PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA-mutated advanced OC as a single agent in the treatment and maintenance setting, particularly in platinum-sensitive disease. PARP inhibitors are well tolerated; however, further careful assessment of moderate and late-onset toxicity is mandatory in the maintenance and adjuvant setting, respectively. PARP inhibitors are also being evaluated in combination with chemotherapeutic and novel targeted agents to potentiate antitumour activities. Current research is extending the use of PARP inhibitors beyond BRCA mutations to other sensitising molecular defects that result in HR-deficient cancer, and is defining an HR-deficiency signature. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC

Studies of Ice Movements on the Ward Hunt Ice Shelf by Means of Triangulation-Trilateration

Ward Hunt Island is surrounded by more than 2000 sq km of ice shelf. In 1964 and 1965 the University of New Brunswick Department of Surveying Engineering made a survey of the ice shelf in which geodimeter distance measurements and angular theodolite measurements were combined in a system of triangulation-trilateration in the form of a chain of quadrilaterals to achieve relative positioning accuracies of ± 2 cm for the survey markers. Shelf ice movements of 30 cm with respect to solid ground occurred between 1964 and 1965. The relative position change between the markers on shelf ice was < 4 cm.Études des mouvements de la glace de la barrière de Ward Hunt, au moyen de la triangulation et de la trilatéralisation. Les auteurs décrivent une méthode par laquelle ils ont établi des mesures précises des mouvements de la glace sur la barrière de l'île de Ward Hunt. Ils ont combiné des mesures de distance au géodimètre et des mesures angulaires au théodolite en un système de triangulation et de trilatéralisation, sous forme d'une chaîne de tétragones, avec une précision de l'ordre ±1 à 2 cm. dans la localisation relative des repères forés dans la glace de la barrière.Entre 1964 et 1965, on a observé des mouvements de 30 cm. de la glace par rapport à la terre ferme. Les déplacements des repères sur la glace ont été inférieurs à 4 cm. Il s'agit de la première utilisation connue du géodimètre dans l'Arctique

Design and construction of a high charge and high current 1 - 1/2 cell L-band RF photocathode gun

The Argonne Wakefield Accelerator has been successfully commissioned and used for conducting wakefield experiments in dielectric loaded structures and plasmas. Although the initial wakefield experiments were successful, higher drive beam quality would substantially improve the wakefield accelerating gradients. In this paper we present a new 1-1/2 cell L-band photocathode RF gun design. This gun will produce 10-100 nC beam with 2-5 ps rms pulse length and normalized emittance less than 100 mm mrad. The final gun design and numerical simulations of the beam dynamics are presented

Recreational mountain biking - a new tool in rural development

Rural development should lead to improved quality of life and economic prosperity of regions without burdening ecosystems and all landscape components. Recreational activities or tourism have a significant influence on the development of the regions but also represent important pressure on the natural environment. Only such recreational activities that are geared towards sustainability in the cultural landscape should be supported. We present one example of the sustainable recreation form – mountain biking – and efforts to established the mountain bike destination close to the City of Pisek in the Czech Republic. The decision on the existence or the absence of the project by the City of Pisek was supported by a feasibility study carried out by the expert team from Mendel University in Brno. The socio-economic impact assessment of the project was based on the Cost-Benefit Analysis. The values of the indicators for evaluating the effectiveness of investments reached the levels at which the project could be recommended for the realization. Results of the economic evaluation refers to the excess of the positive effects of the project over its negative consequences. Despite these positive results of the study, the Council of the City of Pisek decided not to support the project of this mountain bike destination

Observations of Microwave Continuum Emission from Air Shower Plasmas

We investigate a possible new technique for microwave measurements of ultra-high energy cosmic ray (UHECR) extensive air showers which relies on detection of expected continuum radiation in the microwave range, caused by free-electron collisions with neutrals in the tenuous plasma left after the passage of the shower. We performed an initial experiment at the AWA (Argonne Wakefield Accelerator) laboratory in 2003 and measured broadband microwave emission from air ionized via high energy electrons and photons. A follow-up experiment at SLAC (Stanford Linear Accelerator Center) in summer of 2004 confirmed the major features of the previous AWA observations with better precision and made additional measurements relevant to the calorimetric capabilities of the method. Prompted by these results we built a prototype detector using satellite television technology, and have made measurements indicating possible detection of cosmic ray extensive air showers. The method, if confirmed by experiments now in progress, could provide a high-duty cycle complement to current nitrogen fluorescence observations of UHECR, which are limited to dark, clear nights. By contrast, decimeter microwave observations can be made both night and day, in clear or cloudy weather, or even in the presence of moderate precipitation.Comment: 15 pages, 13 figure

Radio-Frequency Measurements of Coherent Transition and Cherenkov Radiation: Implications for High-Energy Neutrino Detection

We report on measurements of 11-18 cm wavelength radio emission from interactions of 15.2 MeV pulsed electron bunches at the Argonne Wakefield Accelerator. The electrons were observed both in a configuration where they produced primarily transition radiation from an aluminum foil, and in a configuration designed for the electrons to produce Cherenkov radiation in a silica sand target. Our aim was to emulate the large electron excess expected to develop during an electromagnetic cascade initiated by an ultra high-energy particle. Such charge asymmetries are predicted to produce strong coherent radio pulses, which are the basis for several experiments to detect high-energy neutrinos from the showers they induce in Antarctic ice and in the lunar regolith. We detected coherent emission which we attribute both to transition and possibly Cherenkov radiation at different levels depending on the experimental conditions. We discuss implications for experiments relying on radio emission for detection of electromagnetic cascades produced by ultra high-energy neutrinos.Comment: updated figure 10; fixed typo in equation 2.2; accepted by PR

Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC50 range: 0.052–10.9 μmol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib