Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

Recent data suggest that expression of the membrane P170-glycoprotein (P-gp) may confer resistance to the topoisomerase- I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 μM completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function. © 1999 Cancer Research Campaig

The GAPS programme at TNG : XLIX. TOI-5398, the youngest compact multi-planet system composed of an inner sub-Neptune and an outer warm Saturn

Context. Short-period giant planets (P ≲ 10 days, Mp >0.1 MJ) are frequently found to be solitary compared to other classes of exo-planets. Small inner companions to giant planets with P ≲ 15 days are known only in five compact systems: WASP-47, Kepler-730, WASP-132, TOI-1130, and TOI-2000. Here, we report the confirmation of TOI-5398, the youngest known compact multi-planet system composed of a hot sub-Neptune (TOI-5398 c, Pc = 4.77271 days) orbiting interior to a short-period Saturn (TOI-5398 b, Pb = 10.590547 days) planet, both transiting around a 650 ± 150 Myr G-type star. Aims. As part of the Global Architecture of Planetary Systems (GAPS) Young Object project, we confirmed and characterised this compact system, measuring the radius and mass of both planets, thus constraining their bulk composition. Methods. Using multi-dimensional Gaussian processes, we simultaneously modelled stellar activity and planetary signals from the Transiting Exoplanet Survey Satellite (TESS) Sector 48 light curve and our High Accuracy Radial velocity Planet Searcher (HARPS-N) radial velocity (RV) time series. We confirmed the planetary nature of both planets, TOI-5398 b and TOI-5398 c, and obtained a precise estimation of their stellar parameters. Results. Through the use of astrometric, photometric, and spectroscopic observations, our findings indicate that TOI-5398 is a young, active G dwarf star (650 ± 150 Myr) with a rotational period of Prot = 7.34 days. The transit photometry and RV measurements enabled us to measure both the radius and mass of planets b, Rb = 10.30 ± 0.40 R⊕, Mb = 58.7 ± 5.7 M⊕, and c, Rc = 3.52 ± 0.19 R⊕, Mc = 11.8 ± 4.8 M⊕. TESS observed TOI-5398 during sector 48 and no further observations are planned in the current Extended Mission, making our ground-based light curves crucial for improvement of the ephemeris. With a transmission spectroscopy metric (TSM) value of around 300, TOI-5398 b is the most amenable warm giant (10 < P < 100 days) for JWST atmospheric characterisation

Geoscience teaching and student interest in secondary schools-preliminary results from an interest research in Greece, Spain and Italy

The results of a topic-interest study on geosciences among 14- to 17-year-old school students are reported. The research was organized in the framework of the European project Geoschools to investigate the interest of students in the context of teaching strategies for geosciences in secondary schools. A questionnaire was designed as the main data-collection tool, based on the results of a comparison on geosciences curricula among the five European countries (Austria, Greece, Portugal, Italy, and Spain) which are the partners in the GEOschools project. The present study focuses on results from Greece and Spain but also includes preliminary results from Italy, for comparison purposes. Questionnaires were distributed in 20 schools (through 20 teachers with around 600 students) in each participating country. Specifically, a sample of 554, 14- to 15-year-old students were surveyed in 20 schools across Greece, a sample of 155, 14- to 17-year-old students was surveyed in seven schools in Aragón (Spain), and a sample of 624, 14- and 16-year-old children was surveyed in 11 schools in Sicily (Italy) to identify their main topics of interest in geosciences. Additional surveys in Spain in Castilla-La Mancha (Guadalajara), Madrid, Catalonia, and in the province of Gerona (134 students, 14–17 years old) and from Portugal (284 students) are still in the process of evaluation. Results indicate that the most attractive topics for children are Natural Hazards and Palaeontology. Teaching strategies also raise interest. Children from Spain generally show less interest in geosciences than do children of the same age from Greece. A discussion on the high educational potential of geological heritage is included, providing clear case examples for showing geological problems. © The European Association for Conservation of the Geological Heritage 2013