We investigated the ability of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) to interact with gemcitabine (GEM) in inducing pancreatic cancer cell death. The combined treatment with TSA and GEM synergistically inhibited growth of four pancreatic adenocarcinoma cell lines and induced apoptosis. This effect was associated with the induction of reactive oxygen species (ROS) by GEM, increased expression of the pro-apoptotic BIM gene by both TSA and GEM and downregulation of the 5'-nucleotidase UMPH type II gene by TSA. The expression of other genes critical for GEM resistance (nucleoside transporters, deoxycytidine kinase, cytidine deaminase, and ribonucleotide reductase genes) was not affected by TSA. The functional role of ROS in cell growth inhibition by GEM was supported by (i) a significantly reduced GEM-associated growth inhibition by the free radical scavenger N-acetyl-L-cysteine, and (ii) a positive correlation between the basal level of ROS and sensitivity to GEM in 10 pancreatic cancer cell lines. The functional role of both Bim and 5'-nucleotidase UMPH type II in cell growth inhibition by TSA and GEM was assessed by RNA interference assays. In vivo studies on xenografts of pancreatic adenocarcinoma cells in nude mice showed that the association of TSA and GEM reduced to 50% the tumour mass and did not cause any apparent form of toxicity, while treatments with TSA or GEM alone were ineffective. In conclusion, the present study demonstrates a potent anti-tumour activity of TSA/GEM combination against pancreatic cancer cells in vitro and in vivo, strongly supporting the use of GEM in combination with an HDAC inhibitor for pancreatic cancer therapy.
The aim of the study was to verify whether antibiotics excreted by the normal pancreas are also excreted in human necrotizing pancreatitis, reaching the tissue sites of the infection. Twelve patients suffering from acute necrotizing pancreatitis were treated with imipenem-cilastatin (0.5 g), mezlocillin (2 g), gentamicin (0.08 g), amikacin (0.5 g), pefloxacin (0.4 g), and metronidazole (0.5 g). Serum and necrotic samples were collected simultaneously at diferent time intervals after parenteral drug administration by computed tomographyguided needle aspiration, intraoperatively, and from surgical drainages placed during surgery. Drug concentrations were determined by microbiological and high-performance liquid chromatography assays. All antibiotics reached the necrotic tissues, but with varying degrees of penetration, this being low for aminoglycosides (13%) and high in the case of pefloxacin (89%o) and metronidazole (990%). The concentrations of pefloxacin (13.0 to 23 ,Lg/g) and metronidazole (8.4 ,ug/g) in the necrotic samples were distinctly higher than the MICs for the organisms most commonly isolated in this disease; the concentrations in tissue of imipenem (3.35 ,ug/g) and mezlocillin (8.0 and 15.0 ,ug/g) did not always exceed the MICs for 90% of strains tested, whereas the aminoglycoside concentrations in necrotic tissue (0.5 p.g/g) were inadequate. Repeated administration of drugs (for 3, 7, 17, and 20 days) seems to enhance penetration of pefloxacin, imipenem, and metronidazole into necrotic pancreatic tissue. The choice of antibiotics in preventing infected necrosis during necrotizing pancreatitis should be based on their antimicrobial activity, penetration rate, persistence, and therapeutic concentrations in the necrotic pancreatic area. These requisites are provided by pefloxacin and metronidazole and to a variable extent by imipenem and mezlocillin.Superinfection of necrotic tissue in the course of acute necrotizing pancreatitis is a decisive prognostic factor with regard to morbidity and mortality (2,3,5,7,20,25,33,34,40).This has prompted attempts to identify the patients at septic risk (3,5,20), the microorganisms responsible for the superinfection (1), the times of infection in the natural history of the disease (3,20), the therapeutic measures to be adopted (1-3, 5, 20, 34), and possible effective prophylaxis (7,9,10,19,23,25,33).The ideal antibiotic for therapy and/or prophylaxis should be targeted at the microorganisms responsible for the septic complications and should reach the infection site in therapeutic concentrations.To date, several studies have been conducted to evaluate the penetration of various different antibiotics into healthy pancreatic tissue and juice (4, 7-11, 28, 35-38). None of these studies has been conducted with humans in the course of disease, and to the best of our knowledge, the effective ability of antibiotics to penetrate the infection risk areas has never been assessed. Such areas of the retroperitoneum are characterized by the presence of necrotic fragments of pa...
An appropriate and timely management, including early diagnosis and accurate prognostication, is the mainstay for managed care of patients with acute ischemic stroke. Since red blood cell distribution width (RDW) was found to be an independent predictor of clinical outcomes in patients with thrombotic disorders, we designed a retrospective observational study to investigate whether the RDW value may also retain predictive significance in stoke patients undergoing thrombolytic therapy. This retrospective study was based on all patients admitted to the Emergency Department (ED) of the University Hospital of Verona (Italy) with a diagnosis of ischemic stroke, who underwent systemic thrombolysis between January 2013 and June 2015. The RDW value along with basal clinical characteristics was recorded at ED admission. The final study population consisted of 316 patients. A significant association was found between stroke severity (NIHSS score) and RDW ( = 0.322; < 0.001). The median RDW value in patients with clinical improvement after thrombolysis was significantly lower than in patients without (13.4 vs. 14.1%; < 0.001). The diagnostic accuracy (area under the curve) of RDW for predicting the lack of neurological improvement was 0.667. In univariate analysis, RDW >14.5% was associated with increased rate of no neurological improvement (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.37-4.13), an association remaining significant also in multivariate analysis (OR, 1.85; 95% CI, 1.13-3.32). Survivor curve analysis showed that patients with RDW values ≥14.5% had a higher risk of 1-year mortality and shorter survival. These results suggest that RDW assessment at ED admission may provide valuable diagnostic and prognostic information in patients with acute ischemic stroke.
The availability of prediction tools for risk stratification after acute stroke is seen as a valuable perspective for tailored clinical management. This retrospective study was aimed to identify significant predictors of poor outcome in patients presenting with acute ischemic stroke, which could then be used for constructing a prediction model. The study population consisted of 837 patients admitted to the Stoke Unit of University Hospital of Verona (Italy) for acute ischemic stroke within 12 h of symptoms onset. In multivariate analysis, age, use of thrombolysis, red blood cell distribution width (RDW) and NIHSS score at admission were found to be significant predictors of 3-month functional decline. A nomogram constructed by integrating these four variables exhibited an area under the curve of 0.832 for predicting functional impairment. The >80% risk cut-off derived from the nomogram was associated with 0.91 positive predictive value, whereas a risk probability <10% displayed 0.93 negative predictive value for predicting functional impairment. These results demonstrate that a prediction tool integrating some important clinical, laboratory and demographic variables may enable an efficient risk stratification of poor outcome after acute stroke.
BackgroundThe urokinase plasminogen activator receptor is highly expressed and its gene is amplified in about 50% of pancreatic ductal adenocarcinomas; this last feature is associated with worse prognosis. It is unknown whether the level of its soluble form (suPAR) in urine may be a diagnostic-prognostic marker in these patients.MethodsThe urinary level of suPAR was measured in 146 patients, 94 pancreatic ductal adenocarcinoma and 52 chronic pancreatitis. Urine from 104 healthy subjects with similar age and gender distribution served as controls. suPAR levels were normalized with creatinine levels (suPAR/creatinine, ng/mg) to remove urine dilution effect.ResultsUrinary suPAR/creatinine values of pancreatic ductal adenocarcinoma patients were significantly higher (median 9.8; 25th-75th percentiles 5.3-20.7) than those of either healthy donors (median 0; 0-0.5) or chronic pancreatitis patients (median 2.7; 0.9-4.7). The distribution of values among cancer patients was widespread and asymmetric, 53% subjects having values beyond the 95th percentile of healthy donors. The values of suPAR/creatinine did not correlate with tumour stage, Ca19-9 or CEA levels. Higher values correlated with poor prognosis among non-resected patients at univariate analysis; multivariate Cox regression identified high urinary suPAR/creatinine as an independent predictor of poor survival among all cancer patients (odds ratio 2.10, p = 0.0023), together with tumour stage (stage III odds ratio 2.65, p = 0.0017; stage IV odds ratio 4.61, p < 0.0001) and female gender (odds ratio 1.85, p = 0.01).ConclusionsA high urinary suPAR/creatinine ratio represents a useful marker for the identification of a subset of patients with poorer outcome.
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