STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes.

Epstein-Barr virus (EBV) causes lymphomas and epithelial cell cancers. Though generally silent in B lymphocytes, this widely prevalent virus can cause endemic Burkitt lymphoma and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. By learning how EBV breaches barriers to cell proliferation, we hope to undermine those strategies to treat EBV lymphomas and potentially other cancers. We had previously found that EBV, through activation of cellular STAT3 prevents phosphorylation of Chk1, and thereby, suppresses activation of the intra-S phase cell-cycle checkpoint, a potent barrier to oncogene-driven proliferation. This observation prompted us to examine the consequences on DNA repair since homologous recombination repair, the most error-free form, requires phosphoChk1. We now report that the defect in Chk1 phosphorylation also curtails RAD51 nucleation, and thereby, homologous recombination repair of DNA double strand breaks. The resulting reliance on error-prone microhomology-mediated end-joining (MMEJ) repair makes EBV-transformed cells susceptible to PARP inhibition and simultaneous accrual of genome-wide deletions and insertions resulting from synthesis-dependent MMEJ. Analysis of transcriptomic and drug susceptibility data from hundreds of cancer lines reveals a STAT3-dependent gene-set predictive of susceptibility of cancers to synthetic lethal PARP inhibition. These findings i) demonstrate how the tumor virus EBV re-shapes cellular DNA repair, ii) provide the first genome-wide evidence for insertions resulting from MMEJ in human cells, and iii) expand the range of cancers (EBV-related and -unrelated) that are likely to respond to synthetic lethal inhibitors given the high prevalence of cancers with constitutively active STAT3.

Metal-Oxide Based Nanomaterials: Synthesis, Characterization and Their Applications in Electrical and Electrochemical Sensors.

Pure, mixed and doped metal oxides (MOX) have attracted great interest for the development of electrical and electrochemical sensors since they are cheaper, faster, easier to operate and capable of online analysis and real-time identification. This review focuses on highly sensitive chemoresistive type sensors based on doped-SnO2, RhO, ZnO-Ca, Smx-CoFe2-xO4 semiconductors used to detect toxic gases (H2, CO, NO2) and volatile organic compounds (VOCs) (e.g., acetone, ethanol) in monitoring of gaseous markers in the breath of patients with specific pathologies and for environmental pollution control. Interesting results about the monitoring of biochemical substances as dopamine, epinephrine, serotonin and glucose have been also reported using electrochemical sensors based on hybrid MOX nanocomposite modified glassy carbon and screen-printed carbon electrodes. The fundamental sensing mechanisms and commercial limitations of the MOX-based electrical and electrochemical sensors are discussed providing research directions to bridge the existing gap between new sensing concepts and real-world analytical applications.

Anti-TNFα therapy for inflammatory bowel diseases is associated with Epstein-Barr virus lytic activation.

Anti-TNFα therapy, known to suppress T-cell immunity, is increasingly gaining popularity for treatment of autoimmune diseases including inflammatory bowel diseases (IBD). T-cell suppression increases the risk of B-cell EBV-lymphoproliferative diseases and lymphomas. Since EBV-lytic activation is essential for development of EBV-lymphomas and there have been reports of EBV-lymphomas in patients treated with anti-TNFα therapy, we investigated if patients treated with anti-TNFα antibodies demonstrate greater EBV-lytic activity in blood. Peripheral blood mononuclear cells from 10 IBD patients solely on anti-TNFα therapy compared to 3 control groups (10 IBD patients not on immunosuppressive therapy, 10 patients with abdominal pain but without IBD, and 10 healthy subjects) were examined for the percentage of T-cells, EBV load and EBV-lytic transcripts. Patients on anti-TNFα therapy had significantly fewer T-cells, greater EBV load, and increased levels of transcripts from EBV-lytic genes of all kinetic classes compared to controls. Furthermore, exposure of EBV-infected B-cell lines to anti-TNFα antibodies resulted in increased levels of BZLF1 mRNA; BZLF1 encodes for ZEBRA, the viral latency-to-lytic cycle switch. Thus, IBD patients treated with anti-TNFα antibodies have greater EBV loads likely due to enhanced EBV-lytic gene expression and anti-TNFα antibodies may be sufficient to activate the EBV lytic cycle. Findings from this pilot study lay the groundwork for additional scientific and clinical investigation into the effects of anti-TNFα therapy on the life cycle of EBV, a ubiquitous oncovirus that causes lymphomas in the setting of immunocompromise.

Nano-Hybrid Ag@LCCs Systems with Potential Wound-Healing Properties.

The synthesis of contaminant-free silver@linear carbon chains (Ag@LCCs) nanohybrid systems, at different Ag/LCCs ratios, by pulsed laser ablation was studied. The ablation products were first characterized by several diagnostic techniques: conventional UV-Vis optical absorption and micro-Raman spectroscopies, as well as scanning electron microscopy, operating in transmission mode. The experimental evidence was confirmed by the theoretical simulations' data. Furthermore, to gain a deeper insight into the factors influencing metal@LCCs biological responses in relation to their physical properties, in this work, we investigated the bioproperties of the Ag@LCCs nanosystems towards a wound-healing activity. We found that Ag@LCC nanohybrids maintain good antibacterial properties and possess a better capability, in comparison with Ag NPs, of interacting with mammalian cells, allowing us to hypothesize that mainly the Ag@LCCs 3:1 might be suitable for topical application in wound healing, independent of (or in addition to) the antibacterial effect.

Developing an eLearning tool formalizing in YAWL the guidelines used in a transfusion medicine service.

The blood transfusion is a complex activity subject to a high risk of eventually fatal errors. The development and application of computer-based systems could help reducing the error rate, playing a fundamental role in the improvement of the quality of care. This poster presents an under development eLearning tool formalizing the guidelines of the transfusion process. This system, implemented in YAWL (Yet Another Workflow Language), will be used to train the personnel in order to improve the efficiency of care and to reduce errors.

Evaluation of biological response induced by molybdenum oxide nanocolloids on in vitro cultured NIH/3T3 fibroblast cells by micro-Raman spectroscopy.

Tailored colloids of uniformly sized and engineered molybdenum oxide nanoparticles were produced, for the first time, by pulsed laser ablation in water. This green technique ensures the formation of contaminant-free nanostructures and the absence of by-products, very useful issues in biological applications. A selective tuning of MoO chemical bonding configurations and a suitable control of nanoparticles size distributions were achieved during the ablation processes by varying the water temperature and by applying an external electric field. The metal redox properties are fundamental factors governing both cell uptake and interaction mode with Mo oxide nanoparticles. Micro-Raman spectroscopy was used to investigate the existence of cellular changes induced by Mo oxide colloids on the fibroblast cell line NIH/3T3 in relation to the molecular vibrations due to proteins, lipids and nucleic acids. The label-free micro-Raman spectroscopy provides an easy and noninvasive method to monitor the harmful effect of toxic agents on cells through ROS production or redox-dependent mechanisms. In view of potential biological applications, molybdenum oxide nanoparticles cytotoxicity towards NIH/3T3 cells was also investigated. A statistical analysis shows that, in the 10-100 µg/mL Mo concentration range, all the colloids are cytotoxic, progressively reducing the cell viability down to 75% upon increasing the concentration. The effect is less pronounced for the oxygen deficient MoO3 samples where cell viability does not fall below 85%. These results open the way to identify potential bioactive products affecting cellular redox status, by using only the Raman spectral data, even before performing lengthy and expensive specific clinical analyses.

Engineering Structurally Interacting RNA (sxRNA).

RNA-based three-way junctions (3WJs) are naturally occurring structures found in many functional RNA molecules including rRNA, tRNA, snRNA and ribozymes. 3WJs are typically characterized as resulting from an RNA molecule folding back on itself in cis but could also form in trans when one RNA, for instance a microRNA binds to a second structured RNA, such as a mRNA. Trans-3WJs can influence the final shape of one or both of the RNA molecules and can thus provide a means for modulating the availability of regulatory motifs including potential protein or microRNA binding sites. Regulatory 3WJs generated in trans represent a newly identified regulatory category that we call structurally interacting RNA or sxRNA for convenience. Here we show that they can be rationally designed using familiar cis-3WJ examples as a guide. We demonstrate that an sxRNA "bait" sequence can be designed to interact with a specific microRNA "trigger" sequence, creating a regulatable RNA-binding protein motif that retains its functional activity. Further, we show that when placed downstream of a coding sequence, sxRNA can be used to switch "ON" translation of that sequence in the presence of the trigger microRNA and the amount of translation corresponded with the amount of microRNA present.

Urinary Schistosomiasis in an Adolescent Refugee from Africa: An Uncommon Cause of Hematuria and an Emerging Infectious Disease in Europe.

We report a case of urinary schistosomiasis in an adolescent refugee from Gambia (arrived to Italy illegally), who was brought to the Emergency Department of our hospital. The patient complained of gross hematuria and, in the absence of clinical evidence of bacterial urinary infection, was admitted to the pediatric ward, considering his provenience and social setting. An appropriate collection and microscopic analysis of urine samples led to the detection of bilharzia. Much attention should be paid to this emerging disease in Europe by physicians in order to recognize and treat it timely, which could prevent future and higher costs for public health systems and could reduce the potential risk of environmental spreading. In fact, there are some areas in Italy where the parasite can find its intermediate host to complete its lifecycle.

[Air pollution and cardiac and respiratory function in three groups of patients]. / Inquinamento atmosferico e funzionalità cardiaca e respiratoria in tre gruppi di pazienti.

The association between exposure to urban air pollution and cardiac or respiratory impairments in susceptible subjects was evaluated in a panel study including 11 patients with chronic obstructive pulmonary disease (COPD), 7 with ischemic heart disease (IHD), and 11 asthmatics resident in Rome (Italy). Patients underwent repeated 24 h Holter EKG monitoring, 12 h pulse oximetry at night and spirometry examinations during 1999 summer and winter. Multiple linear regression models for repeated individual measures (fixed-effect) were used to analyse the relationship between average daily concentrations of pollutants (PM10-2.5, PM2.5 NO2 and O3) and outcome variables, controlling for meteorological conditions, survey period, and week-ends. In the BPCO panel, increasing ambient PM2.5 levels were associated with increased heart rate and decreased respiratory function. In the asthmatic panel, inverse associations between pulmonary function and both NO2 and PM10-2.5 concentrations were observed, as well as direct association between ambient NO2 concentrations and NO in exhaled breath. In the IHD panel an increase of hearth rate variability associated with increasing concentration of PM2.5 was observed.

Effects of formoterol inhaled dry powder on exercise performance in chronic obstructive pulmonary disease: a single-center, randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: Inhaled bronchodilators commonly are used to reduce the work of breathing in patients with chronic obstructive pulmonary disease (COPD). The effects of bronchodilators are assessed in terms of symptom relief and/or improvements in spirometric indices. However, disability in COPD patients also is related to determinants such as exercise tolerance, which cannot be predicted on the basis of respiratory function. The effect of bronchodilators, such as inhaled beta2-agonists, on exercise performance of COPD patients needs to be tested. OBJECTIVE: This study investigated the effects of formoterol inhaled dry powder on exercise performance assessed using the shuttle walking test (SWT) in patients with mild to moderate COPD. METHODS: Patients having COPD with mild to moderate airway obstruction performed a pulmonary function test and an SWT before and after inhalation, on 2 consecutive days, of formoterol 12 µg or placebo, given by dry powder inhaler, according to a double-blind, placebo-controlled, crossover study design. Breathlessness was measured using the Borg scale (BS) and a visual analog scale at baseline and after an SWT. RESULTS: Twenty patients (15 men, 5 women; mean [SD] age, 65.95 [8.32] years) were included in the study. Forced expiratory volume in 1 second (FEV1) (P = 0.009), forced mid-expiratory flow (FEF25-75) (P = 0.011), and SWT (P = 0.005) improved significantly more with formoterol than placebo. Breathlessness decreased with formoterol, but the difference compared with placebo was statistically significant only when measured using the BS (P = 0.023). In the pooled placebo and formoterol tests, changes in the SWT were unrelated to changes in FEV1 (r = 0.18) and in FEF25-75 (r = 0.31). CONCLUSIONS: The results of this study showed that formoterol inhaled dry powder significantly improved exercise performance in patients with COPD and that this effect was at least partially independent of achieved bronchodilation. A larger cohort of patients should be studied and a more comprehensive protocol performed to verify whether the increase in exercise tolerance after administration of formoterol is related to a decrease in expiratory flow limitation during exercise and/or to systemic effects of the drug. Another issue to be clarified is whether the improvement in exercise capacity can significantly decrease disability in patients with severe COPD.

The dilemma of the symbols: analogies between philosophy, biology and artificial life.

This article analyzes some analogies going from Artificial Life questions about the symbol-matter connection to Artificial Intelligence questions about symbol-grounding. It focuses on the notion of the interpretability of syntax and how the symbols are integrated in a unity ("binding problem"). Utilizing the DNA code as a model, this paper discusses how syntactic features could be defined as high-grade characteristics of the non syntactic relations in a material-dynamic structure, by using an emergentist approach. This topic furnishes the ground for a confutation of J. Searle's statement that syntax is observer-relative, as he wrote in his book "Mind: A Brief Introduction". Moreover the evolving discussion also modifies the classic symbol-processing doctrine in the mind which Searle attacks as a strong AL argument, that life could be implemented in a computational mode. Lastly, this paper furnishes a new way of support for the autonomous systems thesis in Artificial Life and Artificial Intelligence, using, inter alia, the "adaptive resonance theory" (ART).