Elongation Factor TFIIS Prevents Transcription Stress and R-Loop Accumulation to Maintain Genome Stability

Although correlations between RNA polymerase II (RNAPII) transcription stress, R-loops, and genome instability have been established, the mechanisms underlying these connections remain poorly understood. Here, we used a mutant version of the transcription elongation factor TFIIS (TFIISmut), aiming to specifically induce increased levels of RNAPII pausing, arrest, and/or backtracking in human cells. Indeed, TFIISmut expression results in slower elongation rates, relative depletion of polymerases from the end of genes, and increased levels of stopped RNAPII; it affects mRNA splicing and termination as well. Remarkably, TFIISmut expression also dramatically increases R-loops, which may form at the anterior end of backtracked RNAPII and trigger genome instability, including DNA strand breaks. These results shed light on the relationship between transcription stress and R-loops and suggest that different classes of R-loops may exist, potentially with distinct consequences for genome stability.Cancer Research UK FC001166UK Medical Research Council FC001166Wellcome Trust FC001166European Research Council 693327, ERC2014 AdG669898Ministerio de Economía y Competitividad BFU2013-42918-P, BFU2016-75058-

AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells

PPARαs are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc.) used to treat hyperlipidemia. Since PPARα transcriptional activity can be negatively regulated by JNK, the inhibition of JNK activity could increase the effectiveness of PPARα ligands. We analysed the effects of AS601245 (a JNK inhibitor) and clofibrate alone or in association, on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Proliferation was inhibited in a dose-dependent way by clofibrate and AS601245. Combined treatment synergistically reduced cell proliferation, cyclin D1 and PCNA expression and induced apoptosis and differentiation. Reduction of cell proliferation, accompanied by the modulation of p21 expression was observed in HepG2 cells, also. Gene expression analysis revealed that some genes were highly modulated by the combined treatment and 28 genes containing PPRE were up-regulated, while clofibrate alone was ineffective. Moreover, STAT3 signalling was strongly reduced by combined treatment. After combined treatment, the binding of PPARα to PPRE increased and paralleled with the expression of the PPAR coactivator MED1. Results demonstrate that combined treatment increases the effectiveness of both compounds and suggest a positive interaction between PPARα ligands and anti-inflammatory agents in humans

Correlation of NM23-H1 cytoplasmic expression with metastatic stage in human prostate cancer tissue

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SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)

The increasing number of examinations and interventional radiological procedures that require the administration of contrast medium (CM) in patients at risk for advanced age and/or comorbidities highlights the problem of CM-induced renal toxicity. A multidisciplinary group consisting of specialists of different disciplines-radiologists, nephrologists and oncologists, members of the respective Italian Scientific Societies-agreed to draw up this position paper, to assist clinicians increasingly facing the challenges posed by CM-related renal dysfunction in their daily clinical practice.The major risk factor for acute renal failure following CM administration (post-CM AKI) is the preexistence of renal failure, particularly when associated with diabetes, heart failure or cancer.In accordance with the recent guidelines ESUR, the present document reaffirms the importance of renal risk assessment through the evaluation of the renal function (eGFR) measured on serum creatinine and defines the renal risk cutoff when the eGFR is < 30 ml/min/1.73 m2 for procedures with intravenous (i.v.) or intra-arterial (i.a.) administration of CM with renal contact at the second passage (i.e., after CM dilution with the passage into the pulmonary circulation).The cutoff of renal risk is considered an eGFR < 45 ml/min/1.73 m2 in patients undergoing i.a. administration with first-pass renal contact (CM injected directly into the renal arteries or in the arterial district upstream of the renal circulation) or in particularly unstable patients such as those admitted to the ICU.Intravenous hydration using either saline or Na bicarbonate solution before and after CM administration represents the most effective preventive measure in patients at risk of post-CM AKI. In the case of urgency, the infusion of 1.4% sodium bicarbonate pre- and post-CM may be more appropriate than the administration of saline.In cancer patients undergoing computed tomography, pre- and post-CM hydration should be performed when the eGFR is < 30 ml/min/1.73 m2 and it is also advisable to maintain a 5 to 7 days interval with respect to the administration of cisplatin and to wait 14 days before administering zoledronic acid.In patients with more severe renal risk (i.e., with eGFR < 20 ml/min/1.73 m2), particularly if undergoing cardiological interventional procedures, the prevention of post-CM AKI should be implemented through an internal protocol shared between the specialists who treat the patient.In magnetic resonance imaging (MRI) using gadolinium CM, there is a lower risk of AKI than with iodinated CM, particularly if doses < 0.1 mmol/kg body weight are used and in patients with eGFR > 30 ml/min/1.73 m2. Dialysis after MRI is indicated only in patients already undergoing chronic dialysis treatment to reduce the potential risk of systemic nephrogenic fibrosis

L'applicazione delle "Linee guida" del progetto europeo COME-IN! Cooperazione per una piena accessibilit\ue0 ai musei - verso una maggiore inclusione. L'esempio del Museo Archeologico di Udine

Dal 2014 il Museo Archeologico di Udine ha iniziato un percorso orientato all’accessibilità della struttura museale, degli allestimenti e delle iniziative culturali organizzate, che è approdato, grazie ai finanziamenti del progetto europeo COME-IN! ad una nuova fase di rivisitazione in termini di accessibilità e inclusività. Questo processo ha riguardato non solo l’allestimento del Museo Archeologico, inaugurato nel 2013, ma ha interessato l’intera struttura e in generale i servizi forniti dai Civici Musei di Udine. L’obiettivo di inserire in maniera armoniosa ed equilibrata tutti gli interventi previsti da progetto si è concretizzato nel coinvolgimento di professionisti e associazioni che hanno collaborato in base alle proprie competenz

MET inhibition sensitizes rhabdomyosarcoma cells to NOTCH signaling suppression

Rhabdomyosarcoma (RMS) is a pediatric myogenic soft tissue sarcoma. The Fusion-Positive (FP) subtype expresses the chimeric protein PAX3-FOXO1 (P3F) while the Fusion-Negative (FN) is devoid of any gene translocation. FP-RMS and metastatic FN-RMS are often unresponsive to conventional therapy. Therefore, novel therapeutic approaches are needed to halt tumor progression. NOTCH signaling has oncogenic functions in RMS and its pharmacologic inhibition through gamma-secretase inhibitors blocks tumor growth in vitro and in vivo. Here, we show that NOTCH signaling blockade resulted in the up-regulation and phosphorylation of the MET oncogene in both RH30 (FP-RMS) and RD (FN-RMS) cell lines. Pharmacologic inhibition of either NOTCH or MET signaling slowed proliferation and restrained cell survival compared to control cells partly by increasing Annexin V and CASP3/7 activation. Co-treatment with NOTCH and MET inhibitors significantly amplified these effects and enhanced PARP1 cleavage in both cell lines. Moreover, it severely hampered cell migration, colony formation, and anchorage-independent growth compared to single-agent treatments in both cell lines and significantly prevented the growth of FN-RMS cells grown as spheroids. Collectively, our results unveil the overexpression of the MET oncogene by NOTCH signaling targeting in RMS cells and show that MET pathway blockade sensitizes them to NOTCH inhibition

Contributi alla flora vascolare di Toscana. VII (357-439)

New localities and/or confirmations concerning 83 specific and subspecific plant taxa of Tuscan vascular flora, belonging to 71 genera and 33 families are presented: Carpobrotus (Aizoaceae), Alternanthera (Amaranthaceae), Leucojum (Amaryllidaceae), Anacyclus, Andryala, Carduus, Centaurea, Cichorium, Erigeron, Helichrysum, Helminthotheca, Hieracium, Limbarda, Pilosella, Scolymus, Sonchus, Tagetes, Urospermum, Xanthium (Asteraceae), Mahonia (Berberidaceae), Myosotis (Boraginaceae), Biscutella, Ionopsidium, Raphanus, Rapistrum (Brassicaceae), Buxus (Buxaceae), Vaccaria (Caryophyllaceae), Cistus (Cistaceae), Calystegia, Cuscuta (Convolvulaceae), Cymodocea (Cymodoceaceae), Cyperus (Cyperaceae), Amorpha, Emerus, Lathyrus, Lotus, Ononis, Trifolium, Vicia (Fabaceae), Quercus (Fagaceae), Geranium (Geraniaceae), Myriophyllum (Haloragaceae), Malva (Malvaceae), Epipogium, Himantoglossum (Orchidaceae), Orobanche (Orobanchaceae), Osyris (Santalaceae), Oxalis (Oxalidaceae), Pinus (Pinaceae), Anisantha, Avellinia, Avena, Corynephorus, Crypsis, Cutandia, Elytrigia, Lolium, Panicum, Polypogon, Sporobolus (Poaceae), Rumex (Polygonaceae), Lysimachia (Primulaceae), Eranthis, Ranunculus (Ranunculaceae), Rubus (Rosaceae), Crucianella, Galium (Rubiaceae), Verbascum (Scrophulariaceae), Solanum (Solanaceae), Tamarix (Tamaricaceae), Viola (Violaceae). In the end, the conservation status of the units and eventual protection of the cited biotopes are discussed

Notulae to the Italian native vascular flora: 10

In this contribution, new data concerning the distribution of native vascular flora in Italy are presented. It includes new records, confirmations, exclusions, and status changes to the Italian administrative regions for taxa in the genera Artemisia, Chaetonychia, Cirsium, Cynanchum, Genista, Hieracium, Iberis, Melica, Misopates, Myosotis, Thalictrum, Trifolium, Utricularia, Veronica, and Vicia. Nomenclatural and distribution updates, published elsewhere, and corrigenda are provided as supplementary material

Results of the first European Source Apportionment intercomparison for Receptor and Chemical Transport Models

In this study, the performance of the source apportionment model applications were evaluated by comparing the model results provided by 44 participants adopting a methodology based on performance indicators: z-scores and RMSEu, with pre-established acceptability criteria. Involving models based on completely different and independent input data, such as receptor models (RMs) and chemical transport models (CTMs), provided a unique opportunity to cross-validate them. In addition, comparing the modelled source chemical profiles, with those measured directly at the source contributed to corroborate the chemical profile of the tested model results. The most used RM was EPA- PMF5. RMs showed very good performance for the overall dataset (91% of z-scores accepted) and more difficulties are observed with SCE time series (72% of RMSEu accepted). Industry resulted the most problematic source for RMs due to the high variability among participants. Also the results obtained with CTMs were quite comparable to their ensemble reference using all models for the overall average (>92% of successful z-scores) while the comparability of the time series is more problematic (between 58% and 77% of the candidates’ RMSEu are accepted). In the CTM models a gap was observed between the sum of source contributions and the gravimetric PM10 mass likely due to PM underestimation in the base case. Interestingly, when only the tagged species CTM results were used in the reference, the differences between the two CTM approaches (brute force and tagged species) were evident. In this case the percentage of candidates passing the z-score and RMSEu tests were only 50% and 86%, respectively. CTMs showed good comparability with RMs for the overall dataset (83% of the z-scores accepted), more differences were observed when dealing with the time series of the single source categories. In this case the share of successful RMSEu was in the range 25% - 34%.JRC.C.5-Air and Climat

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

<p>Abstract</p> <p>Background</p> <p>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.</p> <p>Methods/Design</p> <p>The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.</p> <p>Discussion</p> <p>The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p