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Belle II DEPFET, PXD, and SVD Collaborations: et al., The Belle II experiment comes with a substantial upgrade of the Belle detector and will operate at the SuperKEKB energy-asymmetric ee collider with energies tuned to ϒ(4S) resonance s=10.588 GeV. The accelerator has successfully completed the first phase of commissioning in 2016 and the first electron–positron collisions in Belle II took place in April 2018. Belle II features a newly designed silicon vertex detector based on DEPFET pixel and double-sided strip layers. Currently, a subset of the vertex detector is installed (Phase 2 of the experiment). Installation of the full detector (Phase 3) will be completed by the end of 2018. This paper describes the Phase 2 arrangement of the Belle II silicon vertex detector, with focus on the interconnection of detectors and their integration with the software framework of Belle II. Alignment issues are discussed based on detector simulations and first acquired data., This work is supported by MSCA-RISE, European Union project JENNIFER (EU grant n. 644294), MEXT, Japan, WPI, and JSPS (Japan); ARC (Australia); BMWFW (Austria); MSMT, Czech Republic, GAUK 404316 (Czech Republic); AIDA-2020 (Germany); DAE, India and DST (India); INFN (Italy); NRF-2016K1A3A7A09005605 and RSRI (Korea); MNiSW (Poland); Federal Ministry of Education and Research (BMBF, Germany); and MINECO, Spain grant FPA2015-71292-C2-1-P (Spain).

Proceedings of the 29th International Workshop on Vertex Detectors (VERTEX2020), Tsukuba, Japan (Online); Journal of the Physical Society of Japan 34, 010002 (2021). doi:10.7566/JPSCP.34.010002, The Belle II experiment at the super KEK B factory (SuperKEKB) started its physics operation with the full detector setup in March 2019, and it aims at collecting 50 ab$^{���1}$ of $e^+e^���$ collision data. The vertex detector (VXD) of Belle II contains a 4-layer silicon vertex detector (SVD) using double sided silicon strips and an inner 2-layer pixel detector (PXD) that is based on the depleted P-channel Field Effect Transistor (DEPFET) technology. The signal generation and amplification are combined in pixels with a minimum pitch of 55 �� 50 ��m$^2$. The sensors are thinned down to 75 ��m, and each module has interconnects and ASICs integrated on the sensor with silicon frames for mechanical support. This approach led to a material budget of around 0.21% X$_0$ per layer including the cooling structure in the acceptance region. The PXD has an integration time of around 20 ��s, a signal-to-noise ratio of around 50 and a detecting efficiency of better than 99%. Its two layers are arranged at the radii of 14 and 22 mm around the interaction point, and an impact parameter resolution of better than 15 ��m has been achieved. Due to its close proximity to the beam line and its sensitivity to few-keV photons, the PXD also plays an important role in background studies., Published by The Physical Society of Japan, Tokyo

Belle-II DEPFET and PXD Collaboration: et al., The Belle II experiment at the SuperKEKB energy-asymmetric e+ e- collider has completed a series of substantial upgrades and started collecting data in 2019. The experiment is expected to accumulate a data set of 50 ab−1 to explore new physics beyond the Standard Model at the intensity frontier. The pixel detector (PXD) of Belle II plays a key role in vertex determination. It has been developed using the DEpleted P-channel Field Effect Transistor (DEPFET) technology, which combines low power consumption in the active pixel area and low intrinsic noise with a very small material budget. In this paper, commissioning and performance of the PXD measured with first collision data are presented., This work is supported by MEXT, Japan, WPI, Japan, and JSPS (Japan); MSMT, GAUK 404316, MSCA-RISE project JENNIFER-2 (EU grant n. 822070) (Czech Republic); Federal Ministry of Education and Research (BMBF, Germany) and MINECO, Spain grant FPA2015-71292-C2-1-P (Spain).

Background Viscum album L. (Santalaceae), commonly known as mistletoe, is a hemiparasitic plant traditionally used in complementary cancer treatment. Its antitumor potential is mostly attributed to the presence of aqueous soluble metabolites; however, the use of ethanol as solvent also permits the extraction of pharmacological compounds with antitumor potential. The clinical efficacy of mistletoe therapy inspired the present work, which focuses on ethanolic extracts (V. album “mother tinctures”, MT) prepared from different host trees. Methods Samples from three European subspecies (album, austriacum, and abietis) were harvested, and five different V. album-MT strains were prepared. The following phytochemical analyses were performed: thin layer chromatography (TLC), high-performance liquid chromatography (HPLC) and liquid chromatography-high resolution mass spectrometry (LC-HRMS). The proliferation assay was performed with WST-1 after incubation of tumor (Yoshida and Molt-4) and fibroblast cell lines (NIH/3 T3) with different MT concentrations (0.5 to 0.05% v/v). The cell death mechanism was investigated by flow cytometry (FACS) using Annexin V-7AAD. Results Chemical analyses of MT showed the presence of phenolic acids, flavonoids and lignans. The MT flavonoid and viscotoxin contents (mg/g fresh weight) were highest in Quercus robur (9.67 ± 0.85 mg/g) and Malus domestica (3.95 ± 0.58 mg/mg), respectively. The viscotoxin isoform proportions (% total) were also different among the VA subspecies with a higher content of A3 in V. album growing on Abies alba (60.57 ± 2.13). The phytochemical compounds as well as the viscotoxin contents are probably related to the antitumor effects of MT. The cell death mechanisms evaluated by colorimetric and FACS methodologies involved necrotic damage, which was host tree-, time- and dose- dependent, with different selectivity to tumor cells. Mother tincture from V. album ssp. abietis was the most effective at inducing in vitro cellular effects, even when incubated at the smallest concentration tested, probably because of the higher content of VT A3. Conclusion Our results indicate the promising antitumor potential of Viscum album ethanolic extracts and the importance of botanical and phytochemical characterization for in vitro anti-proliferative effects.

Belle-II DEPFET and PXD Collaboration: et al., A DEpleted P-channel Field Effect Transistor (DEPFET) based pixel detector was developed for the Belle II VerteX Detector (VXD). It is designed to achieve a good impact parameter resolution better than 15𝜇m at the very high luminosity conditions of this experiment. In the first half of 2018 four final production modules have been deployed in the commissioning run of the detector and their performance is discussed., This work is supported by MEXT, WPI, and JSPS (Japan); MSMT, GAUK 404316, MSCA-RISE project JENNIFER (EU grant n. 644294) (Czech Republic); Federal Ministry of Education and Research (BMBF, Germany) and MINECO grant FPA2015-71292-C2-1-P (Spain).

Silicon Photomultipliers (SiPMs) are a promising candidate for replacing conventional photomultiplier tubes (PMTs) in many applications, thanks to ongoing developments and advances in their technology. Conventional SiPMs are generally an array of avalanche photo diodes, operated in Geiger mode and read out in parallel, thus leading to the necessity of a high ohmic quenching resistor. This resistor enables passive quenching and is usually located on top of the array, limiting the fill factor of the device. In this paper, a novel detector concept with a bulk integrated quenching resistor will be recapped. In addition, due to other advantages of this novel detector design, a new concept, in which these devices will be utilized as tracking detectors for particle physics applications will be introduced, as well as first simulation studies and experimental measurements of this new approach.

The Belle II experiment features a substantial upgrade of the Belle detector and will operate at the SuperKEKB energy-asymmetric e+e− collider at KEK in Tsukuba, Japan. The accelerator completed its first phase of commissioning in 2016, and the Belle II detector saw its first electron-positron collisions in April 2018. Belle II features a newly designed silicon vertex detector based on double-sided strip layers and DEPFET pixel layers. A subset of the vertex detector was operated in 2018 to determine background conditions (Phase 2 operation). The collaboration completed full detector installation in January 2019, and the experiment started full data taking. This paper will report on the final arrangement of the silicon vertex detector part of Belle II with a focus on online monitoring of detector conditions and data quality, on the design and use of diagnostic and reference plots, and on integration with the software framework of Belle II. Data quality monitoring plots will be discussed with a focus on simulation and acquired cosmic and collision data.

In the upgrade of the Belle detector at KEK (Tsukuba, Japan) the two innermost layers of the vertex detector will be realized by a pixel detector (PXD) consisting of DEPFET (DEpleted P-channel Field Effect Transistor) matrices. As the position of the detector will be very close to the beam pipe, it will suffer from intense radiation levels. The main radiation background is the luminosity related 4-fermion final state radiation, which damages the silicon bulk material and the silicon dioxide from the gate contacts. With the dose expected at Belle II, the DEPFET suffers mainly from additional leakage current and increase in noise. In addition, defects in the silicon dioxide change transistor parameters, e.g. the threshold voltage. We will show results on the hardness factor of electrons after a 10 MeV electron irradiation which was performed in the dose and energy range relevant for the PXD. In addition, we present X-ray irradiations of DEPFET equivalent test structures and compare radiation hardness for different oxide parameters in the prototype production.

Isolierverglasungen bestehen im Regelfall aus zwei oder drei Scheiben Floatglas. In besonderen Fallen, wie beispielsweise zur Absturzsicherung, muss zumindest eine der beiden Scheiben aus Verbundsicherheitsglas hergestellt werden. Bezuglich des Einsatzes der Glasarten wird auf die einschlagige Literatur verwiesen. Im Folgenden wird die Ermittlung der Schnittgrosen behandelt und eine systematische Vorgehensweise unter Zuhilfenahme des Kraftgrosenverfahrens anhand der tabellierten Hilfswerte beschrieben, sodass anschliesend der Spannungs- und der Durchbiegungsnachweis – bei einfachen Systemen ohne die Inanspruchnahme spezieller Rechenprogramme, nur mit Verwendung tabellierter Werte – gefuhrt werden konnen. Determination of bending moments and dimensioning of insulating glazings As a rule, insulating glazings consist of two or three panes of float glass. In special cases, such as for fall protection, at least one of the panes must be produced from laminated safety glass. Regarding the different utilisation of the panes, reference is made to the relevant literature. The following section discuss the determination of bending moments and a systematic approach is described by using the force method based on the tabulated auxiliary values to conduct tension and deflection analysis – for ordinary systems without the use of any special computer programme, but only by using the tabulated values.

X-ray free-electron lasers provide unique opportunities for exploring ultrafast dynamics and for imaging the structures of complex systems. Understanding the response of individual atoms to intense X-rays is essential for most free-electron laser applications. First experiments have shown that, for light atoms, the dominant interaction mechanism is ionization by sequential electron ejection, where the highest charge state produced is defined by the last ionic state that can be ionized with one photon. Here, we report an unprecedentedly high degree of ionization of xenon atoms by 1.5 keV free-electron laser pulses to charge states with ionization energies far exceeding the photon energy. Comparing ion charge-state distributions and fluorescence spectra with state-of-the-art calculations, we find that these surprisingly high charge states are created via excitation of transient resonances in highly charged ions, and predict resonance enhanced absorption to be a general phenomenon in the interaction of intense X-rays with systems containing high-Z constituents. Researchers create high ionization states, up to Xe36+, using 1.5 keV free-electron laser pulses. The higher than expected ionization may be due to transient resonance-enhanced absorption and the effect may play an important role in interactions of intense X-rays with high-Z elements and radiation damage.

The Mercury imaging X-ray spectrometer (MIXS) on board of ESA's fifth cornerstone mission BepiColombo will be the first space instrument using DEpleted P-channel FET (DEPFET) based detectors. The MIXS spectrometer comprises two channels with identical focal plane detectors and is dedicated to energy resolved imaging of X-ray fluorescence from the mercurial surface. We report on the characterization, integration, and spectroscopic qualification of MIXS flight detectors. Detector chips were precharacterized at die level in order to select the best dies for integration and to do homogeneity and yield studies. Then, the detector chips were integrated to MIXS Detector Plane Arrays (DPAs), a complicated process due to the sophisticated mechanical structure, which allows the thermal decoupling of the detector from its readout and control chips. After integration, spectroscopic qualification measurements were done in order to analyze the detector performance and to prove the excellent spectroscopic performance of the DEPFET Macropixel detectors over a wide temperature range. The integration and spectroscopic qualification of all flight grade modules is now successfully completed.

We present a new high resolution X-ray imager based on a pnCCD detector and a polycapillary optics. The properties of the pnCCD like high quantum efficiency, high energy resolution and radiation hardness are maintained, while color corrected polycapillary lenses are used to direct the fluorescence photons from every spot on a sample to a corresponding pixel on the detector. The camera is sensitive to photons from 3 to 40 keV with still 30% quantum efficiency at 20 keV. The pnCCD is operated in split frame mode allowing a high frame rate of 400 Hz with an energy resolution of 152 eV for Mn K α (5.9 keV) at 450 kcps. In single-photon counting mode (SPC), the time, energy and position of every fluorescence photon is recorded for every frame. A dedicated software enables the visualization of the elements distribution in real time without the need of post-processing the data. A description of the key components including detector, X-ray optics and camera is given. First experiments show the capability of the camera to perform fast full-field X-Ray Fluorescence (FF-XRF) for element analysis. The imaging performance with a magnifying optics (3×) has also been successfully tested.

Focal plane instrumentation based on DEPFET Macropixel devices, being a combination of the Detector– Amplifier structure DEPFET with a silicon drift chamber (SDD), has been proposed for the MIXS (Mercury Imaging X-ray Spectrometer) instrument on ESA’s Mercury exploration mission BepiColombo. MIXS images X-ray fluorescent radiation from the Mercury surface with a lightweight X-ray mirror system on the focal plane detector to measure the spatially resolved element abundance in Mercury’s crust. The sensor needs to have an energy resolution better than 200 eV FWHM at 1 keV and is required to cover an energy range from 0.5 to 10 keV, for a pixel size of 300 � 300 mm 2. Main challenges for the instrument are radiation damage and the difficult thermal environment in the mercury orbit. The production of the first batch of flight devices has been finished at the MPI semiconductor laboratory. Prototype modules have been assembled to verify the electrical properties of the devices; selected results are presented here. The prototype devices, Macropixel prototypes for the SIMBOL-X focal plane, are electrically fully compatible, but have a pixel size of 0.5 � 0.5 mm 2 . Excellent homogeneity and near

The company PNSensor and the MPI Semiconductor Laboratory are developing and have produced first prototypes of pnCCDs with an avalanche readout which aim at single photon sensitivity in the visible wavelength range. This resolution is provided by an avalanche diode integrated in the readout chain of every CCD column. The diode features a new topology and can collect signal electrons from the CCDs’ depleted buried channel. The pixel-structure has been derived from pnCCDs and was optimized for lowest leakage current and for compatibility with the avalanche structures. All advantages of the pnCCDs are maintained, including high quantum efficiency (between 80% and 100%), high frame rate (up to 1000 frames/s) and low leakage current. Possible applications are in the field of High Time Resolution Astrophysics (HTRA). There, fast imaging of faint objects in the visible, such as, e.g. close binary stars or fast rotating neutron stars, requires single photon sensitivity and high frame rates. We present results from proof-of-principle tests carried out on first laboratory prototypes of such devices.

To expand the detection efficiency Silicon Drift Detectors (SDDs) with various customized radiation entrance windows, optimized detector areas and geometries have been developed. Optimum values for energy resolution, peak to background ratio (P/B) and high count rate capability support the development. Detailed results on sensors optimized for light element detection down to Boron or even lower will be reported. New developments for detecting medium and high X-ray energies by increasing the effective detector thickness will be presented. Gamma-ray detectors consisting of a SDD coupled to scintillators like CsI(Tl) and LaBr3(Ce) have been examined. Results of the energy resolution for the 137Cs 662 keV line and the light yield (LY) of such detector systems will be reported.

The Mercury Imaging X-ray Spectrometer (MIXS) is one of the instruments on board the Mercury Planetary Orbiter of the fifth European Space Agency (ESA) cornerstone mission BepiColombo. This spectrometer comprises two instruments and allows imaging X-ray spectroscopy of the Mercurian surface. The focal plane arrays for the energy and spatial resolved detection of X-rays are based on depleted P-channel FET (DEPFET) macropixel detectors. We report on the first electrical qualification measurements of DEPFET macropixel flight hardware, which are done at room temperature. The measurement of the transistor properties of all DEPFET pixels allows the selection of 100% electrically defect-free devices at an early stage directly after completion of the production process. Additionally, these measurements allow to investigate topics such as the homogeneity of transistor parameters across the detector matrix, to monitor die-to-die variations for matrices from the same wafer, and to investigate the differences between dies from different wafers in order to learn about the stability and reproducibility of the production process. The test results demonstrate good homogeneity and yield for the investigated detector matrices from the first production batch.

The Depleted Field Effect Transistor (DEPFET) detector–amplifier structure forms the basis of a variety of detectors being developed at the MPI semiconductor laboratory. These detectors are foreseen to be used in astronomy and particle physics as well as other fields of science. The detector developments are described together with some intended applications. They comprise the X-ray astronomy missions XEUS and SIMBOL-X as well as the vertex detector of the planned International Linear Collider (ILC). All detectors are produced in the MPI semiconductor laboratory that has a complete silicon technology available.

In January 2007, the ‘AGO Kommission Mamma’ for the 5th time updated the ‘AGO Recommendations for the Diagnostic and Therapy of Breast Cancer’ that were established and published for the first time

A special type of charge-coupled device, the pnCCD, has been developed in the nineties as focal-plane detector for the X-ray astronomy mission XMM-Newton of the European Space Agency. The pnCCD detector has been in operation since the satellite launch in 1999. It is performing up to date spectroscopy of X-rays in combination with imaging and high time resolution. The excellent performance of the flight camera is still maintained; in particular, the energy resolution has been nearly constant since launch. In order to satisfy the requirements of future X-ray astronomy missions as well as those of ground-based experiments, a new type of pnCCD has been developed. The ‘frame store pnCCD’ shows various optimizations in device design and fabrication process. Devices with up to 256×512 pixels have been fabricated in 2004 and recently tested. Simultaneously, a programmable analog signal processor for the readout of the CCD signals, the DUO CAMEX, has been developed. The readout noise of the new detector has a value of 2 electrons ENC which is less than half of the figure of the XMM-Newton pnCCD. We measured an energy resolution that is close to the theoretical limit given by the Fano noise. In particular the low-energy response of the new devices was substantially improved. The quantum efficiency for X-rays is at least 90% in the entire energy band from 0.3 keV up to 11 keV. This is due to the ultra-thin photon entrance window as well as the full depletion of the 450 μm thick back-illuminated pnCCD. The position resolution is better than the pixel sizes of 75 μm×75 μm or 51 μm×51 μm because the signal charge is spread over up to four pixels which allows a more accurate event position determination. ‘Out of time’ events are substantially reduced to the order of 0.1% by operating the pnCCD in frame store mode. Higher operating temperatures, e.g. −20 °C, are possible due to the smaller thermally generated dark-current level of the new devices and the operation at higher frame rates. Low power consumption applications like for the ROSITA X-ray astronomy mission with low frame rates of, e.g. 20 images/s, as well as high frame rate applications, e.g. 200 images/s, are possible with the same device.

DEPFET pixel detectors are unique devices in terms of energy and spatial resolution because very low noise (ENC = 2.2e at room temperature) operation can be obtained by implementing the amplifying transistor in the pixel cell itself. Full DEPFET pixel matrices have been built and operated for autoradiographical imaging with imaging resolutions of 4.3 +- 0.8 um at 22 keV. For applications in low energy X-ray astronomy the high energy resolution of DEPFET detectors is attractive. For particle physics, DEPFET pixels are interesting as low material detectors with high spatial resolution. For a Linear Collider detector the readout must be very fast. New readout chips have been designed and produced for the development of a DEPFET module for a pixel detector at the proposed TESLA collider (520x4000 pixels) with 50 MHz line rate and 25 kHz frame rate. The circuitry contains current memory cells and current hit scanners for fast pedestal subtraction and sparsified readout. The imaging performance of DEPFET devices as well as present achievements towards a DEPFET vertex detector for a Linear Collider are presented., 6 pages, 10 figures, Talk given at IEEE2003, Portland OR, October 2003

The performance requirements of vertex detectors for future linear collider experiments is very challenging especially for the detector's innermost sensor layers. The DEPleted Field Effect Transistor (DEPFET) combining detector and amplifier operation is capable to meet these requirements. A silicon technology is presented which allows production of large sensor arrays consisting of linear DEPFET detector structures. The envisaged pixel array offers a low noise and low power operation. To ensure a high radiation length a thinning technology based on direct wafer bonding is proposed.

There is increasing evidence that tumors elicit specific T-cell responses in a substantial proportion of patients. Recently, we have shown that in patients with colorectal cancer specific T cells against the tumor-associated antigens (TAA) Ep-CAM, her-2/neu or CEA can be detected in peripheral blood using IFNγ-ELISPOT assay. In our study, we have analyzed T-cell responses against HLA-A*0201-restricted epitopes of these TAA in peripheral blood of patients with breast cancer and colorectal cancer. Surprisingly, a complete absence of ex vivo T-cell responses against these TAA was found in 20 patients with breast cancer. In contrast, specific T cells were detectable in 12 of 49 patients with colorectal cancer against at least 1 of these TAA, confirming our previous results. T-cell responses against influenza-derived peptides were similar in both malignancies. The results of our study indicate a difference either of tumor immunogenicity or of the migratory pattern of tumor-specific T cells between breast cancer and colorectal cancer patients. The findings reported here have implications for the development of antigen-specific T-cell therapies. © 2003 Wiley-Liss, Inc.

Future x-ray observatories, such as the proposed ATHENA+ mission, will investigate bright and rapidly evolving radiation sources. To reach the scientific goals, high speed, spatial resolving sensors with excellent spectroscopic performance are mandatory. Well suited for this task are matrices of Depleted P-channel Field Effect Transistors (DEPFETs). DEPFETs provide intrinsic signal amplification, 100 percent fill factor, charge storage capability and a low read noise. Previous studies of DEPFET matrices of 256 × 256 pixels demonstrated an excellent energy resolution of 126 eV FWHM at 5.9 keV (compared to the theoretical Fano limit 120 eV). Usually these matrices are read out on demand, using e.g. the ASTEROID ASIC. Because the DEPFET is always sensitive, charge collected during the readout, causes so called misfits, which increase the background. For low frame rates this can be neglected. However, for fast timings, as suggested for ATHENA+, this effect reduces the spectral performance. We will present measurements on DEPFET macropixel structures, read out using a semi-Gaussian shaper, which demonstrate the excellent spectroscopic performance of these devices. Furthermore we will investigate the effect of misfits on the spectral background of DEPFET devices read out on demand. These measurements show the necessity to suppress misfits when the devices are operated for fast timing modes. As will be shown this can be done using so called gateable DEPFETs. The general advantage of gateable DEPFETs at fast timings, in terms of peak-to-background ratio will be demonstrated.

Development of high quantum efficiency photon detectors is needed for many low light level (LLL) applications. Recently a new type of photodetector was introduced, the so-called Silicon PhotoMultiplier (SiPM). Its good characteristics (fast response, high gain and single photon resolution capability) make SiPM suitable for many applications. Yet its quantum efficiency is still not satisfactory ( 40 % ) for LLL applications. A new detector concept is presented that promises very high ( > 80 % ) quantum efficiency in a wide wavelength range (300–1000 nm). Combining the drift diode with an avalanche structure placed on the opposite side of the large-area radiation entrance window on the fully depleted bulk, one obtains a large-area device that focuses the photoelectron onto a small “point-like” avalanche region. Engineering of the shallow radiation entrance window provides high quantum efficiency in the desired wavelength range. Such a device can be used as a building block for a “silicon photomultiplier”. Extensive simulations have demonstrated the validity of this concept. A production of test devices for the optimization and characterization of avalanche regions and technology parameters has been carried out. The first results from this “proof of principle” production are presented.

The Mercury Imaging X-ray Spectrometer (MIXS) is an instrument on board of the 5th ESA cornerstone mission BepiColombo. This Spectrometer comprises two instruments for imaging x-ray spectroscopy of the Mercury surface. The detector plane arrays (DPA) for the energy and spatial resolved detection of x-rays are based on DEPFET (Depleted P-channel FET) macropixel detectors with 64×64 pixel each and 300×300 μm 2 pixel size. The MIXS target energy band is from 0.5 to 7 keV with an energy resolution better than 200 eV at 1 keV at mission end. This allows to access the Fe-L line at about 0.7 keV, which was not accessible to previous instruments, and to separate the x-ray lines of the elements of interest. Before a detector chip is integrated into a detector module, it is electrically pre-characterized in order to select only the best chips for the complex and time-consuming integration. The high degree of complexity of the integration process comes from the need to thermally decouple the detector chip from its readout and steering ASICs by a sophisticated mechanical structure, due to the limited amount of cooling power available for the instrument. After the spectroscopic characterization of the detector modules, the flight and flight spare detectors were calibrated at the PTB (Physikalisch-Technische Bundesanstalt) beamlines at the BESSY-II synchrotron. We report on the pre-characterization, integration, qualification and calibration of MIXS flight and flight spare detectors, which is now successfully completed.

Physical review letters 108, 5 (2012). doi:10.1103/PhysRevLett.108.245005, Published by APS, College Park, Md.

To improve the signal to noise level, devices for optical and x-ray astronomy use techniques to suppress background events. Well known examples are e.g. shutters or frame-store Charge Coupled Devices (CCDs). Based on the DEpleted P-channel Field Effect Transistor (DEPFET) principle a so-called Gatebale DEPFET detector can be built. Those devices combine the DEPFET principle with a fast built-in electronic shutter usable for optical and x-ray applications. The DEPFET itself is the basic cell of an active pixel sensor build on a fully depleted bulk. It combines internal amplification, readout on demand, analog storage of the signal charge and a low readout noise with full sensitivity over the whole bulk thickness. A Gatebale DEPFET has all these benefits and obviates the need for an external shutter. Two concepts of Gatebale DEPFET layouts providing a built-in shutter will be introduced. Furthermore proof of principle measurements for both concepts are presented. Using recently produced prototypes a shielding of the collection anode up to 1 • 10 −4 was achieved. Predicted by simulations, an optimized geometry should result in values of 1 • 10 −5 and better. With the switching electronic currently in use a timing evaluation of the shutter opening and closing resulted in rise and fall times of 100ns.

Objective Endometrial cancer is classified into: Type I estrogen-dependent endometrioid adenocarcinoma, with good prognosis and type 2 non-estrogen-dependent cancer with serous or clear cell histology and poor prognosis. Grade 3 endometrioid cancers (G3 EEC), share features of type 1 and type 2 cancer and have not been classified as either. This study compares immunohistochemistry and survival in G3 EEC and type 2 cancers. Methods Clinicopathological data compared with immunohistochemistry and survival in 156 consecutive patients with poor prognosis cancer—G3 EEC, uterine papillary serous (UPSC) and clear cell carcinoma (CC), sarcoma, carcinosarcoma and endometrial tumors of mixed histology. 131 (84%) datasets were complete, 25 tumors comprising sarcoma, carcinosarcoma or mixed histologies were excluded. Tissue microarray constructed and tested for estrogen receptor (ER), progesterone receptor (PR), p53 and human epidermal growth factor receptor-2 (Her-2). Results There was no significant difference in the mean age for G3 EEC (n=68) and USPC+CC (n=38), (68.01 and 67.08 respectively, p=0.697) or stage at diagnosis (p=0.384). For ER, PR, p53 and Her-2, there was no significant difference in marker positivity between G3 EEC and UPSC+CC (p=0.612, 0.132, 0.16 and 0.132 respectively). With a mean follow-up time 148months Disease specific and recurrence-free survival between G3 EEC and USPC+CC was similar (p=0.842 and 0.863). Conclusion G3 EEC and UPSC+CC share similar clinical, immunohistochemistry and poor survival. G3 EEC is better characterised as type 2 cancer and should be treated with similar adjuvant therapy to UPSC/CC.

X-ray crystallography provides the vast majority of macromolecular structures, but the success of the method relies on growing crystals of sufficient size. In conventional measurements, the necessary increase in X-ray dose to record data from crystals that are too small leads to extensive damage before a diffraction signal can be recorded(1-3). It is particularly challenging to obtain large, well-diffracting crystals of membrane proteins, for which fewer than 300 unique structures have been determined despite their importance in all living cells. Here we present a method for structure determination where single-crystal X-ray diffraction 'snapshots' are collected from a fully hydrated stream of nanocrystals using femtosecond pulses from a hard-X-ray free-electron laser, the Linac Coherent Light Source(4). We prove this concept with nanocrystals of photosystem I, one of the largest membrane protein complexes(5). More than 3,000,000 diffraction patterns were collected in this study, and a three-dimensional data set was assembled from individual photosystem I nanocrystals (similar to 200 nm to 2 mm in size). We mitigate the problem of radiation damage in crystallography by using pulses briefer than the timescale of most damage processes(6). This offers a new approach to structure determination of macromolecules that do not yield crystals of sufficient size for studies using conventional radiation sources or are particularly sensitive to radiation damage.

The start-up of the Linac Coherent Light Source (LCLS), the new femtosecond hard X-ray laser facility in Stanford, California, has brought high expectations of a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. Two papers in this issue of Nature present proof-of-concept experiments showing the LCLS in action. Chapman et al. tackle structure determination from nanocrystals of macromolecules that cannot be grown in large crystals. They obtain more than three million diffraction patterns from a stream of nanocrystals of the membrane protein photosystem I, and assemble a three-dimensional data set for this protein. Seibert et al. obtain images of a non-crystalline biological sample, mimivirus, by injecting a beam of cooled mimivirus particles into the X-ray beam. The start-up of the new femtosecond hard X-ray laser facility in Stanford, the Linac Coherent Light Source, has brought high expectations for a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. This new capability is tested for the problem of imaging a non-crystalline biological sample. Images of mimivirus are obtained, the largest known virus with a total diameter of about 0.75 micrometres, by injecting a beam of cooled mimivirus particles into the X-ray beam. The measurements indicate no damage during imaging and prove the concept of this imaging technique. X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions1,2,3,4. Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma1. The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval2. Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source5. Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000 K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies.

One of the X-ray imaging detectors in development for the European XFEL (X-ray Free Electron Laser) is the DSSC (DEPFET Sensor with Signal Compression). The DSSC sensor array will have a format of 1024 × 1024 pixels with a pixel size in the order of 200 µm. It is optimized for the detection of low-energy X-ray photons and designed to operate at frame rates up to 4.5 MHz with a dynamic range of several thousand photons per pixel and frame and single photon resolution at small photon numbers. The DSSC system's core component is an active pixel sensor based on the DEPFET (DEpleted P-channel Field Effect Transistor) structure. A DEPFET is an integrated detector-amplifier combining internal amplification, full sensitivity over the whole bulk thickness, analog data storage, readout on demand, low serial noise, and absence of reset noise. For the DSSC-adaptation of the DEPFET principle the new feature of signal compression has been added, i.e. the device has a high gain at small signals and a reduced gain at large signals. With this strongly non-linear response the DSSC-DEPFET provides the required high charge handling capacity with simultaneous single photon resolution for low-energy X-rays. This paper presents the concept of the DSSC-DEPFET. Its functionality is demonstrated by measurements of a first series of prototypes.

We report on the first results from a new setup for electrical qualification measurements of DEPFET pixel detector matrices. In order to measure the transistor properties of all pixels, the DEPFET device is placed into a benchtest setup and electrically contacted via a probecard. Using a switch matrix, each pixel of the detector array can be addressed individually for characterization. These measurements facilitate to pre-select the best DEPFET matrices as detector device prior to the mounting of the matrix and allow to investigate topics like the homogeneity of transistor parameters on device, wafer and batch level in order to learn about the stability and reproducibility of the production process. Especially with regard to the detector development for the IXO Wide Field Imager (WFI), this yield learning will be an important tool. The first electrical qualification measurements with this setup were done on DEPFET macropixel detector flight hardware, which will form the FPAs of the Mercury Imaging X-ray Spectrometer (MIXS) on board of the 5th ESA cornerstone mission BepiColombo. The DEPFET array consists of 64×64 macropixel for which the transfer, output and clear characteristics were measured.

The International X-ray Observatory (IXO) will be a joint X-ray observatory mission by ESA, NASA and JAXA. It will have a large effective area (3 m 2 at 1.25 keV) grazing incidence mirror system with good angular resolution (5 arcsec at 0.1–10 keV) and will feature a comprehensive suite of scientific instruments: an X-ray Microcalorimeter Spectrometer, a High Time Resolution Spectrometer, an X-ray Polarimeter, an X-ray Grating Spectrometer, a Hard X-ray Imager and a Wide-Field Imager. The Wide Field Imager (WFI) has a field-of-view of 18 ft � 18 ft. It will be sensitive between 0.1 and 15 keV, offer the full angular resolution of the mirrors and good energy resolution. The WFI will be implemented as a 6 in. wafer-scale monolithical array of 1024 � 1024 pixels of 100 � 100mm 2 size. The DEpleted P-channel Field-Effect Transistors (DEPFET) forming the individual pixels are devices combining the functionalities of both detector and amplifier. Signal electrons are collected in a potential well below the transistor’s gate, modulating the transistor current. Even when the device is powered off, the signal charge is collected and kept in the potential well below the gate until it is explicitly cleared. This makes flexible and fast readout modes possible.

X-ray detectors based on arrays of DEPFET macropixels, which consist of a silicon drift detector combined with a detector/amplifier structure DEPFET as readout node, provide a convenient and flexible way to adapt the pixel size of a focal plane detector to the resolving power of any given X-ray optical system. Macropixels combine the traditional benefits of an SDD, like scalability, arbitrary geometry and excellent QE even in the low energy range, with the advantages of DEPFET structures: Charge storage capability, near Fano-limited energy resolution, low power consumption and high speed readout. Being part of the scientific payload of ESA's BepiColombo mission, the MIXS instrument will be the first instrument to make use of DEPFET macropixel based FPA detectors in space. MIXS will perform a complete planetary X-ray fluorescence analysis of Mercury's crust with high spectral and spatial resolution. MIXS will contain two focal plane detectors consisting of a 64 × 64 macropixel matrix with 300 × 300 μm2 pixel size. The main challenges for the instrument are the difficult radiation and thermal environment around Mercury, requiring high speed readout and sophisticated thermal management to reduce the impact of thermally generated leakage current within an irradiated detector. Dedicated VLSI integrated readout electronics has been developed for MIXS: a fast, radiation hard, low power, high voltage switch circuit to control the device, and a low noise, high speed amplifier/shaper IC. Detector assemblies have been built, electrical screening tests for the flight models and spectroscopical qualification tests are in progress.

To study the impact of circulating vascular endothelial growth factors (VEGF) -A, -C and -D and their soluble receptors VEGFR-1/-2 on disease invasion and progression in patients with pre-invasive (CIN), invasive (PCC) and recurrent (RCC) cervical cancer.Blood samples were obtained from 125 women, including 50 cases of CIN, 51 of PCC and 24 of RCC, before treatment. Soluble (s) biomarker levels were determined by ELISA and tested for correlation with histopathological factors.With disease progression, sVEGF-A (p = 0.007) and sVEGFR-2 (p = 0.014) significantly increased, while sVEGF-D (p = 0.046) decreased. sVEGFR-2 levels were increased in node+ patients (p = 0.024) and in metastatic disease (p = 0.003). sVEGF-A values were higher in HPV+ cases (p = 0.019). In detecting disease invasiveness, sensitivity and specificity were 76% and 48% for sVEGF-A, 52% and 32% for sVEGF-D, 25% and 94% for sVEGF-C, 93% and 6% for sVEGFR-1 and 73% and 34% for sVEGFR-2, respectively.In cervical neoplasia, a switch from a lymphangiogenic phenotype towards a hemangiogenic phenotype occurs with disease invasion and progression. The sensitivity and specificity values, however, seem not convincing enough to establish these factors as clinical markers for disease invasiveness in cervical cancer.

BepiColombo, ESA's fifth cornerstone mission, is a planetary exploration mission to Mercury. On board of BepiColombo's Mercury Planetary Orbiter (MPO), the MIXS instrument will perform a complete X-ray fluorescence analysis of Mercury's crust with unprecedented spectral and spatial resolution. This is achieved by using a lightweight X-ray mirror system and by using of DEPFET based Macropixel devices as X-ray detectors. DEPFET based Macropixel detectors combine the advantages of the DEPFETs, like flexible readout modes, Fano-limited energy resolution and low power consumption, with the properties of the drift detectors, like arbitrary scalable pixel size and geometry. In addition, the excellent properties of the entrance window, like good QE even in the low energy range and 100% fill factor, are preserved. An energy resolution better than 200 eV FWHM @ 1 keV and an energy range from 0.5 keV to 10 keV, for a pixel size of 300 x 300 square micron, is required. To be sensitive to the Iron-L energy, the quantum efficiency at 0.5 keV is required to be larger than 80%. Main challenges for the instrument are the difficult radiation and thermal environment in the mercury orbit. The production of the first batch of flight devices has been finished at the MPI semiconductor laboratory, and first laboratory modules have been built. The properties of the sensors have been evaluated at the BESSY facility, and the devices have been used for XRF measurements at the ELETTRA synchrotron facility in Trieste. The results of the first tests will be presented here.

Simbol-X is a French-Italian-German hard energy X-ray mission with a projected launch in 2014. Being sensitive in the energy range from 500 eV to 80 keV it will cover the sensitivity gap beyond the energy interval of today's telescopes XMM-Newton and Chandra. Simbol-X will use an imaging telescope of nested Wolter-I mirrors. To provide a focal length of 20 m it will be the first mission of two independent mirror and detector spacecrafts in autonomous formation flight. The detector spacecraft's payload is composed of an imaging silicon low energy detector in front of a pixelated cadmium-telluride hard energy detector. Both have a sensitive area of 8 × 8 cm 2 to cover a 12 arcmin field of view and a pixel size of 625 × 625 μm 2 adapted to the telescope's resolution of 20 arcsec. The additional LED specifications are: high energy resolution, high quantum efficiency, fast readout and optional window mode, monolithic device with 100 % fill factor and suspension mounting, and operation at warm temperature. To match these requirements the low energy detector is composed of 'active macro pixels', combining the large, scalable area of a Silicon Drift Detector and the low-noise, on-demand readout of an integrated DEPFET amplifier. Flight representative prototypes have been processed at the MPI semiconductor laboratory, and the prototype's measured performance demonstrates the technology readiness.

Focal plane instrumentation based on the combined Detector-Amplifier structure DEPFET (Depleted P-channel FET) are being considered for the application in a large variety of experiments in X-ray astronomy and high energy physics. DEPFET based detectors show excellent energy resolution and can be read out at high speed. In addition, they combine low power consumption with the attractive features of random accessibility of pixels and on-demand readout. They feature all advantages of a sideways depleted device in terms of fill factor and quantum efficiency, and so-called macropixel devices, being a combination of a DEPFET with a drift ring structure, allow for large flexibility in terms of pixel size. Presently, DEPFET based focal plane instrumentation for X-ray imaging spectroscopy is being developed for a variety of space experiments with very different requirements. The payload of the French-Italian X-ray Astronomy mission SIMBOL-X includes a focal plane array based on DEPFET macropixels, and one of the instruments on board the European Mercury exploration mission BepiColombo, the so-called MIXS (Mercury Imaging X-ray Spectrometer) instrument, also uses DEPFET macropixel based focal plane arrays for the detection of X-rays. In both cases, the performance of the respective X-ray optics demands the use of macropixel matrices due to the large required pixel sizes. The MPI semiconductor laboratory in Munich has produced prototype devices for SIMBOL-X with a large sensitive area as well as the first flight grade devices for the MIXS instrument; and the first large-area detectors have been tested. The devices show excellent performance in terms of energy resolution, peak-to-background ratio and homogeneity. Here, the requirements of the respective experiments on their detectors are outlined, together with the strategies to comply with the requirements by choosing a suitable readout strategy and an appropriate design of the focal plane instrumentation. Finally, the first test results of the large area macropixel prototype devices are shown.

DEPFET Macropixel detectors, based on the fusion of the combined Detector-Amplifier structure DEPFET with a silicon drift chamber (SDD) like drift ring structure, combine the excellent properties of the DEPFETs with the advantages of the drift detectors. As both device concepts rely on the principle of sideways depletion, a device entrance window with excellent properties is obtained at full depletion of the detector volume. DEPFET based focal plane arrays have been proposed for the Focal Plane Detectors for the MIXS (Mercury Imaging X-ray Spectrometer) instrument on BepiColombo, ESAs fifth cornerstone mission, with destination Mercury. MIXS uses a lightweight Wolter Type 1 mirror system to focus fluorescent radiation from the Mercury surface on the FPA detector, which yields the spatially resolved relative element abundance in Mercurys crust. In combination with the reference information from the Solar Intensity X-ray Spectrometer (SIXS), the element abundance can be measured quantitatively as well. The FPA needs to have an energy resolution better than 200 eV FWHM @ 1 keV and is required to cover an energy range from 0.5 keV to 10 keV, for a pixel size of 300 x 300 μm2. Main challenges for the instrument are the increase in leakage current due to a high level of radiation damage, and the limited cooling resources due to the difficult thermal environment in the mercury orbit. By applying an advanced cooling concept, using all available cooling power for the detector itself, and very high speed readout, the energy resolution requirement can be kept during the entire mission lifetime up to an end-of-life dose of ~ 3 × 1010 10 MeV p / cm2. The production of the first batch of flight devices has been finished at the MPI semiconductor laboratory, and first prototype modules have been built. The results of the first tests will be presented here.

Distinct expression patterns of keratins reflect different epithelial prototypes and different epithelial differentiation pathways. In order to get evidence of the expression of keratins in a hormone-dependent tissue in man, we investigated 70 epithelial tissue specimens by means of SDS-gel electrophoresis and immunoblot. Every tissue probe belonged to different generation phases such as sexual maturity, climacteric and postmenopausal period and pregnancy. Keratins 1(avb), 4(avb), 5(avb), 10(avb), 13, 14 were detected regularly whereas keratins 6, 16, and 19 are expressed irregularly. During all generation phases, with the exception of pregnancy, the keratins 1 and 10, associated with the epidermal differentiation, and keratins 4 and 13, associated with the differentiation to a non-keratinizing stratified epithelium, are synthesized simultaneously. However in pregnancy, i.e. pregnancy at term of delivery, only K4/K13 are expressed, while K1/K10 are below the detection limit. In terms of keratin expression vaginal epithelium represents a mosaic of differentiation. Only in pregnancy the 'pure' type of a nonkeratinizing epithelium is seen, apparently as a result of the high concentration of estrogens.

Minimization of the total detector capacitance due the small area readout node on one hand and to the integration of the front-end FET directly onto the detector (see Fig. 1a) on the other hand, combined with an ultra-low leakage current process makes the SDD with integrated FET an excellent energy resolving device with measured energy resolution down to 123 eV for Mn-Kα line at moderate temperatures (easily reached with Peltier cooling, e.g. -20°C) and very short shaping times 0.5 to 1 μs. These are performance values which can not be achieved by any other EDS detector.

The viscotoxin composition of the vegetative part of V. album determined by HPLC was found to be different in the three European subspecies. The characteristic differences in viscotoxin composition were not affected by the host species and by the harvesting seasons investigated. However, host-dependent differences in the total amount of viscotoxins were detected.

Since the anti-HER2 monoclonal antibody trastuzumab made its triumphant advance into breast cancer therapy, new selective agents, including pan-HER inhibitors are entering clinical practice.This study investigates the expression of the four HER-family members, HER1-4, in 48 primary breast carcinomas (PBC) and corresponding distant metastases (CDM) by immunohistochemistry and fluorescence in situ hybridisation.Concordance rate between PBC and CDM was 79% for HERI and HER2, 67% for HER3 and 56% or HER4. Expression of HER1-3 was associated with poor prognosis compared to HER-negative disease (p = 0.036). HER4 overexpression was associated with a better outcome (p = 0.003).Though most tumours demonstrate a stable HER expression pattern, both loss and acquisition of HER receptor overexpression can occur during metastasis. HER4 overexpression predicts prolonged survival compared to receptor negative disease, while the opposite is true for HER1-3. Consequences for modem antibody therapy are discussed.

The need of high quality spectroscopic semiconductor imaging detectors in X-ray astronomy was the principal driving force in founding the MPI Semiconductor Laboratory. Detectors developed in this laboratory are based on new function principles and are processed in the silicon detector processing line established within the laboratory. We describe the development of pnCCDs as already used in the XMM-Newton European X-ray observatory and foreseen for eROSITA, the DEPFET based pixel detector for XEUS and a new development which makes it possible to measure charge with a precision below one elementary charge. A noise value of 0.25 electron r.m.s. has already been reached.