Evaluation of a modular all-in-one high-resolution PET detector and readout electronics setup.

Objective. The all-in-one solution and modularity of the C13500 series TOF-PET detector modules (Hamamatsu Photonics K.K., Hamamatsu, Japan) make them a highly attractive candidate for the development of positron emission tomography (PET) systems. However, the commercially available portfolio targets clinical whole-body PET systems with a scintillation crystal cross area of 3.1 × 3.1 mm2. To extend the modules for high resolution (preclinical or organ specific) systems, the support for smaller scintillation crystals is required.Approach.In this work, a PET detector was developed based on the TOF-PET modules using a light sharing approach, 16 × 16 lutetium oxyorthosilicate (LSO) scintillation crystals with a size of 1.51 × 1.51 × 10.00 mm3readout with 8 × 8 photosensor channels of size 3.0 × 3.0 mm2. In addition to hardware and software development, the optimized parameter settings for the adapted configuration were evaluated.Main Results.A factor of two in amplification of the analog signal compared to the minimum gain setting was necessary for an accurate crystal identification (peak-to-valley ratio 14.9 ± 5.9). A further increase to a factor of three was not determined as optimum as the time over threshold duration, thus pile-up probability, increased from 1032.1 ± 109.5 to 1789.5 ± 218.5 ns (photopeak position). With this amplification a full width at half maximum (FWHM) energy resolution of 14.1 ± 2.0% and a high linearity of the energy detection was obtained. A FWHM coincidence resolving time (CRT) of 313 ps was achieved by using a low timing threshold, increasing the bandwidth of the front-end circuit and using a narrow ± 1σenergy window. To approximately double the sensitivity and reduce the power consumption, the timing parameters were adjusted resulting in a FWHM CRT of 354 ps (±2σ).Significance.Based on the results obtained with the proof-of-concept detector setup, we confirm the modularity and flexibility of the all-in-one TOF-PET detector modules for the future development of application-specific high-resolution PET systems.

Design and performance simulation studies of a breast PET insert integrable into a clinical whole-body PET/MRI scanner.

Objective. Three different breast positron emission tomography (PET) insert geometries are proposed for integration into an existing magnetic resonance imaging (MRI) breast coil (Breast Biopsy Coil, NORAS MRI products) to be used inside a whole-body PET/MRI scanner (Biograph mMR, Siemens Healthineers) to enhance the sensitivity and spatial resolution of imaging inside the breast.Approach. Monte Carlo simulations were performed to predict and compare the performance characteristics of the three geometries in terms of the sensitivity, spatial resolution, scatter fraction, and noise equivalent count rate (NECR). In addition, the background single count rate due to organ uptake in a clinical scan scenario was predicted using a realistic anthropomorphic phantom.Main results. In the center of the field of view (cFOV), absolute sensitivities of 3.1%, 2.7%, and 2.2% were found for Geometry A (detectors arranged in two cylinders), Geometry B (detectors arranged in two partial cylinders), and Geometry C (detectors arranged in two half cylinders combined with two plates), respectively. The full width at half maximum spatial resolution was determined to be 1.7 mm (Geometry A), 1.8 mm (Geometry B) and 2.0 mm (Geometry C) at 5 mm from the cFOV. Designs with multiple scintillation-crystal layers capable of determining the depth of interaction (DOI) strongly improved the spatial resolution at larger distances from the transaxial cFOV. The system scatter fractions were 33.1% (Geometries A and B) and 32.3% (Geometry C). The peak NECRs occurred at source activities of 300 MBq (Geometry A), 310 MBq (Geometry B) and 340 MBq (Geometry C). The background single-event count rates were 17.1 × 106cps (Geometry A), 15.3 × 106cps (Geometry B) and 14.8 × 106cps (Geometry C). Geometry A in the three-layer DOI variant exhibited the best PET performance characteristics but could be challenging to manufacture. Geometry C had the lowest impact on the spatial resolution and the lowest sensitivity among the investigated geometries.Significance. Geometry B in the two-layer DOI variant represented an effective compromise between the PET performance and manufacturing difficulty and was found to be a promising candidate for the future breast PET insert.

Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"

Dual layer doI detector modules for a dedicated mouse brain PET/MRI.

The outcome of preclinical imaging studies are enhanced by simultaneous, high-resolution anatomical and molecular data, which advanced PET/MRI systems provide. Nevertheless, mapping of neuroreceptors and accurate quantification of PET tracer distribution in mouse brains is not trivial. The restricted spatial resolution and sensitivity in commercial animal PET systems limits the image quality and the quantification accuracy. We are currently developing a PET/MRI system dedicated for mouse brain studies. The PET system will offer system dimensions of approx. 30 mm in diameter and an axial length of more than 38 mm. This work discusses two system geometries including their associated block detectors. Both configurations were based on a dual layer offset structure with small crystals sizes, in the order of 1  × 1 × 4/6 mm3, to provide discrete depth of interaction information. The detector for configuration 'A' was based on a 4 × 4 silicon photomultiplier (SiPM) array attached to an optical diffusor, and a 12 × 12 as well as a 9 × 11 LSO crystal array, to achieve optimal system sensitivity. This configuration was evaluated by a double layer of 12 × 12 crystals. Configuration 'B' was composed of three 2 × 2 SiPM arrays equipped with a 1 mm diffusor to read out an LSO stack of 20  × 6 and 19  × 5 individual crystals. The average peak-to-valley ratio of the inner/outer layer was 3.5/3.6 for detector 'A', and 3.4/2.8 for detector 'B'. The average full width at half maximum (FWHM) energy resolution of the block detectors were 22.24% ± 3.36% for 'A' and 30.67% ± 5.37% for 'B'. The FWHM of the full block timing resolution of the inner/outer layer was 1.4 ns/1.2 ns for detector 'A' and 1.8 ns/1.4 ns for 'B'. The performance of the crystal position profile, the energy, and timing resolution indicate that configuration 'A' is more appropriate for a mouse brain PET/MRI system.

Optimization, evaluation and calibration of a cross-strip DOI detector.

This study depicts the evaluation of a SiPM detector with depth of interaction (DOI) capability via a dual-sided readout that is suitable for high-resolution positron emission tomography and magnetic resonance (PET/MR) imaging. Two different 12 × 12 pixelated LSO scintillator arrays with a crystal pitch of 1.60 mm are examined. One array is 20 mm-long with a crystal separation by the specular reflector Vikuiti enhanced specular reflector (ESR), and the other one is 18 mm-long and separated by the diffuse reflector Lumirror E60 (E60). An improvement in energy resolution from 22.6% to 15.5% for the scintillator array with the E60 reflector is achieved by taking a nonlinear light collection correction into account. The results are FWHM energy resolutions of 14.0% and 15.5%, average FWHM DOI resolutions of 2.96 mm and 1.83 mm, and FWHM coincidence resolving times of 1.09 ns and 1.48 ns for the scintillator array with the ESR and that with the E60 reflector, respectively. The measured DOI signal ratios need to be assigned to an interaction depth inside the scintillator crystal. A linear and a nonlinear method, using the intrinsic scintillator radiation from lutetium, are implemented for an easy to apply calibration and are compared to the conventional method, which exploits a setup with an externally collimated radiation beam. The deviation between the DOI functions of the linear or nonlinear method and the conventional method is determined. The resulting average of differences in DOI positions is 0.67 mm and 0.45 mm for the nonlinear calibration method for the scintillator array with the ESR and with the E60 reflector, respectively; Whereas the linear calibration method results in 0.51 mm and 0.32 mm for the scintillator array with the ESR and the E60 reflector, respectively; and is, due to its simplicity, also applicable in assembled detector systems.

Combined PET/MRI: Global Warming-Summary Report of the 6th International Workshop on PET/MRI, March 27-29, 2017, Tübingen, Germany.

The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tübingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.

Evaluation of the accuracy of nine electronic apex locators by using Micro-CT.

AIM: To determine the accuracy of locating the apical constriction using apex locators. METHODOLOGY: Extracted teeth were micro-CT scanned preoperatively to localize the apical constriction. Electronic length measurements of 91 root canals were made using nine electronic apex locators (EAL) connected to a mounting model. Distances from the major foramen were recorded at each scale bar of the EALs, and a file was fixed in the canal at a position indicated by each EAL to be the apical constriction. A second micro-CT scan was conducted, and distances from the file tip to constriction and major foramen were calculated for each EAL. The accuracy of EALs was determined with a tolerance of 0.1, 0.25, 0.5 and 1 mm, and the 95% confidence interval was used to compare the EALs. A rank analysis was performed in which measurements beyond the major foramen were considered as inaccurate. RESULTS: Regardless of the type of teeth, there was no significant difference in the accuracy of determining the apical constriction and major foramen between the nine EALs within a tolerance of ±0.5 mm and 1 mm, but there was a significant difference for the tolerances of ±0.1 and 0.25 mm. The highest ranks close to the constriction (98% and 94%) and to the major foramen (86% and 73%) were observed in Dentaport ZX and Elements Diagnostic Unit, respectively. Overestimation of working length beyond the major foramen was observed in all EALs (5% to 71%) when the scale for the major foramen, as recommended by the manufacturers, was used. However, when the scale for the constriction was used, only 3% of the measurements were beyond the major foramen. CONCLUSION: Electronic apex locators were able to determine the apical constriction. Using EALs to determine the major foramen led to overestimation of the working length. Therefore, it may be recommended to use the EAL scale of the constriction.

A novel optically transparent RF shielding for fully integrated PET/MRI systems.

Preclinical imaging benefits from simultaneous acquisition of high-resolution anatomical and molecular data. Additionally, PET/MRI systems can provide functional PET and functional MRI data. To optimize PET sensitivity, we propose a system design that fully integrates the MRI coil into the PET system. This allows positioning the scintillators near the object but requires an optimized design of the MRI coil and PET detector. It further requires a new approach in realizing the radiofrequency (RF) shielding. Thus, we propose the use of an optically transparent RF shielding material between the PET scintillator and the light sensor, suppressing the interference between both systems. We evaluated two conductive foils (ITO, 9900) and a wire mesh. The PET performance was tested on a dual-layer scintillator consisting of 12 × 12 LSO matrices, shifted by half a pitch. The pixel size was 0.9 × 0.9 mm2; the lengths were 10.0 mm and 5.0 mm, respectively. For a light sensor, we used a 4 × 4 SiPM array. The RF attenuation was measured from 320 kHz to 420 MHz using two pick-up coils. MRI-compatibility and shielding effect of the materials were evaluated with an MRI system. The average FWHM energy resolution at 511 keV of all 144 crystals of the layer next to the SiPM was deteriorated from 15.73 ± 0.24% to 16.32 ± 0.13%, 16.60 ± 0.25%, and 19.16 ± 0.21% by the ITO foil, 9900 foil, mesh material, respectively. The average peak-to-valley ratio of the PET detector changed from 5.77 ± 0.29 to 4.50 ± 0.39, 4.78 ± 0.48, 3.62 ± 0.16, respectively. The ITO, 9900, mesh attenuated the scintillation light by 11.3 ± 1.6%, 11.0 ± 1.8%, 54.3 ± 0.4%, respectively. To attenuate the RF from 20 MHz to 200 MHz, mesh performed better than copper. The results show that an RF shielding material that is sufficiently transparent for scintillation light and is MRI compatible can be obtained. This result enables the development of a fully integrated PET detector and MRI coil assembly.

Validity of longitudinal sections for determining the apical constriction.

AIM: To validate the use of longitudinal sections against cross sections using micro-CT for disclosing the topography and location of the apical constriction. METHODOLOGY: Seventy extracted human teeth with 117 completely developed roots were micro-CT scanned and reconstructed at a voxel size of 27 µm. The 3DSlicer program was used to navigate the longitudinal sections parallel to the long axis of the canal and also to rotate and tilt the views. Each root canal was evaluated in both mesio-distal and bucco-lingual planes. Constriction topographies were identified as described in the literature. In each canal, the number of different topographies detected was recorded. Further, serial cross-sectional analysis of the apical portion of the canal was performed. Reconstructed plots of canal areas were assessed to locate the constriction and determine its form. A descriptive analysis of both longitudinal and cross section methods was conducted. In each canal, the frequency of constriction forms was calculated in the mesio-distal or bucco-lingual aspects and the 99% confidence interval was computed. RESULTS: When both aspects of the longitudinal sections were pooled, all root canals had two or more topographies and consequently different locations of the apical constriction. In contrast, cross-sectional analysis constantly yielded one constriction form per canal. CONCLUSION: Compared to cross-sectional analysis, longitudinal sections of the root canal conveyed inconsistent results regarding the topography and the location of the apical constriction.

Combined PET/MRI: from Status Quo to Status Go. Summary Report of the Fifth International Workshop on PET/MR Imaging; February 15-19, 2016; Tübingen, Germany.

This article provides a collaborative perspective of the discussions and conclusions from the fifth international workshop of combined positron emission tomorgraphy (PET)/magnetic resonance imaging (MRI) that was held in Tübingen, Germany, from February 15 to 19, 2016. Specifically, we summarise the second part of the workshop made up of invited presentations from active researchers in the field of PET/MRI and associated fields augmented by round table discussions and dialogue boards with specific topics. This year, this included practical advice as to possible approaches to moving PET/MRI into clinical routine, the use of PET/MRI in brain receptor imaging, in assessing cardiovascular diseases, cancer, infection, and inflammatory diseases. To address perceived challenges still remaining to innovatively integrate PET and MRI system technologies, a dedicated round table session brought together key representatives from industry and academia who were engaged with either the conceptualisation or early adoption of hybrid PET/MRI systems. Discussions during the workshop highlighted that emerging unique applications of PET/MRI such as the ability to provide multi-parametric quantitative and visual information which will enable not only overall disease detection but also disease characterisation would eventually be regarded as compelling arguments for the adoption of PET/MR. However, as indicated by previous workshops, evidence in favour of this observation is only growing slowly, mainly due to the ongoing inability to pool data cohorts from independent trials as well as different systems and sites. The participants emphasised that moving from status quo to status go entails the need to adopt standardised imaging procedures and the readiness to act together prospectively across multiple PET/MRI sites and vendors.

Combined PET/MRI: Multi-modality Multi-parametric Imaging Is Here: Summary Report of the 4th International Workshop on PET/MR Imaging; February 23-27, 2015, Tübingen, Germany.

This paper summarises key themes and discussions from the 4th international workshop dedicated to the advancement of the technical, scientific and clinical applications of combined positron emission tomography (PET)/magnetic resonance imaging (MRI) systems that was held in Tübingen, Germany, from February 23 to 27, 2015. Specifically, we summarise the three days of invited presentations from active researchers in this and associated fields augmented by round table discussions and dialogue boards with specific topics. These include the use of PET/MRI in cardiovascular disease, paediatrics, oncology, neurology and multi-parametric imaging, the latter of which was suggested as a key promoting factor for the wider adoption of integrated PET/MRI. Discussions throughout the workshop and a poll taken on the final day demonstrated that attendees felt more strongly that PET/MRI has further advanced in both technical versatility and acceptance by clinical and research-driven users from the status quo of last year. Still, with only minimal evidence of progress made in exploiting the true complementary nature of the PET and MRI-based information, PET/MRI is still yet to achieve its potential. In that regard, the conclusion of last year's meeting "the real work has just started" still holds true.

Identification of RIP1 as a critical mediator of Smac mimetic-mediated sensitization of glioblastoma cells for Drozitumab-induced apoptosis.

This study aims at evaluating the combination of the tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL)-receptor 2 (TRAIL-R2)-specific antibody Drozitumab and the Smac mimetic BV6 in preclinical glioblastoma models. To this end, the effect of BV6 and/or Drozitumab on apoptosis induction and signaling pathways was analyzed in glioblastoma cell lines, primary glioblastoma cultures and glioblastoma stem-like cells. Here, we report that BV6 and Drozitumab synergistically induce apoptosis and reduce colony formation in several glioblastoma cell lines (combination index<0.1). Also, BV6 profoundly enhances Drozitumab-induced apoptosis in primary glioblastoma cultures and glioblastoma stem-like cells. Importantly, BV6 cooperates with Drozitumab to suppress tumor growth in two glioblastoma in vivo models including an orthotopic, intracranial mouse model, underlining the clinical relevance of these findings. Mechanistic studies reveal that BV6 and Drozitumab act in concert to trigger the formation of a cytosolic receptor-interacting protein (RIP) 1/Fas-associated via death domain (FADD)/caspase-8-containing complex and subsequent activation of caspase-8 and -3. BV6- and Drozitumab-induced apoptosis is blocked by the caspase inhibitor zVAD.fmk, pointing to caspase-dependent apoptosis. RNA interference-mediated silencing of RIP1 almost completely abolishes the BV6-conferred sensitization to Drozitumab-induced apoptosis, indicating that the synergism critically depends on RIP1 expression. In contrast, both necrostatin-1, a RIP1 kinase inhibitor, and Enbrel, a TNFα-blocking antibody, do not interfere with BV6/Drozitumab-induced apoptosis, demonstrating that apoptosis occurs independently of RIP1 kinase activity or an autocrine TNFα loop. In conclusion, the rational combination of BV6 and Drozitumab presents a promising approach to trigger apoptosis in glioblastoma, which warrants further investigation.

Combined PET/MR: The Real Work Has Just Started. Summary Report of the Third International Workshop on PET/MR Imaging; February 17-21, 2014, Tübingen, Germany.

This paper summarises the proceedings and discussions at the third annual workshop held in Tübingen, Germany, dedicated to the advancement of the technical, scientific and clinical applications of combined PET/MRI systems in humans. Two days of basic scientific and technical instructions with "hands-on" tutorials were followed by 3 days of invited presentations from active researchers in this and associated fields augmented by round-table discussions and dialogue boards with specific themes. These included the use of PET/MRI in paediatric oncology and in adult neurology, oncology and cardiology, the development of multi-parametric analyses, and efforts to standardise PET/MRI examinations to allow pooling of data for evaluating the technology. A poll taken on the final day demonstrated that over 50 % of those present felt that while PET/MRI technology underwent an inevitable slump after its much-anticipated initial launch, it was now entering a period of slow, progressive development, with new key applications emerging. In particular, researchers are focusing on exploiting the complementary nature of the physiological (PET) and biochemical (MRI/MRS) data within the morphological framework (MRI) that these devices can provide. Much of the discussion was summed up on the final day when one speaker commented on the state of PET/MRI: "the real work has just started".

Development of a novel depth of interaction PET detector using highly multiplexed G-APD cross-strip encoding.

PURPOSE: The aim of this study was to develop a prototype PET detector module for a combined small animal positron emission tomography and magnetic resonance imaging (PET/MRI) system. The most important factor for small animal imaging applications is the detection sensitivity of the PET camera, which can be optimized by utilizing longer scintillation crystals. At the same time, small animal PET systems must yield a high spatial resolution. The measured object is very close to the PET detector because the bore diameter of a high field animal MR scanner is limited. When used in combination with long scintillation crystals, these small-bore PET systems generate parallax errors that ultimately lead to a decreased spatial resolution. Thus, we developed a depth of interaction (DoI) encoding PET detector module that has a uniform spatial resolution across the whole field of view (FOV), high detection sensitivity, compactness, and insensitivity to magnetic fields. METHODS: The approach was based on Geiger mode avalanche photodiode (G-APD) detectors with cross-strip encoding. The number of readout channels was reduced by a factor of 36 for the chosen block elements. Two 12 × 2 G-APD strip arrays (25 µm cells) were placed perpendicular on each face of a 12 × 12 lutetium oxyorthosilicate crystal block with a crystal size of 1.55 × 1.55 × 20 mm. The strip arrays were multiplexed into two channels and used to calculate the x, y coordinates for each array and the deposited energy. The DoI was measured in step sizes of 1.8 mm by a collimated (18)F source. The coincident resolved time (CRT) was analyzed at all DoI positions by acquiring the waveform for each event and applying a digital leading edge discriminator. RESULTS: All 144 crystals were well resolved in the crystal flood map. The average full width half maximum (FWHM) energy resolution of the detector was 12.8% ± 1.5% with a FWHM CRT of 1.14 ± 0.02 ns. The average FWHM DoI resolution over 12 crystals was 2.90 ± 0.15 mm. CONCLUSIONS: The novel DoI PET detector, which is based on strip G-APD arrays, yielded a DoI resolution of 2.9 mm and excellent timing and energy resolution. Its high multiplexing factor reduces the number of electronic channels. Thus, this cross-strip approach enables low-cost, high-performance PET detectors for dedicated small animal PET and PET/MRI and potentially clinical PET/MRI systems.

Akt2/PKBbeta-sensitive regulation of renal phosphate transport.

AIM: The protein kinase B (PKB)/Akt is known to stimulate the cellular uptake of glucose and amino acids. The kinase is expressed in proximal renal tubules. The present study explored the influence of Akt/PKB on renal tubular phosphate transport. METHODS: The renal phosphate transporter NaPi-IIa was expressed in Xenopus oocytes with or without PKB/Akt and Na(+) phosphate cotransport determined using dual electrode voltage clamp. Renal phosphate excretion was determined in Akt2/PKBbeta knockout mice (akt2(-/-)) and corresponding wild-type mice (akt2(+/+)). Transporter protein abundance was determined using Western blotting and phosphate transport by (32)P uptake into brush border membrane vesicles. RESULTS: The phosphate-induced current in NaPi-IIa-expressing Xenopus oocytes was significantly increased by the coexpression of Akt/PKB. Phosphate excretion [micromol per 24 h per g BW] was higher by 91% in akt2(-/-) than in akt2(+/+) mice. The phosphaturia of akt2(-/-) mice occurred despite normal transport activity and expression of the renal phosphate transporters NaPi-IIa, NaPi-IIc and Pit2 in the brush border membrane, a significantly decreased plasma PTH concentration (by 46%) and a significantly enhanced plasma 1,25-dihydroxyvitamin D(3) concentration (by 46%). Moreover, fractional renal Ca(2+) excretion was significantly enhanced (by 53%) and bone density significantly reduced (by 11%) in akt2(-/-) mice. CONCLUSIONS: Akt2/PKBbeta plays a role in the acute regulation of renal phosphate transport and thus contributes to the maintenance of phosphate balance and adequate mineralization of bone.

Combined PET/MR imaging--technology and applications.

The combination of PET and MR in one imaging device has certain advantages over conventional imaging modalities. These include: no additional radiation dose from the MR, superior soft tissue contrast and a multitude of tracers for PET. Certain technical challenges exist when designing a PET/MR system. On the one hand these stem from the presence of the strong MR magnetic field and the addition of PET components to the MR system. Different approaches are presented to overcome these technical obstacles ranging from long optical fibers to systems that use semiconductor light detectors for photon counting. The applications of combined PET/MR are profound in the field of oncology and allow imaging of the four main processes in cancer formation: apoptosis resistance, angiogenesis, proliferation and metastasis. PET/MR has also many clinical and research applications in neurology and cardiology. Alternative techniques such as image fusion, hyperpolarized imaging, 17O imaging and whole body diffusion are discussed in respect to their relevance regarding PET/MR. Simultaneous multifunctional and anatomical imaging using PET/MR has a great potential to impact biomedical imaging in research and clinic.

Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent.

The development of new treatments in the post-genomic era requires methods for safe delivery of foreign genetic information in vivo. As a transient, natural and controllable alternative to recombinant viruses or plasmid DNA (pDNA), purified or in vitro transcribed messenger RNA (mRNA) can be used for the expression of any therapeutic protein in vitro and in vivo. As it has been shown previously, the simple injection of naked mRNA results in local uptake and expression. We show here that this process, in the skin, can greatly be modulated according to the injection solution composition and blocked by an excess of competing nucleic acids or a drug affecting cytosolic mobility. Different cell types at the site of injection can take up the foreign nucleic acid molecules and the protein translated from this is detected for no more than a few days. To test this gene transfer method in humans, we produced in vitro transcribed mRNA under good manufacturing practice (GMP) conditions in a dedicated facility. After injection into the human dermis, we could document the translation of the exogenous mRNA. Our results pave the way toward the use of mRNA as a vehicle for transient gene delivery in humans.

Lutetium oxyorthosilicate block detector readout by avalanche photodiode arrays for high resolution animal PET.

Avalanche photodiodes (APDs) have proven to be useful as light detectors for high resolution positron emission tomography (PET). Their compactness makes these devices excellent candidates for replacing bulky photomultiplier tubes (PMTs) in PET systems where space limitations are an issue. The readout of densely packed, 10 x 10 lutetium oxyorthosilicate (LSO) block detectors (crystal size 2.0 x 2.0 x 12 mm3) with custom-built monolithic 3 x 3 APD arrays was investigated. The APDs had a 5 x 5 mm2 active surface and were arranged on a 6.25 mm pitch. The dead space on the edges of the array was 1.25 mm. The APDs were operated at a bias voltage of approximately 380 V for a gain of 100 and a dark current of 10 nA per APD. The standard deviation in gain between the APDs in the array ranged from 1.8 to 6.5% as the gain was varied from 50 to 108. A fast, low-noise, multi-channel charge sensitive preamplifier application-specific integrated circuit (ASIC) was developed for the APD readout. The amplifier had a rise time of 8 ns, a noise floor of 515 e- rms and a 9 e- pF(-1) noise slope. An acquired flood image showed that all 100 crystals from the block detector could be resolved. Timing measurements with single-channel LSO-APD detectors, as well as with the array, against a plastic scintillator and PMT assembly showed a time resolution of 1.2 ns and 2.5 ns, respectively. The energy resolution measured with a single 4.0 x 4.0 x 10 mm3 LSO crystal, wrapped in four-layer polytetrafluoroethylene (PTFE) tape and coupled with optical grease on a single APD of the array, yielded 15% (full width at half maximum, FWHM) at 511 keV. Stability tests over 9 months of operation showed that the APD arrays do not degrade appreciably. These results demonstrate the ability to decode densely packed LSO scintillation blocks with compact APD arrays. The good timing and energy resolution makes these detectors suitable for high resolution PET.

Inter-crystal scatter in a dual layer, high resolution LSO-APD positron emission tomograph.

Improving system efficiency without jeopardizing spatial resolution is one of the main problems of small animal PET scanners. In pursuit of this goal, the future LSO-APD-PET prototype MADPET-II will combine highly granulated detector modules with a dual layer structure. The individual readout of the LSO crystals allows separately handling multiple signals related to those photons scattering between different crystal units (inter-crystal scatter, ICS). The contribution of ICS events can significantly increase the system efficiency. Such coincidences are not characterized by a unique LOR. However, in order to minimize resolution degradation, it would be desirable to identify the primary path of the ICS events. Since ICS is geometry dependent, this work was aimed at investigating the effects of ICS in the performance of the dual layer prototype. Different recovery algorithms to select the primary crystal were implemented and developed, and applied to Monte Carlo simulated data. Some of these algorithms were based on the properties of Compton kinematics. For a centred point source and a 100 keV lower energy threshold, the absolute system efficiency was found to increase by 35% when including ICS events: from 1.8% without ICS events to 2.8% with ICS. Similarly, for a threshold of 200 keV, the contribution of ICS coincidences still represented approximately 20% of the total detected coincidences, leading to an absolute system efficiency of almost 2%. The mispositioning introduced by processing ICS coincidences only led to a moderate broadening of the axial line spread function (LSF), especially at the tails of the profile (FWTM). This effect was also noticeable in the transaxial plane. In presence of scattering media (water-filled cylinder), the resolution degradation was dominated by the contribution of object scatter. The reconstructed images from a simulated homogeneous cylinder filled with activity with a non-active rod at its centre were employed to estimate the impact of ICS on the image quality. In general, the use of ICS coincidences increased the signal-to-noise ratio (SNR) but worsened contrast. The effects of ICS on resolution could be reduced by employing a new identification scheme based on the maximum signal and the Compton kinematics. This method yielded the highest identification rate for the correct photon trajectory, even for a finite energy resolution of 15% (511 keV). This technique also increased the SNR by 17% to 30% and preserved the image contrast. In conclusion, by combining individual crystal readout, a low energy threshold and an appropriate recovery scheme, the processing of ICS coincidences significantly increases the system efficiency without any substantial deterioration of the image quality.