Gamma-secretase inhibition combined with platinum compounds enhances cell death in a large subset of colorectal cancer cells

BACKGROUND: Notch signalling is essential for the development and maintenance of the colonic epithelium. Its inhibition induces a differentiation phenotype in vivo and reduces adenomas in APCmin mice. Whether Notch signals are also required in colorectal cancer (CRC) has remained elusive. Therefore, 64 CRC cell lines were analysed for the occurrence of proteolytically processed, active Notch. RESULTS: 63 CRC lines contained a fragment with approximately the size of the Notch1 intracellular domain (NICD), which is required for signalling. Subsequent analyses with an antibody that specifically recognises the free Val1744 residue generated by gamma-secretase-mediated cleavage of Notch1 showed that a subset of CRC cells lacks this specific Val1744-NICD. Surprisingly, inhibition of Val1744-NICD signalling with different gamma-secretase inhibitors (GSI) did not lead to substantial effects on CRC cell line growth or survival. However, transient activation of Erk upon GSI treatment was detected. Since cisplatin relies on Erk activation for bioactivity in some cells, platinum compounds were tested together with GSI and enhanced cell killing in a subset of Val1744-NICD-positive CRC cell lines was detected. Erk inhibition ablated this combination effect. CONCLUSION: We conclude that gamma-secretase inhibition results in activation of the MAP kinases Erk1/2 and, when used in conjunction, enhances cell death induced by platinum compounds in a large subset of colorectal cancer cell lines.Furthermore the activation of Erk appears to be of particular importance in mediating the enhanced effect seen, as its inhibition abrogates the observed phenomenon. These findings do not only highlight the importance of signalling pathway crosstalk but they may also suggest a new avenue of combination therapy for some colorectal cancers

Hybrid Optical Switching for Data Center Networks

Current data centers networks rely on electronic switching and point-to-point interconnects.When considering future data center requirements, these solutions will raise issues in terms of flexibility, scalability, performance, and energy consumption. For this reason several optical switched interconnects, which make use of optical switches and wavelength division multiplexing (WDM), have been recently proposed. However, the solutions proposed so far suffer from low flexibility and are not able to provide service differentiation. In this paper we introduce a novel data center network based on hybrid optical switching (HOS). HOS combines optical circuit, burst, and packet switching on the same network. In this way different data center applications can be mapped to the optical transportmechanism that best suits their traffic characteristics. Furthermore, the proposed HOS network achieves high transmission efficiency and reduced energy consumption by using two parallel optical switches. We consider the architectures of both a traditional data center network and the proposed HOS network and present a combined analytical and simulation approach for their performance and energy consumption evaluation. We demonstrate that the proposed HOS data center network achieves high performance and flexibility while considerably reducing the energy consumption of current solutions

Hybrid-procedures for the Treatment of Thoracoabdominal Aortic Aneurysms and Dissections

AimThe conventional open repair of thoracoabdominal aneurysms and dissections remains complex and demanding and is associated with significant morbidity and mortality. We present our experience of hybrid open and endovascular treatment of thoracoabdominal aneurysms and dissections.MethodsWithin an experience of 226 aortic stent-grafts between 1998 and April 2006, 6 of the patients (median age 60 years, range 35 to 68 years) with thoracoabdominal aneurysms (Crawford type I, II, III, and V) were treated with a combined endovascular and open surgical approach. Five men and one woman, with median aneurysm diameter of 75mm (range 70–100mm), received revascularization of the renal arteries, the superior mesenteric artery, and the coeliac trunk accomplished via transperitoneal bypass grafting. Aneurysmal exclusion was then performed by stent-graft deployment.ResultsThe entire procedure was technically successful in all patients. The patients were discharged a median of 9 days after the operation, while the postoperative studies revealed the patency of the vessels and no evidence of type I endoleak or secondary rupture of the aneurysm. During follow up (1 to 22 months) spiral-CT scanning revealed distinct shrinkage of the aneurysm, no graft migration or endoleak and patency of all revascularised vessels, except one renal artery in two patients. No patient experienced any temporary or permanent neurological deficit, and no dialysis was necessary.ConclusionThe combined endovascular and open surgical approach is feasible, without cross clamping of the aorta and with minimized ischemia time for renal and visceral arteries, and seems to be an appropriate strategy for patients with a thoraco-abdominal aortic aneurysm or dissection

RECENT ADVANCES IN NTC THICK FILM THERMISTOR PROPERTIES AND APPLICATIONS

An introduction to thermal sensors and thermistor materials is given in brief. After that novel electrical components such as thick film thermistors and thermal sensors based on them are described: Custom designed NTC thermistor pastes based on nickel manganite NiM2O4 micro/nanostructured powder were composed and new planar cell-based (segmented) constructions were printed on alumina. The thick film segmented thermistors were used in novel thermal sensors such as anemometers, water flow meters, gradient temperature sensor of the ground, and other applications. The advances achieved are the consequence of previous improvements of thermistor material based on nickel manganite and modified nickel manganite such as Cu0.2Ni0.5Zn1.0Mn1.3O4 and optimization of thick film thermistor geometries for sensor applications. The thermistor powders where produced by a solid state reaction of MnCO3, NiO, CuO, ZnO powders mixed in proper weight ratio. After calcination the obtained thermistor materials were milled in planetary ball mils, agate mills and finally sieved by 400 mesh sieve. The powders were characterized by XRD and SEM. The new thick film pastes where composed of the powders achieved, an organic vehicle and glass frit. The pastes were printed on alumina, dried and sintered and characterized again by XRD, SEM and electrical measurements. Different thick film thermistor constructions such as rectangular, sandwich, interdigitated and segmented were printed of new thermistor pastes. Their properties such as electrical resistance of the thermistor samples where mutually compared. The electrode effect was measured for all mentioned constructions and surface resistance was determined. It was used for modeling and realizations of high, medium and low ohmic thermistors with different power dissipation and heat loss. Finally all the results obtained lead to thermal sensors based on heat loss for measuring the air flow, water flow, temperature gradient and heat transfer from the air to the ground

Fractal and stereological analyses of insulin-induced rat exocrine pancreas remodelling

Background: The effect of insulin on the endocrine pancreas has been the subject of extensive study, but quantitative morphometric investigations of the exocrine pancreas are scarce. This study was therefore undertaken to investigate the effect of acute and chronic insulin administration (two doses, 0.4 IU and 4 IU) on the morphology of rat pancreas acini. Materials and methods: Semi-fine sections stained with methylene blue and basic fuchsine or haematoxylin and eosin-stained 5-micrometer thick paraffin sections were used for fractal and stereological analysis of exocrine acini. Acute insulin treatment, independent of applied doses increased fractal dimension in line with decreased lacunarity of pancreas acini. Chronic low dose insulin decreased fractal dimension and increased lacunarity of pancreas acini, but a high dose had the opposite effect. The volume densities (Vv) of cytoplasm, granules and nucleus are affected differently: acute low dose and high chronic dose significantly decreased granules Vv, and in line increased cytoplasmic Vv, whereas other examined structures showed slight changes without statistical significance. Results: The results obtained from this investigation indicate that insulin treatment induced structural remodelling of the exocrine pancreas suggesting a substantial role of insulin in its functioning. Conclusions: Additionally, we showed that fine architectural changes in acini could be detected by fractal analysis, suggesting this method as an alternative or addition to routine stereology

Prospects for Observations of Pulsars and Pulsar Wind Nebulae with CTA

The last few years have seen a revolution in very-high gamma-ray astronomy (VHE; E>100 GeV) driven largely by a new generation of Cherenkov telescopes (namely the H.E.S.S. telescope array, the MAGIC and MAGIC-II large telescopes and the VERITAS telescope array). The Cherenkov Telescope Array (CTA) project foresees a factor of 5 to 10 improvement in sensitivity above 0.1 TeV, extending the accessible energy range to higher energies up to 100 TeV, in the Galactic cut-off regime, and down to a few tens GeV, covering the VHE photon spectrum with good energy and angular resolution. As a result of the fast development of the VHE field, the number of pulsar wind nebulae (PWNe) detected has increased from one PWN in the early '90s to more than two dozen firm candidates today. Also, the low energy threshold achieved and good sensitivity at TeV energies has resulted in the detection of pulsed emission from the Crab Pulsar (or its close environment) opening new and exiting expectations about the pulsed spectra of the high energy pulsars powering PWNe. Here we discuss the physics goals we aim to achieve with CTA on pulsar and PWNe physics evaluating the response of the instrument for different configurations.Comment: accepted for publication in Astroparticle Physic

X-ray spectral curvature of High Frequency Peaked BL Lacs: a predictor for the TeV flux

Most of the extragalactic sources detected at TeV energies are BL Lac objects. They belong to the subclass of "high frequency peaked BL Lacs" (HBLs) exhibiting spectral energy distributions with a lower energy peak in the X-ray band; this is widely interpreted as synchrotron emission from relativistic electrons. The X-ray spectra are generally curved, and well described in terms of a log-parabolic shape. In a previous investigation of TeV HBLs (TBLs) we found two correlations between their spectral parameters. (1) The synchrotron peak luminosity L_p increases with its peak energy E_p; (2) the curvature parameter b decreases as E_p increases. The first is consistent with the synchrotron scenario, while the second is expected from statistical/stochastic acceleration mechanisms for the emitting electrons. Here we present an extensive X-ray analysis of a sample of HBLs observed with XMM-Newton and SWIFT but undetected at TeV energies (UBLs), to compare their spectral behavior with that of TBLs. Investigating the distributions of their spectral parameters and comparing the TBL X-ray spectra with that of UBLs, we develop a criterion to select the best HBLs candidates for future TeV observations.Comment: 25 pages, 6 figures, Astrophysical Journal publishe

Convergent evolution of pregnancy-specific glycoproteins in human and horse

Pregnancy-specific glycoproteins (PSGs) are members of the carcinoembryonic antigen cell adhesion molecule (CEACAM) family that are secreted by trophoblast cells. PSGs may modulate immune, angiogenic and platelet responses during pregnancy. Until now, PSGs are only found in species that have a highly invasive (hemochorial) placentation including humans, mice and rats. Surprisingly, analyzing the CEACAM gene family of the horse, which has a non-invasive epitheliochorial placenta, with the exception of the transient endometrial cups, we identified equine CEACAM family members that seem to be related to PSGs of rodents and primates. We identified seven genes that encode secreted PSG-like CEACAMs. Phylogenetic analyses indicate that they evolved independently from an equine CEACAM1-like ancestor rather than from a common PSG-like ancestor with rodents and primates. Significantly, expression of PSG-like genes (CEACAM44, CEACAM48, CEACAM49 and CEACAM55) was found in non-invasive as well as invasive trophoblast cells such as purified chorionic girdle cells and endometrial cup cells. Chorionic girdle cells are highly invasive trophoblast cells that invade the endometrium of the mare where they form endometrial cups and are in close contact with maternal immune cells. Therefore, the microenvironment of invasive equine trophoblast cells has striking similarities to the microenvironment of trophoblast cells in hemochorial placentas, suggesting that equine PSG-like CEACAMs and rodent and primate PSGs have undergone convergent evolution. This is supported by our finding that equine PSG-like CEACAM49 exhibits similar activity to certain rodent and human PSGs in a functional assay of platelet–fibrinogen binding. Our results have implications for understanding the evolution of PSGs and their functions in maternal–fetal interactions