Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines

Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0–2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 × IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 × IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70–89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine–paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences. © 2000 Cancer Research Campaig

Effective linear damping and stiffness coefficients of nonlinear systems for design spectrum based analysis

A stochastic approach for obtaining reliable estimates of the peak response of nonlinear systems to excitations specified via a design seismic spectrum is proposed. This is achieved in an efficient manner without resorting to numerical integration of the governing nonlinear equations of motion. First, a numerical scheme is utilized to derive a power spectrum which is compatible in a stochastic sense with a given design spectrum. This power spectrum is then treated as the excitation spectrum to determine effective damping and stiffness coefficients corresponding to an equivalent linear system (ELS) via a statistical linearization scheme. Further, the obtained coefficients are used in conjunction with the (linear) design spectrum to estimate the peak response of the original nonlinear systems. The cases of systems with piecewise linear stiffness nonlinearity, along with bilinear hysteretic systems are considered. The seismic severity is specified by the elastic design spectrum prescribed by the European aseismic code provisions (EC8). Monte Carlo simulations pertaining to an ensemble of nonstationary EC8 design spectrum compatible accelerograms are conducted to confirm that the average peak response of the nonlinear systems compare reasonably well with that of the ELS, within the known level of accuracy furnished by the statistical linearization method. In this manner, the proposed approach yields ELS which can replace the original nonlinear systems in carrying out computationally efficient analyses in the initial stages of the aseismic design of structures under severe seismic excitations specified in terms of a design spectrum

Calculating the energy spectra of magnetic molecules: application of real- and spin-space symmetries

The determination of the energy spectra of small spin systems as for instance given by magnetic molecules is a demanding numerical problem. In this work we review numerical approaches to diagonalize the Heisenberg Hamiltonian that employ symmetries; in particular we focus on the spin-rotational symmetry SU(2) in combination with point-group symmetries. With these methods one is able to block-diagonalize the Hamiltonian and thus to treat spin systems of unprecedented size. In addition it provides a spectroscopic labeling by irreducible representations that is helpful when interpreting transitions induced by Electron Paramagnetic Resonance (EPR), Nuclear Magnetic Resonance (NMR) or Inelastic Neutron Scattering (INS). It is our aim to provide the reader with detailed knowledge on how to set up such a diagonalization scheme.Comment: 29 pages, many figure

Role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in fluoropyrimidine sensitivity

Platelet-derived endothelial cell growth factor (PD-ECGF)/thymidine phosphorylase (TP) catalyses the reversible phosphorolysis of thymidine to thymine and 2-deoxyribose-1-phosphate and is involved in the metabolism of fluoropyrimidines. It can also activate 5'-deoxyfluorouridine (5'DFUR) and possibly 5-fluorouracil (5FU) and Ftorafur (Ft), but inactivates trifluorothymidine (TFT). We studied the contribution of TP activity to the sensitivity for these fluoropyrimidines by modulating its activity and/or expression level in colon and lung cancer cells using a specific inhibitor of TIP (TPI) or by overproduction of TIP via stable transfection of human TP. Expression was analysed using competitive template-RT-PCR (CT-RT-PCR), Western blot and an activity assay. TP activity ranged from nondetectable to 70678 pmol h(-1) 10(-6) cells, in Colo320 and a TP overexpressing clone Colo320TPI, respectively. We found a good correlation between TIP activity and mRNA expression (r = 0.964, P <0.01) in our cell panel. To determine the role of TIP in the sensitivity to 5FU, 5'DFUR, Ft and TFT, cells were cultured with the various fluoropyrimidines with or without TPI and differences in IC50's were established. TPI modified 5'DFUR, increasing the IC50's 2.5- to 1396-fold in WiDR and Colo320TPI, respectively. 5-Fluorouracil could be modified by inhibiting TP but to a lesser extent than 5'DFUR: IC50's increased 1.9- to 14.7-fold for WiDR and Colo320TPI, respectively. There was no effect on TFT or Ft. There appears to be a threshold level of TP activity to influence the 5'DFUR and 5FU sensitivity, which is higher for 5FU. Even high levels of TP overexpression only had a moderate effect on 5FU sensitivity. (C) 2003 Cancer Research UK

Clinical, quality of life, and economic value of acromegaly disease control

Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998–2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 μg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease

Προχωρημένες Μέθοδοι Προσομοίωσης Κατασκευών από Οπλισμένο Σκυρόδεμα Έναντι Σεισμικών Δράσεων.

93 σ.Εθνικό Μετσόβιο Πολυτεχνείο--Μεταπτυχιακή Εργασία. Διεπιστημονικό-Διατμηματικό Πρόγραμμα Μεταπτυχιακών Σπουδών (Δ.Π.Μ.Σ.) “Δομοστατικός Σχεδιασμός και Ανάλυση των Κατασκευών”Στο πλαίσιο των ερευνητικών προγραμμάτων για τη αποτίμηση της σεισμικής συμπεριφοράς μη κανονικών σε κάτοψη κατασκευών, έχουν λάβει χώρα αρκετά πειράματα κτιρίων κατασκευασμένα σε φυσική κλίμακα. Τα κτίρια αυτά δοκιμάστηκαν ψευδο-δυναμικά, με στόχο την κατανόηση της απόκρισής τους κατά τον σεισμό αλλά και τον προσδιορισμό των αδύνατων σημείων τους. Ειδικά σε μια σεισμογενή περιοχή, όπως είναι η Ελλάδα, στη οποία το μεγαλύτερο σε ποσοστό τμήμα των κτιρίων έχουν κατασκευαστεί προ του έτους 1985, εποχή κατά την οποία τέθηκαν σε εφαρμογή πρόσθετες βελτιωτικές διατάξεις στον αντισεισμικό κανονισμό, αποτελεί ένα σοβαρό πρόβλημα. Επιπλέον, εκτός από την έλλειψη αντισεισμικού σχεδιασμού, η δομική μορφολογία της πλειοψηφίας των κατασκευών αυτών, ευνοεί την ανάπτυξη στρεπτικής απόκρισης κατά το σεισμό, γεγονός που καθιστά ακόμα πιο δυσμενή την κατάσταση. Το έτος 2008 στην Ιταλία, σε κοινή δράση Ελληνικών και Ιταλικών πανεπιστημίων, κατασκευάστηκε σε φυσική κλίμακα ένα τριώροφο κτίριο, αντιπροσωπευτικό εκείνης της περιόδου, προκειμένου να δοκιμαστεί ψευδο-δυναμικά στην Pavia. Αντικείμενο της παρούσης μεταπτυχιακής εργασίας είναι η διερεύνηση μη-γραμμικών μαθηματικών προσομοιωμάτων τύπου force-based beam-column με σκοπό την προσέγγιση μέσω κατάλληλων προγραμμάτων Η/Υ της απόκρισης φορέων εκείνης της εποχής. Τα αποτελέσματα των αναλύσεων που προκείπτουν από την προσομοίωση συγκρίνονται με τα πειραματικά και αξιολογούνται ώστε να προκύψει η προσομοίωση με τα πιο αξιόπιστα αποτελέσματα λαμβάνοντας υπόψη πάντα το υπολογιστικό κόστος. Ακόμη αναλύσεις ευαισθησίας γίνονται για όλους παράγοντες που επηρρεάζουν την τελική απόκριση του κτιρίου, όπως η τοιχοποιία, οι μη-γραμμικότητες γεωμετρίας και υλικών κ.α.The paper focuses on the study of typical reinforced concrete structures build between the years 1950 and 1970 in Southern Europe. These structures have been designed only for gravity loads and, apart from the lack of seismic design, the structural morphology of the majority promotes torsional response. Both experimental and analytical results are presented for a three-storey building that was tested on the shake table of TREES laboratory at EUCENTRE in Pavia, Italy. The building was dynamically tested using the Montenegro 1979 ground motion record (Herceg-Novi station), scaled to different levels of PGA to observe its progressive damage mode and overall capacity deterioration. In this paper the experimental data is compared with numerically obtained results using three different kind of non linear, force-based, fiber beam-column elements. Response parameters, such as damage distribution and drift capacity, are analyzed to identify the limitations of numerical modeling, of each specific element, with respect to the investigated engineering demand parameters.Αλέξανδρος Δ. Τόλη