Haifa, Israel
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Domenech A.,University of Barcelona | Domenech A.,CSIC - Institute of Environmental Assessment And Water Research | Cortes-Francisco N.,CSIC - Institute of Environmental Assessment And Water Research | Palacios O.,CSIC - Institute of Environmental Assessment And Water Research | And 5 more authors.
Journal of Chromatography A | Year: 2014

A multitoxin method has been developed for quantification and confirmation of lipophilic marine biotoxins in mussels by liquid chromatography coupled to high resolution mass spectrometry (HRMS), using an Orbitrap-Exactive HCD mass spectrometer. Okadaic acid (OA), yessotoxin, azaspiracid-1, gymnodimine, 13-desmethyl spirolide C, pectenotoxin-2 and Brevetoxin B were analyzed as representative compounds of each lipophilic toxin group. HRMS identification and confirmation criteria were established. Fragment and isotope ions and ion ratios were studied and evaluated for confirmation purpose. In depth characterization of full scan and fragmentation spectrum of the main toxins were carried out. Accuracy (trueness and precision), linearity, calibration curve check, limit of quantification (LOQ) and specificity were the parameters established for the method validation. The validation was performed at 0.5 times the current European Union permitted levels. The method performed very well for the parameters investigated. The trueness, expressed as recovery, ranged from 80% to 94%, the precision, expressed as intralaboratory reproducibility, ranged from 5% to 22% and the LOQs range from 0.9 to 4.8. pg on column. Uncertainty of the method was also estimated for OA, using a certified reference material. A top-down approach considering two main contributions: those arising from the trueness studies and those coming from the precision's determination, was used. An overall expanded uncertainty of 38% was obtained. © 2014 Elsevier B.V.


Cabrales-Rico A.,Center for Genetic Engineering and Biotechnology | de la Torre B.G.,UPF PRBB | Garay H.E.,Center for Genetic Engineering and Biotechnology | Machado Y.J.,Center for Molecular Immunology | And 10 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

A fully validated bio-analytical method based on Matrix-Assisted-Laser-Desorption/Ionization-Time of Flight Mass Spectrometry was developed for quantitation in human plasma of the anti-tumor peptide CIGB-300. An analog of this peptide acetylated at the N-terminal, was used as internal standard for absolute quantitation. Acid treatment allowed efficient precipitation of plasma proteins as well as high recovery (approximately 80%) of the intact peptide. No other chromatographic step was required for sample processing before MALDI-MS analysis. Spectra were acquired in linear positive ion mode to ensure maximum sensitivity. The lower limit of quantitation was established at 0.5μg/mL, which is equivalent to 160fmol peptide. The calibration curve was linear from 0.5 to 7.5μg/mL, with R2>0.98, and permitted quantitation of highly concentrated samples evaluated by dilution integrity testing. All parameters assessed for five validation batches met the FDA guidelines for industry. The method was successfully applied to analysis of clinical samples obtained in a phase I clinical trial following intravenous administration of CIGB-300 at a dose of 1.6mg/kg body weight. With the exception of Cmax and AUC, pharmacokinetic parameters were similar for ELISA and MALDI-MS methods. © 2014 Elsevier B.V.


Dann E.J.,Blood Bank and Apheresis Unit | Dann E.J.,Rambam Health Care Campus | Dann E.J.,Technion - Israel Institute of Technology | Berkahn L.,Auckland City Hospital | And 9 more authors.
British Journal of Haematology | Year: 2014

Summary: There is no consensus regarding optimal follow-up mode for Hodgkin lymphoma (HL) patients that achieve complete remission following chemotherapy or combined chemo- and radiation therapy. Several studies demonstrated high sensitivity of positron emission tomography/computerized tomography (PET/CT) in detecting disease progression; however, these techniques are currently not recommended for routine follow-up. This retrospective study conducted in two Israeli (N = 291) and one New Zealand academic centres (N = 77), compared a group of HL patients, followed-up with routine imaging every 6 months during the first 2 years after achieving remission, once in the third year, with additional dedicated studies performed due to symptoms or physical findings (Group I) to a group of patients without residual masses who underwent clinically-based surveillance with dedicated imaging upon relapse suspicion (Group II). Five-year overall survival (OS) was 94% and median time to relapse was 8·6 months for both modes. Relapse rates in Groups I and II were 13% and 9%, respectively. During the first 3 years of follow-up, 47·5 and 4·7 studies were performed per detected relapse in Groups I and II, respectively. The current study demonstrated no benefit in either progression-free survival (PFS) or OS in HL patients followed by routine imaging versus clinical follow-up. The cost was 10 times higher for routine imaging. © 2013 John Wiley & Sons Ltd.


Gez E.,Rambam Health Care Campus | Genesin J.,Rambam Health Care Campus | Shahar D.,Rambam Health Care Campus | Semenisty V.,Rambam Health Care Campus | And 5 more authors.
Journal of Radiotherapy in Practice | Year: 2012

Background: In low-risk prostate cancer, the target volume for radiotherapy is the prostate gland only and prostate brachytherapy with an I-125 implant provides the most conformal radiotherapy. Methods: Patients underwent a pre-implant prostate volume study from which a treatment plan was developed 2 weeks prior to implant. A dosimetric study was performed 1 month following the implant. The prescription dose was 145 Gy with the 95% isodose line covering the entire target volume. The maximal dose to the urethra was less than 210 Gy. Follow-up included serum PSA and IPSS evaluation every 3 months during the first year and then every 6 months beginning in the second year. Results: During December 2000-March 2009, 181 patients with early prostate cancer underwent I-125 implant. The median post-implant PSA value of the entire cohort was 0.7 ng/ml. No patient developed clinical failure. In the follow-up, nine patients had biochemical failure according to the RTOG-ASTRO Phoenix definition (Nadir + 2.0 ng/ml). Of these, one patient refused hormonal therapy desiring to preserve sexual potency, and eight patients received hormonal therapy with a decreased serum PSA to 0.0 ng/ml. The treatment side effects were primarily urinary disturbances. Conclusion: An I-125 implant is an effective and well-tolerated treatment and should be recommended for patients with low-risk prostate cancer. © Copyright Cambridge University Press 2012.


Gil J.,Center for Genetic Engineering and Biotechnology | Cabrales A.,Center for Genetic Engineering and Biotechnology | Reyes O.,Center for Genetic Engineering and Biotechnology | Morera V.,Center for Genetic Engineering and Biotechnology | And 7 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2012

Growth hormone-releasing peptide 6 (GHRP-6, His-(DTrp)-Ala-Trp-(DPhe)-Lys-NH 2, MW=872.44Da) is a potent growth hormone secretagogue that exhibits a cytoprotective effect, maintaining tissue viability during acute ischemia/reperfusion episodes in different organs like small bowel, liver and kidneys. In the present work a quantitative method to analyze GHRP-6 in human plasma was developed and fully validated following FDA guidelines. The method uses an internal standard (IS) of GHRP-6 with 13C-labeled Alanine for quantification. Sample processing includes a precipitation step with cold acetone to remove the most abundant plasma proteins, recovering the GHRP-6 peptide with a high yield. Quantification was achieved by LC-MS in positive full scan mode in a Q-Tof mass spectrometer. The sensitivity of the method was evaluated, establishing the lower limit of quantification at 5ng/mL and a range for the calibration curve from 5ng/mL to 50ng/mL. A dilution integrity test was performed to analyze samples at higher concentration of GHRP-6. The validation process involved five calibration curves and the analysis of quality control samples to determine accuracy and precision. The calibration curves showed R 2 higher than 0.988. The stability of the analyte and its internal standard (IS) was demonstrated in all conditions the samples would experience in a real time analyses. This method was applied to the quantification of GHRP-6 in plasma from nine healthy volunteers participating in a phase I clinical trial. © 2011 Elsevier B.V.


Chermesh I.,Rambam Health Care Campus | Hajos J.,Rambam Health Care Campus | Mashiach T.,Quality Assurance Unit | Bozhko M.,Rambam Health Care Campus | And 3 more authors.
European Journal of Preventive Cardiology | Year: 2014

Background: Undernourished patients treated in general surgery departments suffer from prolonged and complicated hospitalizations, and higher mortality rates compared with well nourished patients. Pivotal information regarding patients nutritional status and its effect on clinical outcome is lacking for cardiac surgery patients. We investigated the prevalence of malnutrition risk and its association with 30-day hospital mortality and postoperative complications. Methods and results: Four hundred and three patients who underwent cardiac surgery during 2008 and were screened with the Malnutrition Universal Screening Tool (MUST) on admission were enrolled. Univariate and multivariate logistic regression analyses compared the association of high and low risk for malnutrition with length of hospitalization (LOS), in-hospital and 30-day mortality, and postoperative complications. Almost 20% of the patients were found to be at high risk for malnutrition. Univariate analyses revealed higher in-hospital mortality rates (ρ0.03) and greater incidence of LOS and antibiotic treatment longer than 21 days (ρ0.002 and ρ0.04, respectively), vasopressor treatment longer than 11 days (ρ0.02), and positive blood cultures (ρ0.02) in patients belonging to the high-risk MUST group. Incorporation of the MUST in a multivariate model with the European System for Cardiac Operative Risk Evaluation (EuroSCORE) significantly improved postoperative complications prediction, as well as in-hospital and 30-day mortality, compared with the EuroSCORE alone. Conclusions: Malnutrition is prevalent in patients undergoing cardiac surgery, associated with higher postoperative mortality and morbidity. Preoperative MUST screening has emerged as highly relevant for enabling early diagnosis of patients at malnutrition risk, predicting postoperative mortality and morbidity, thus promoting well timed treatment. Prospective studies are needed to explore whether intervention can decrease malnutrition risk. © The European Society of Cardiology 2012.


Terada T.,Osaka Ohtani University | Okamoto K.-I.,Quality Assurance Unit | Nishikawa J.-I.,Mukogawa Women's University | Miura T.,Osaka Ohtani University | And 2 more authors.
Journal of Biochemical and Molecular Toxicology | Year: 2010

A cDNA of rat liver thioltransferase was cloned and then expressed using pMAL-c expression vector in Escherichia coli. Recombinant rat liver thioltransferase was expressed as a fusion protein with maltose-binding protein and then purified by amylose resin column chromatography to be homogeneity on 12.5% SDS-polyacrylamide gel electrophoretic analysis. The expressed proteins were shown as two bands at around 53 and 41 kDa, suggesting that the highmolecular one was a fusion protein of recombinant thioltransferase (11.7 plus 41 kDa) and the other (smaller one)was amaltose-binding protein (41 kDa). Arecombinant thioltransferase catalyzed a thiol/disulfide exchange reaction in the same way as thioltransferases purified from various sources. Compared with wild type, the mutants C23A, C26A, C79A, and C83A showed 0%, 17%, 82%, and 86% in the enzymatic activity, respectively. In addition, wild-type-transfected bacteria expressed in bacterial cells showed a strong resistance to H2O2 treatment as well as the case of active mutants (C79A and C83A), but inactive mutants (C23A and C26A) showed no resistance to H2O2 treatment as same as mocktransfection. Thioltransferase can be important for survival of bacterial cells under oxidative stress. © 2010 Wiley Periodicals, Inc.

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