The structure of the ternary Eg5–ADP–ispinesib complex

The human kinesin Eg5 is responsible for bipolar spindle formation during early mitosis. Inhibition of Eg5 triggers the formation of monoastral spindles, leading to mitotic arrest that eventually causes apoptosis. There is increasing evidence that Eg5 constitutes a potential drug target for the development of cancer chemotherapeutics. The most advanced Eg5-targeting agent is ispinesib, which exhibits potent antitumour activity and is currently in multiple phase II clinical trials. In this study, the crystal structure of the Eg5 motor domain in complex with ispinesib, supported by kinetic and thermodynamic binding data, is reported. Ispinesib occupies the same induced-fit pocket in Eg5 as other allosteric inhibitors, making extensive hydrophobic interactions with the protein. The data for the Eg5-ADP-ispinesib complex suffered from pseudo-merohedral twinning and revealed translational noncrystallographic symmetry, leading to challenges in data processing, space-group assignment and structure solution as well as in refinement. These complications may explain the lack of available structural information for this important agent and its analogues. The present structure represents the best interpretation of these data based on extensive data-reduction, structure-solution and refinement trials

A phase II irinotecan–cisplatin combination in advanced pancreatic cancer

We report a cisplatin and irinotecan combination in patients with biopsy-proven advanced pancreatic adenocarcinoma. Patients were selected from a specialist centre and required good performance status (KPS>70%), measurable disease on CT scan, and biochemical and haematological parameters within normal limits. Based on a two-stage phase II design, we aimed to treat 22 patients initially. The study was stopped because of the death of the 19th patient during the first treatment cycle, with neutropenic sepsis and multiorgan failure. A total of 89 treatments were administered to 17 patients. Serious grade 3/4 toxicities were haematological (neutropenia) 6%, diarrhoea 6%, nausea 7% and vomiting 6%. Using the clinical benefit response (CBR) criteria, no patients had an overall CBR. For responses confirmed by CT examination, there was one partial response (5%), three stable diseases lasting greater than 6 weeks (16%), with an overall 22% with disease control (PR+SD). The median progression-free and overall survival was 3.1 months (95% CI: 1.3-3.7) and 5.0 (95% CI: 3.9-10.1) months, respectively. Although this synergistic combination has improved the response rates and survival of other solid tumours, we recommend caution when using this combination in the palliation of advanced pancreatic cancer, because of unexpected toxicity

QTc and QTd Changes after Cardiopulmonary Bypass Surgery in Children

The aim of the study was to assess the impact of cardiopulmonary bypass surgery on corrected QT (QTc) and QT dispersion (QTd) intervals. The possible role of inflammation on these variables was investigated

Physiological and antioxidant responses of the sabkha biotope halophyte Limonium delicatulum to seasonal changes in environmental conditions

In saline biotopes, different mechanisms may contribute to the tolerance of halophytes to high soil salinity and temperature, drought and other abiotic stresses, but their relative responses and their ecological plasticity for a given species remain unknown. In this study, we examined the responses of the salt marsh halophyte Limonium delicatulum to changing environmental conditions of its natural habitats (Sabkha “El Kalbia”, Tunisia). The specific aim of the work was to check whether statistically significant correlations could be established between particular stress response mechanisms (ion uptake, activation of antioxidant systems) and soil parameters and climatic data associated with environmental stress. The results showed that the salinity of the soil increased during the months of June, July and August (dry period), concomitantly with a strong accumulation of salt ions in the aerial parts of the plant. Moreover, the highest antioxidant capacity of this halophyte (enzymes and antioxidant molecules) was reached during the same period of the year. The remaining periods (corresponding to the rainy season) did not show a significant difference in enzymes activities and level of antioxidants, with a minimum observed in the months of January and February. These results show a remarkable effect of salinity in the natural habitat on the activity of enzymes and antioxidant molecules. Other edaphic and climatic factors could also be involved to increase antioxidant capacity, such as nutrient deficiency, temperature and precipitation

A Study on the Solutions of a Multiterm FBVP of Variable Order

In the present research study, for a given multiterm boundary value problem (BVP) involving the nonlinear fractional differential equation (NnLFDEq) of variable order, the uniqueness-existence properties are analyzed. To arrive at such an aim, we first investigate some specifications of this kind of variable order operator and then derive required criteria confirming the existence of solution. All results in this study are established with the help of two fixed-point theorems and examined by a practical example

MVsnaclec, a novel C-type lectin protein from Macrovipera lebetina venom, inhibits proliferation, induces apoptosis and suppresses migration in SK-MEL-28 human melanoma cells

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