The identification of target mRNAs is a key step for assessing the role of aberrantly expressed microRNAs in human cancer. MiR-221 is upregulated in human hepatocellular carcinoma (HCC) as well as in ...other malignancies. One proven target of miR-221 is CDKN1B/p27, whose downregulation affects HCC prognosis. Here, we proved that the cyclin-dependent kinase inhibitor (CDKI) CDKN1C/p57 is also a direct target of miR-221. Indeed, downregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to miR-221 transfection into HCC-derived cells and a significant upregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to antimiR-221 transfection. A direct interaction of miR-221 with a target site on the 3' UTR of CDKN1C/p57 mRNA was also demonstrated. By controlling these two CDKIs, upregulation of miR-221 can promote growth of HCC cells by increasing the number of cells in S-phase. To assess the relevance of these studies in primary tumors, matched HCC and cirrhosis samples were assayed for miR-221, for CDKN1B/p27 and CDKN1C/p57 expression. MiR-221 was upregulated in 71% of HCCs, whereas CDKN1B/p27 and CDKN1C/p57 proteins were downregulated in 77% of cases. A significant inverse correlation between miR-221 and both CDKN1B/p27 and CDKN1C/p57 was found in HCCs. In conclusion, we suggest that miR-221 has an oncogenic function in hepatocarcinogenesis by targeting CDKN1B/p27 and CDKN1C/p57, hence promoting proliferation by controlling cell-cycle inhibitors. These findings establish a basis toward the development of therapeutic strategies aimed at blocking miR-221 in HCC.
The occurrence of emerging contaminants is becoming of increasing importance to assess the impact of anthropogenic activities onto the environment. The present study reports for the first time the ...development and validation of an efficient method for the simultaneous determination of fragrance materials in water samples based on the use of a novel multiwalled carbon nanotubes (MWCNTs)-based solid-phase microextraction coating. Helical MWCNTs were selected as adsorbent material due to their outstanding extraction performance. The multicriteria method of desirability functions allowed the optimization of the experimental conditions in terms of extraction time and extraction temperature. Validation proved the reliability of the method for the determination of the analytes at ultra-trace levels, obtaining detection limits in the 0.2–13 ng/L range, good precision, with relative standard deviations lower than 20% and recovery rates in the 80 ± 12%–111 ± 11%. Superior enrichment factors compared to commercial fibers were also calculated. Finally, applicability to real sample analysis was demonstrated.
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•Efficient SPME-GC-MS method for trace analysis of fragrance materials in water.•Helical carbon nanotubes-based SPME coating for efficient fragrances extraction.•Completely automatized method requiring reduced sample handling and volumes.•Detection and quantitation limits at low ng/l levels.
Many drugs currently used in chemotherapy work by hindering the process of ribosome biogenesis. In tumors with functional p53, the inhibition of ribosome biogenesis may contribute to the efficacy of ...this treatment by inducing p53 stabilization. As the level of stabilized p53 is critical for the induction of cytotoxic effects, it seems useful to highlight those cancer cell characteristics that can predict the degree of p53 stabilization following the treatment with inhibitors of ribosome biogenesis. In the present study we exposed a series of p53 wild-type human cancer cell lines to drugs such as actinomycin D (ActD), doxorubicin, 5-fluorouracil and CX-5461, which hinder ribosomal RNA (rRNA) synthesis. We found that the amount of stabilized p53 was directly related to the level of ribosome biogenesis in cells before the drug treatment. This was due to different levels of inactivation of the ribosomal proteins-MDM2 pathway of p53 digestion. Inhibition of rRNA synthesis always caused cell cycle arrest, independent of the ribosome biogenesis rate of the cells, whereas apoptosis occurred only in cells with a high rDNA transcription rate. The level of p53 stabilization induced by drugs acting in different ways from the inhibition of ribosome biogenesis, such as hydroxyurea (HU) and nutlin-3, was independent of the level of ribosome biogenesis in cells and always lower than that occurring after the inhibition of rRNA synthesis. Interestingly, in cells with a low ribosome biogenesis rate, the combined treatment with ActD and HU exerted an additive effect on p53 stabilization. These results indicated that (i) drugs inhibiting ribosome biogenesis may be highly effective in p53 wild-type cancers with a high ribosome biogenesis rate, as they induce apoptotic cell death, and (ii) the combination of drugs capable of stabilizing p53 through different mechanisms may be useful for treating cancers with a low ribosome biogenesis rate.
Multiple rapid swallowing (MRS) stimulates neural inhibition resulting in abolition of contractions in the oesophageal body (OB) and complete lower oesophageal sphincter (LOS) relaxation which is ...followed by peristalsis and LOS contraction. The aim of this study was to evaluate the yield of MRS to detect abnormalities in inhibitory or excitatory oesophageal mechanisms in patients with oesophageal symptoms and either normal standard manometry or ineffective oesophageal motility (IOM). MRS (five water swallows, 2 mL, separated by 2–3 s) was evaluated in 23 healthy subjects, 109 symptomatic patients with normal standard sleeve manometry and in 48 patients with IOM. Healthy subjects had complete inhibition of OB motility during MRS and a strong motor response after MRS, i.e. amplitude of OB contractions in the oesophageal body and LOS tone being higher than after single swallows. Almost 70% of patients with oesophageal symptoms and normal manometry had abnormal MRS, mainly consistent on inability to increase amplitude of OB contractions after MRS. Nearly, half of the patients with IOM were able to normalize OB contractions after MRS. MRS is a simple complementary test that can be added to standard oesophageal manometry. Two‐thirds of patients with normal manometry show abnormal MRS that could potentially underlie their symptoms. A normal response to MRS in patients with severe IOM might be used to predict response to prokinetic treatment.
•We focused on the quality of public schools in Rome in terms of energy consumption.•We analyze consistency of existing school buildings.•The study evaluates the energy efficiency of envelopes and ...thermal plants.•We compare measured consumptions and theoretical consumptions.•The study defines the reasons of an urgent action of refurbishment.
The aim of this paper is to assess the quality of public schools in Rome in order to create a good database as a first-step in defining possible intervention strategies to reduce energy consumption in this sector. The urgency is not only determined by the criticality of the current situation but also by the observation of how a very important voice of losses is related to inefficiencies in the management of buildings and plants that can be easily overcome with simple and low cost actions.
The measures adopted to reduce consumption in school building sector were defined according to the dimensional, technological and architectural features of the schools. The analysis was performed by comparing the costs parameterized for standard retrofit interventions for the existing envelopes and plants to the benefits achievable by the interventions in terms of energy and money saving through a simple payback time analysis (PBT) useful to identify priorities for action. Finally, it has been estimated the environmental benefit achievable in 20 years through a spread action of refurbishment on plants and on envelopes.
Severe duodeno-gastro-oesophageal reflux (DGOR) is a risk factor for oesophagitis and Barrett's oesophagus. Patients with non-erosive reflux disease (NERD) have a slight increase in DGOR. Patients ...with gastro-oesophageal reflux disease (GORD), who are taking proton pump inhibitors (PPIs), still have reflux but of weakly acidic pH and persistence of bile. In these two groups of patients, heartburn might be due to increased oesophageal mucosal permeability and dilated intercellular spaces (DIS). We aimed to assess whether experimental short exposure of the oesophageal mucosa to bile acids, in low concentrations (at acidic, weakly acidic and neutral conditions) can increase mucosal permeability and provoke DIS.
Rabbit oesophageal mucosa was studied in diffusion and Ussing chambers. We assessed the effects of different solutions containing bile acids, applied to the mucosal side, on transepithelial electrical resistance (R(T)) and permeability to fluorescein. The diameter of intercellular spaces was assessed by using transmission electron microscopy.
Incubation of oesophageal mucosa with acidic solutions (pH 2.0) containing a range of bile acids (0.5-5 mmol/l) markedly decreased R(T) and increased mucosal permeability. Weakly acidic solutions (pH 5.0), and to some extent neutral solutions (pH 7.4), containing some bile acids also decreased R(T) and increased permeability, although the effects were much less marked and in some combinations no effect was seen. Exposure to bile acids provoked DIS in acid and weakly acidic conditions but not in neutral (pH 7.4) solutions.
Experimental short exposure of the oesophageal mucosa to solutions with a bile acid concentration and acidity similar to that observed in the gastric contents of patients with NERD or ERD, and who are taking PPIs, may impair oesophageal mucosal integrity and even induce dilated intercellular spaces. Such a situation could, theoretically, underlie the occurrence and/or persistence of symptoms in these patients.
In this crossover trial, we evaluated a new technique for enteral nutrition using orogastric intubation. Twelve volunteers were randomly assigned to both orogastric (OGI) and conventional nasogastric ...intubation (NGI) with a 15-day interval. The tip of the orogastric tube was fixed intraorally into an upper molar. Participants were asked to remain intubated for 24 hours and rated efficacy and safety using a Likert scale (1: worst / 10: best). Tolerance in hours was longer during OGI (median 21 versus 12.5; p=0.022). OGI was superior in comfort (median 7 versus 3; p=0.002), aesthetic (median 10 versus 1; p=0.002), speech (median 5.5 versus 3; p=0.014) and swallowing (median 8 versus 2; p=0.004). Both procedures were tolerated with mild local complaints. Diet volume through the tube was greater during NGI (p = 0.014). In healthy participants, orogastric intubation with dental fixation showed greater efficacy and similar safety to nasogastric intubation.
NCT03670238.
The INFN Tier-1 datacentre provides computing resources to several HEP and Astrophysics experiments. These are organized in Virtual Organizations submitting jobs to our computing facilities through ...Computing Elements, acting as Grid interfaces to the Local Resource Manager. We are phasing-out our current LRMS (IBM/Platform LSF 9.1.3) and CEs (CREAM) set to adopt HTCondor as a replacement for LSF and HTCondor-CE in place of CREAM. A small instance has been set up to practice with the cluster management and evaluate the feasibility of our migration plans to a new LRMS and CE set. A second cluster instance has been setup to work on production. A number of management tools have been adapted or rewritten in order to integrate the new system with the existing infrastructure. Two different accounting solution for the HTCondor-CE have been implemented, and the more reliable one have been adopted. A python tool has been written to disentangle the management of HTCondor machines from our puppet instance, and to enable a quicker configuration of the cluster nodes. The monitoring tools tied to the old system are being adapted to also work on the new one. Finally, the most relevant setup steps have been documented in a public wiki page and a support mailing has been created to help other INFN sites willing to migrate their LRMS and CE to HTCondor. This document reports about our experience with HTCondor-CE on top of HTCondor and the integration of this system into our infrastructure.
To evaluate the usefulness of percutaneous radio-frequency (RF) thermal ablation of nonresectable hepatocellular carcinoma (HCC) after occlusion of the tumor arterial supply.
Sixty-two patients with ...cirrhosis and biopsy-proved HCC underwent RF ablation after interruption of the tumor arterial supply by means of occlusion of either the hepatic artery with a balloon catheter (40 patients) or the feeding arteries with gelatin sponge particles (22 patients).
After a single RF procedure in 56 patients and after two procedures in six patients, spiral computed tomography (CT) demonstrated a nonenhancing area corresponding in shape to the previously identified HCC, which was suggestive of complete necrosis. No major complications occurred. Two patients subsequently underwent surgical resection; the remaining 60 patients were followed up with spiral CT. During a mean follow-up of 12.1 months, 11 HCC nodules showed areas of local progression; 49 were identified as nonenhancing areas with a 40%-75% reduction in maximum diameter. The 1-year estimate of failure risk was 19% for local recurrence and 45% for overall intrahepatic recurrence. The estimated 1-year survival was 87%. Histopathologic analysis of one autopsy and two surgical specimens revealed more than 90% necrosis in one specimen and 100% necrosis in two.
HCC nodules 3.5-8.5 cm in diameter can be ablated in one or two RF sessions after occlusion of the tumor arterial supply.
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