Stochastic modelling of the role of cisplatin in altered fractionation schedules for head and neck cancer

Advanced head and neck cancers are one of the most challenging cancers facing the oncologists due to their aggressiveness attributable to the high hypoxic content and the tumour's ability to repopulate during radiotherapy. Alterations of radiotherapy fractionation schedules are possible ways to improve tumour control. Clinical trials have shown that both hyperfractionated radiotherapy (multiple fractions a day, over the same treatment time), and accelerated radiotherapy (higher doses per fraction, six days a week, over 5 weeks or less) are more effective than conventional radiotherapy in the management of head and neck cancer. However, the treatment choice between hyperfractionated and accelerated radiotherapy is still debated, due to very similar results obtained regarding tumour control. Furthermore, while radiotherapy alone has an impact on the short-term prognosis of advanced head and neck cancer, the long-term benefits have been moderate. Cisplatin is a chemotherapeutic agent which combined with conventional radiotherapy has shown to improve patient survival. The present paper employs a Monte Carlo modelling approach in assessing the effect of combined cisplatin-altered fractionation schedule on tumour response. The growth of a head and neck carcinoma has been modelled using probabilistic functions sampled by computer generated random number sequences, maintaining the biological constitution of a tumour. The tumour growth model has been built to simulate the in vivo processes taking place before and after radiotherapy/chemotherapy. The model has shown that adding cisplatin to radiotherapy improves tumour control in both hyperfractionated and accelerated radiotherapy.     

Antibacterial activity of marine macroalgae against fish pathogenic Vibrio species

In mariculture, diseases of microbial origin can cause significant economic losses worldwide; the evolution of microorganism resistance to antibiotics has resulted in a growing need for new antibacterial compounds that are effective in veterinary medicine and characterized by limited undesirable side effects. Increased attention has recently been turned to seaweeds as a promising source for metabolites with antimicrobial activity. Vibriosis is a common disease, caused by bacteria of the genus Vibrio, that can result in high mortality in aquaculture. The aim of this study was to identify seaweeds with antibacterial activity against some pathogenic Vibrio species, in order to identify a possible alternative to the commonly used antibiotics in aquaculture. Chloroform/methanol lipidic extracts of six seaweed species (Chaetomorpha linum, Cladophora rupestris, Gracilaria dura, Gracilaria gracilis, Gracilariopsis longissima, Ulva prolifera) were tested for their antibacterial activities against six fish pathogenic Vibrio species using the disc diffusion method. Different susceptibilities to lipidic algal extracts were observed. All six of the seaweed extracts tested demonstrated inhibition of Vibrio ordalii. The best was that from Gracilariopsis longissima, showing activity against Vibrio ordalii, Vibrio salmonicida, Vibrio alginolyticus and Vibrio vulnificus. The results confirmed the potential use of seaweed extracts as a source of antibacterial compounds or as a health-promoting feed for aquaculture.     

Neoadjuvant cisplatin for head and neck cancer: Simulation of a novel schedule for improved therapeutic ratio

Current clinical studies support the role of neoadjuvant cisplatin administration prior to curative radiotherapy or radio-chemotherapy for advanced head and neck cancer. Nevertheless, based on locoregional control rates the studies indicate that there is need to redesign cisplatin-based schedules for induction chemotherapy, thus the ideal treatment regimen is yet to be established. While the pharmacokinetics/dynamics of daily cisplatin regimens correspond better with the cell cycle properties of head and neck cancers, weekly regimens are more commonly employed in clinics due to lower complications. Yet, the high rates of adverse events induced by current cisplatin schedules often represent a limiting factor in the overall success of the treatment.The aim of the present paper was to model the pharmacodynamic properties of cisplatin and to simulate and compare various neoadjuvant treatment regimens in regards to their effect on tumour control. Treatment simulation was undertaken on a virtual squamous cell carcinoma of the head and neck, previously grown by computer-based probabilistic methods.The model suggests that a novel cisplatin treatment, given every three days is comparable, in regards to tumour control, with the daily administration and more effective than the weekly regimen in neoadjuvant settings. Endpoints were assessed in terms of cell population regrowth after treatment cessation followed by two weeks of unperturbed growth. Simulation of two weeks low-dose daily cisplatin followed by two weeks ‘free growth’ lead to 15% population regrowth, while weekly high-dose cisplatin over three weeks, followed by two weeks unperturbed growth resulted in 52% tumour cell regrowth. The proposed novel schedule of low-dose third-daily cisplatin gives closer tumour regrowth to daily administration (27% versus 15%) than to the weekly regimen (52%) and also similar cell distribution along the cell cycle as the daily one, suggesting therefore comparable response to subsequent treatment.The advantage of using a third-daily drug regimen would be a decrease in normal tissue complication rates compared to daily administration and possibly an increase in tumour control when compared to the ‘conventional’ weekly cisplatin delivery.     

Flora Delle Acque Circostanti L'Isola Di Pianosa (Is. Tremiti)

Abstract

The marine flora of the Isle of Pianosa (Isles Tremiti). – The little Isle Pianosa (Middle Adriatic) presents an algal flora typical for clear, deep seas. Its main components are here described. Endolithic flora on calcareous rocks has been particularly well examined.     

The mucus of Sabella spallanzanii (Annelida, Polychaeta): Its involvement in chemical defence and fertilization success

In several species mucus typically forms a slippery coating that performs many specialised roles including the defence against infection and protection for eggs. In the present study we focused on the mucus of the polychaete Sabella spallanzanii in order to ascertain its involvement in chemical defence and fertilization success. The observations were carried out over an annual cycle according to different phases of the reproductive cycle. Mucus of S. spallanzanii showed a natural lysozyme-like activity with a maximum at pH 6.0 and I = 0.175. This activity was present in all the sampling times except for January (T₄) which corresponds to the reproductive period of this species. The electrophoretic analysis revealed at least ten major protein bands, with molecular weights ranging from 16 to 90 kDa, and six minor components, with molecular weights ranging from 14 to 116 kDa. This pattern was reported all over the year except for the reproductive period when not only the lysozyme-like activity decreased but the number of protein bands was also reduced. During this period microscopical observations of the mucus indicated that only fertilised eggs enveloped in the mucus were released out of the tubes where the worms live. This supports previous hypothesis that fertilization does not occur in the water column but it takes place in the tube just after egg release (in situ fertilization). This fertilization strategy, not involving egg dispersal in the water column, ensures a high success of fertilization. The mucus of S. spallanzanii therefore represents the ideal mean where eggs are released and fertilized as well as a compartment involved in defending the worms from bacterial attack serving as medium into which the antibacterial substances are exuded. The defensive role of lysozyme is important taking into account that this polychaete lives in eutrophic environments such as harbours where bacteria, including pathogens to man and marine organism, are abundant.     

A nuclear magnetic resonance study of the diastereoisomer complexes formed between a terguride derivative and naproxen

¹H NMR (600 MHz) measurements of chemical shift changes were made in acidified (DCI) CD₃OD/D₂O 1:9 v/v equimolar solutions of (S)- and (R,S)-6-methoxy-α-methyl-2-naphthaleneacetic acid (naproxen) in the presence of 1-(3-aminopropyl)-(5R,8S,10R)-terguride (AMP-TER). The most significant bonding interactions concurring to the formation of diastereoisomer complexes are seen as chemical shifts in proximity to the positively charged nitrogen N(6)-CH₃ and of H(12), H(13), H(14) protons of the ergoline skeleton, both the adducts having an electrostatic term and different π–π stabilizing interactions. Chemical shift data exclude any contribution of the aminopropyl chain to the chiral recognition mechanism. These findings provide an experimental basis for the enantiodiscriminative process accounting for the observed chromatographic resolutions of arylcarboxylic acids on chiral stationary phases derived from AMP-TER. © 1994 Wiley-Liss, Inc.     

Oxygen Radical Injury and Loss of High-Energy Compounds in Anoxic and Reperfused Rat Heart: Prevention By Exogenous Fructose-1, 6-Bisphosphate

Isolated Langendorff-perfused rat hearts after 10 minutes preperfusion, were subjected to a substrate-free anoxic perfusion (20 minutes) followed by 20 minutes reperfusion with a glucose-containing oxygen-balanced medium. Under the same perfusion conditions, the effect of exogenous 5mM fructose-1, 6-bisphosphate has been investigated. The xanthine dehydrogenase to xanthine oxidase ratio, concentrations of high-energy phosphates and the TBA-reactive material (TBARS) were determined at the end of each perfusion period in both control and fructose-1, 6-bisphosphate-treated hearts. Results indicate that anoxia induces the irreversible transformation of xanthine dehydrogenase into oxidase as a consequence of the sharp decrease of the myocardial energy metabolism. This finding is supported by the protective effect exerted by exogenous fructose-1, 6-bisphosphate which is able to maintain the correct xanthine dehydrogenase/oxidase ratio by preventing the depletion of phosphorylated compounds during anoxia. Moreover, in control hearts, the release oflactate dehydrogenase during reperfusion, is paralleled by a 50% increase in the concentration of tissue TBARS. On the contrary, in fructose-1, 6-bisphosphate-treated hearts this concentration does not significantly change after reoxygenation, while a slight but significant increase of lactate dehydrogenase activity in the perfusates is observed.

On the whole these data indicate a direct contribution of oxygen-derived free radicals to the worsening of post-anoxic hearts. A hypothesis on the mechanism of action of fructose-1, 6-bisphosphate in anoxic and reperfused rat heart and its possible application in the clinical therapy of myocardial infarction are presented.