of c-SRC inhibition, in correlation with TS expression and PEM sensitivity, were evaluated. PEM and dasatinib, a SRC inhibitor, were administered as single agents, in combination or sequentially. Cell viability, apoptosis and migration, as well as TS expression and SRC activation have been assessed. CONCLUSIONS: These data indicate that dasatinib sensitizes mesothelioma cells to PEM through TS down-regulation

Retrospective study testing next generation sequencing of selected cancer-associated genes in resected prostate cancer

PURPOSE: Prostate cancer (PCa) has a highly heterogeneous outcome. Beyond Gleason Score, Prostate Serum Antigen and tumor stage, nowadays there are no biological prognostic factors to discriminate between indolent and aggressive tumors. The most common known genomic alterations are the TMPRSS-ETS translocation and mutations in the PI3K, MAPK pathways and in p53, RB and c-MYC genes. The aim of this retrospective study was to identify by next generation sequencing the most frequent genetic variations (GVs) in localized and locally advanced PCa underwent prostatectomy and to investigate their correlation with clinical-pathological variables and disease progression. RESULTS: Identified non-synonymous GVs included TP53 p.P72R (78% of tumors), two CSFR1 SNPs, rs2066934 and rs2066933 (70%), KDR p.Q472H (67%), KIT p.M541L (28%), PIK3CA p.I391M (19%), MET p.V378I (10%) and FGFR3 p.F384L/p.F386L (8%). TP53 p.P72R, MET p.V378I and CSFR1 SNPs were significantly associated with the HI risk group, TP53 and MET variations with T≥T2c. FGFR3 p.F384L/p.F386L was correlated with T≤T2b. MET p.V378I mutation, detected in 20% of HI risk patients, was associated with early biochemical recurrence. EXPERIMENTAL DESIGN: Nucleic acids were obtained from tissue samples of 30 high (HI) and 30 low-intermediate (LM) risk patients, according to D'Amico criteria. Genomic DNA was explored with the Ion_AmpliSeq_Cancer_Hotspot_Panel_v.2 including 50 cancer-associated genes. GVs with allelic frequency (AF) ≥10%, affecting protein function or previously associated with cancer, were correlated with clinical-pathological variables. CONCLUSION: Our results confirm a complex mutational profile in PCa, supporting the involvement of TP53, MET, FGFR3, CSF1R GVs in tumor progression and aggressiveness

Effect of Aqueous Extract of Maca Addition to an Extender for Chilled Canine Semen

Antioxidant supplementation has been proposed as a new strategy to improve the long-term preservation of semen. The aim of this study was to evaluate the effect of Maca supplementation of semen extender on quality-related canine semen parameters during cooling. Ejaculates from nine dogs were cooled for 7 days in the absence (control group) or in the presence of 10, 20 and 50 μL/mL of an aqueous extract of Maca. Sperm were evaluated for sperm viability, motility, DNA fragmentation and lipid peroxidation after 3 h, 24 h, 4 days and 7 days of storage. The addition of 10 μL/mL of Maca preserved sperm DNA and plasma membrane integrity at 3 h and increased sperm curvilinear velocity after 24 h. Treatment with 20 and 50 μL/mL of Maca increased the percentage of hyperactivated sperm after 3 h. Moreover, semen treated with 20 μL/mL of Maca decreased lipid peroxidation at 24 h. A significant reduction of sperm DNA and plasma membrane integrity as well as of kinetics parameters between 3 and 24 h of refrigerated storage with the higher concentration tested was observed. Although Maca was not able to protect canine semen with extended refrigeration storage time, it increased hyperactivation and preserved DNA integrity in short-term storage

Oligo-antigenic diet in the treatment of chronic anal fissures. Evidence for a relationship between food hypersensitivity and anal fissures.

Abstract OBJECTIVES: Patients with chronic constipation due to food hypersensitivity (FH) had an elevated anal sphincter resting pressure. No studies have investigated a possible role of FH in anal fissures (AFs). We aimed to evaluate (1) the effectiveness of diet in curing AFs and to evaluate (2) the clinical effects of a double-blind placebo-controlled (DBPC) challenge, using cow's milk protein or wheat. METHODS: One hundred and sixty-one patients with AFs were randomized to receive a "true-elimination diet" or a "sham-elimination diet" for 8 weeks; both groups also received topical nifedipine and lidocaine. Sixty patients who were cured with the "true-elimination diet" underwent DBPC challenge in which cow's milk and wheat were used. RESULTS: At the end of the study, 69% of the "true-diet group" and 45% of the "sham-diet group" showed complete healing of AFs (P<0.0002). Thirteen of the 60 patients had AF recurrence during the 2-week cow's milk DBPC challenge and 7 patients had AF recurrence on wheat challenge. At the end of the challenge, anal sphincter resting pressure significantly increased in the patients who showed AF reappearance (P<0.0001), compared with the baseline values. The patients who reacted to the challenges had a significantly higher number of eosinophils in the lamina propria and intraepithelial lymphocytes than those who did not react to the challenges. CONCLUSIONS: An oligo-antigenic diet combined with medical treatment improved the rate of chronic AF healing. In more than 20% of the patients receiving medical and dietary treatment, AFs recurred on DBPC food challenge