Analysis of the potential of cancer cell lines to release tissue factor-containing microvesicles: correlation with tissue factor and PAR2 expression

BackgroundDespite the association of cancer-derived circulating tissue factor (TF)-containing microvesicles and hypercoagulable state, correlations with the incidence of thrombosis remain unclear.MethodsIn this study the upregulation of TF release upon activation of various cancer cell lines, and the correlation with TF and PAR2 expression and/or activity was examined. Microvesicle release was induced by PAR2 activation in seventeen cell lines and released microvesicle density, microvesicle-associated TF activity, and phoshpatidylserine-mediated activity were measured. The time-course for TF release was monitored over 90 min in each cell line. In addition, TF mRNA expression, cellular TF protein and cell-surface TF activities were quantified. Moreover, the relative expression of PAR2 mRNA and cellular protein were analysed. Any correlations between the above parameters were examined by determining the Pearson’s correlation coefficients.ResultsTF release as microvesicles peaked between 30–60 min post-activation in the majority of cell lines tested. The magnitude of the maximal TF release positively correlated with TF mRNA (c = 0.717; p

Management of metastatic renal cell carcinoma – mini review

The management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the last decade. A number of different systemic molecular targeted agents that have been recently approved have improved the survival of patients with mRCC. This mini-review focuses on the implementation of multi-modality therapy in the management of mRCC and the approved indications of the various available novel agents. These novel agents have expanded our armamentarium and improved clinical outcomes of this challenging disease that has considerable biological heterogeneity and clinical variability. 

Employing infrared microscopy (IRM) in combination with a pre-trained neural network to visualise and analyse the defect distribution in Cadmium Telluride crystals

While Cadmium Telluride (CdTe) excels in terms of photon radiation absorption properties and outperforms silicon (Si) in this respect, the crystal growth, characterization and processing into a radiation detector is much more complicated. Additionally, large concentrations of extended crystallographic defects, such as grain boundaries, twins, and tellurium (Te) inclusions, vary from crystal to crystal and can reduce the spectroscopic performance of the processed detector. A quality assessment of the material prior to the complex fabrication process is therefore crucial. To locate the Te-defects, we scan the crystals with infrared microscopy (IRM) in different layers, obtaining a 3D view of the defect distribution. This provides us with important information on the defect density and locations of Te inclusions, and thus a handle to assess the quality of the material. For the classification of defects in the large amount of IRM image data, a convolutional neural network is employed. From the post-processed and analysed IRM data, 3D defect maps of the CdTe crystals are created, which make different patterns of defect agglomerations inside the crystals visible. In total, more than 100 crystals were scanned with the current IRM setup. In this paper, we compare two crystal batches, each consisting of 12 samples. We find significant differences in the defect distributions of the crystals.Peer reviewe

Processing and Interconnections of Finely Segmented Semiconductor Pixel Detectors for Applications in Particle Physics and Photon Detection

Radiation hardness is in the focus of the development of particle tracking and photon imaging detector installations. Semiconductor detectors, widely used in particle physics experiments, have turned into capacitive-coupled (AC-coupled) detectors from the originally developed conductively coupled (DC-coupled) detectors. This is due to the superior isolation of radiation-induced leakage current in AC-coupled detectors. However, some modern detector systems, such as the tracking detectors in the CERN LHC CMS or ATLAS experiments, are still DC-coupled. This originates from the difficulty of implementing AC coupling on very small pixel detector areas. In this report, we describe our advances in the detector processing technology. The first topic is the applications of the atomic layer deposition processing technology, which enables the very high densities of capacitance and resistance that are needed when the dimensions of the physical segmentation of pixel detectors need to be scaled down. The second topic is the flip-chip/bump-bonding interconnection technology, which is necessary in order to manufacture pixel detector modules on a large scale with a more than 99% yield of noise-free and faultless pixels and detector channels.Peer reviewe

Study of interpad-gap of HPK 3.1 production LGADs with Transient Current Technique

The Phase-2 upgrade of the Large Hadron Collider (LHC) to High-Luminosity LHC (HL-LHC) allows an increase in the operational luminosity value by a factor of 5-7 that will result in delivering 3000 fb(-1) or more integrated luminosity. Due to high luminosity, the number of interactions per bunch crossings (pileup) will increase up to a value of 140-200. To cope with high pileup rates, a precision minimum ionising particles (MIPs) timing detector (MTD) with a time resolution of similar to 30-40 ps and hermetic coverage up to a pseudo-rapidity of vertical bar eta vertical bar = 3 is proposed by the Compact Muon Solenoid (CMS) experiment. An endcap part (1.6 <vertical bar eta vertical bar <3) of the MTD, called the endcap timing layer, will be based on low-gain avalanche detector (LGAD) technology. LGADs provide a good timing resolution due to a combination of a fast signal rise time and high signal-to-noise ratio. The performance of the ETL depends on optimising the crucial features of the sensors, namely; gain, signal homogeneity, fill factor, leakage current, uniformity of multiple-pad sensors and long term stability. The paper mainly focuses on the study of the fill factor of LGADs with varying temperature and irradiation at varying proton fluences as these sensors will be operated at low temperatures and are subjected to a high radiation environment. The 3.1 production of LGADs from Hamamatsu Photonics K.K. (HPK) includes 2x2 sensors with different structures, in particular, different values of narrower inactive region widths between the pads, called the no-gain region. In this paper, the term interpad-gap is used instead of no-gain region in order to follow the conventional terminology. These sensors have been designed to study their fill factor, which is the ratio of the area within the active region (gain region) to the total sensor area. A comparative study on the dependence of breakdown voltage with the interpad-gap width for the sensors has been carried out. Using infrared light (as the electron-hole pair creation by IR laser mimics closely to the traversing of MIPs) from the Scanning-Transient Current Technique (Scanning-TCT) set-up shows that the fill factor does not vary significantly with a variation in temperature and irradiation at high proton fluences.Peer reviewe

Modeling the impact of defects on the charge collection efficiency of a Cadmium Telluride detector

Cadmium telluride is a favorable material for X-ray detection as it has an outstanding characteristic for room temperature operation. It is a high-Z material with excellent photon radiation absorption properties. However, CdTe single crystals may include a large number of extended crystallographic defects, such as grain boundaries, twins, and tellurium (Te) inclusions, which can have an impact on detector performance. A Technology Computer Aided Design (TCAD) local defect model has been developed to investigate the effects of local defects on charge collection efficiency (CCE). We studied a 1 mm thick Schottky-type CdTe radiation detector with transient current technique by using a red laser at room temperature. By raster scanning the detector surface we were able to study signal shaping within the bulk, and to locate surface defects by observing their impact on the CCE. In this paper we present our TCAD model with localized defect, and compare the simulation results to TCT measurements. In the model an inclusion with a diameter of 10 mu m was assumed. The center of the defect was positioned at 6 mu m distance from the surface. We show that the defect has a notable effect on current transients, which in turn affect the CCE of the CdTe detector. The simulated charge collection at the position of the defect decreases by 80 % in comparison to the defect-free case. The simulations show that the defects give a characteristic shape to TCT signal. This can further be used to detect defects in CdTe detectors and to estimate the overall defect density in the material.Peer reviewe

Processing of AC-coupled n-in-p pixel detectors on MCz silicon using atomic layer deposited aluminium oxide

We report on the fabrication of capacitively (AC) coupled n(+)-in-p pixel detectors on magnetic Czochralski silicon substrates. In our devices, we employ a layer of aluminium oxide (Al2O3) grown by atomic layer deposition (ALD) as dielectric and field insulator, instead of the commonly used silicon dioxide (SiO2). As shown in earlier research, Al2O3 thin films exhibit high negative oxide charge, and can thus serve as a substitute for p-stop/p-spray insulation implants between pixels. In addition, they provide far higher capacitance densities than SiO2 due to their high dielectric constant, permitting more efficient capacitive coupling of pixels. Furthermore, metallic titanium nitride (TiN) bias resistors are presented as an alternative to punch-through or poly-Si resistors. Devices obtained by the above mentioned process are characterized by capacitance-voltage and current-voltage measurements, and by 2 MeV proton microprobe. Results show the expected high negative charge of the Al2O3 dielectric, uniform charge collection efficiency over large areas of pixels, and acceptable leakage current densities.Peer reviewe

Characterization of Heavily Irradiated Dielectrics for Pixel Sensors Coupling Insulator Applications

An increase in the radiation levels during the high-luminosity operation of the Large Hadron Collider calls for the development of silicon-based pixel detectors that are used for particle tracking and vertex reconstruction. Unlike the conventionally used conductively coupled (DC-coupled) detectors that are prone to an increment in leakage currents due to radiation, capacitively coupled (AC-coupled) detectors are anticipated to be in operation in future collider experiments suitable for tracking purposes. The implementation of AC-coupling to micro-scale pixel sensor areas enables one to provide an enhanced isolation of radiation-induced leakage currents. The motivation of this study is the development of new generation capacitively coupled (AC-coupled) pixel sensors with coupling insulators having good dielectric strength and radiation hardness simultaneously. The AC-coupling insulator thin films were aluminum oxide (Al2O3) and hafnium oxide (HfO2) grown by the atomic layer deposition (ALD) method. A comparison study was performed based on the dielectric material used in MOS, MOSFET, and AC-coupled pixel prototypes processed on high resistivity p-type Magnetic Czochralski silicon (MCz-Si) substrates. Post-irradiation studies with 10 MeV protons up to a fluence of 10(15) protons/cm(2) suggest HfO2 to be a better candidate as it provides higher sensitivity with negative charge accumulation on irradiation. Furthermore, even though the nature of the dielectric does not affect the electric field within the AC-coupled pixel sensor, samples with HfO2 are comparatively less susceptible to undergo an early breakdown due to irradiation. Edge-transient current technique (e-TCT) measurements show a prominent double-junction effect as expected in heavily irradiated p-type detectors, in accordance with the simulation studies.Peer reviewe

Quality assessment of cadmium telluride as a detector material for multispectral medical imaging

Cadmiumtelluride (CdTe) is a high-Z material with excellent photon radiation absorption properties, making it a promising material to include in radiation detection technologies. However, the brittleness of CdTe crystals as well as their varying concentration of defects necessitate a thorough quality assessment before the complex detector processing procedure. We present our quality assessment of CdTe as a detector material for multispectralmedical imaging, a research which is conducted as part of the Consortium Project Multispectral Photon-counting for Medical Imaging and Beam characterization (MPMIB). The aim of the project is to develop novel CdTe detectors and obtain spectrum-per-pixel information that make the distinction between different radiation types and tissues possible. To evaluate the defect density inside the crystals - which can deteriorate the detector performance - we employ infrared microscopy (IRM). Posterior data analysis allows us to visualise the defect distributions as 3D defect maps. Additionally, we investigate front and backside differences of the material with current-voltage (IV) measurements to determine the preferred surface for the pixelisation of the crystal, and perform test measurements with the prototypes to provide feedback for further processing. We present the different parts of our quality assessment chain and will close with first experimental results obtained with one of our prototype photon-counting detectors in a small tomographic setup.Peer reviewe

Characterization of magnetic Czochralski silicon devices with aluminium oxide field insulator : effect of oxygen precursor on electrical properties and radiation hardness

Aluminium oxide (Al2O3) has been proposed as an alternative to thermal silicon dioxide (SiO2) as field insulator and surface passivation for silicon detectors, where it could substitute p-stop/p-spray insulation implants between pixels due to its negative oxide charge, and enable capacitive coupling of segments by means of its higher dielectric constant. Al2O3 is commonly grown by atomic layer deposition (ALD), which allows the deposition of thin layers with excellent precision. In this work, we report the electrical characterization of single pad detectors (diodes) and MOS capacitors fabricated on magnetic Czochralski silicon substrates and using Al2O3 as field insulator. Devices are studied by capacitance-voltage, current-voltage, and transient current technique measurements. We evaluate the influence of the oxygen precursors in the ALD process, as well as the effect of gamma irradiation, on the properties of these devices. We observe that leakage currents in diodes before the onset of breakdown are low for all studied ALD processes. Charge collection as measured by transient current technique (TCT) is also independent of the choice of oxygen precursor. The Al2O3 films deposited with O-3 possess a higher negative oxide charge than films deposited by H2O, However, in diodes a higher oxide charge is linked to earlier breakdown, as has been predicted by simulation studies. A combination of H2O and O-3 precursors results in a good compromise between the beneficial properties provided by the respective individual precursors.Peer reviewe