Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC.

The T cell receptor (TCR) expressed by T lymphocytes initiates protective immune responses to pathogens and tumors. To explore the structural basis of how TCR signaling is initiated when the receptor binds to peptide-loaded major histocompatibility complex (pMHC) molecules, we used cryogenic electron microscopy to determine the structure of a tumor-reactive TCRαß/CD3δγε2ζ2 complex bound to a melanoma-specific human class I pMHC at 3.08 Å resolution. The antigen-bound complex comprises 11 subunits stabilized by multivalent interactions across three structural layers, with clustered membrane-proximal cystines stabilizing the CD3-εδ and CD3-εγ heterodimers. Extra density sandwiched between transmembrane helices reveals the involvement of sterol lipids in TCR assembly. The geometry of the pMHC/TCR complex suggests that efficient TCR scanning of pMHC requires accurate pre-positioning of T cell and antigen-presenting cell membranes. Comparisons of the ligand-bound and unliganded receptors, along with molecular dynamics simulations, indicate that TCRs can be triggered in the absence of spontaneous structural rearrangements.

Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells.

Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rß1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rß1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rß2/IL-12Rß1 and IL-23 receptor (IL-23R) complexes, which reveal "non-canonical" topologies where IL-12Rß1 directly engages the common p40 subunit. We targeted the shared IL-12Rß1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8+ T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.

Structural and Mechanistic Principles of ABC Transporters.

ATP-binding cassette (ABC) transporters constitute one of the largest and most ancient protein superfamilies found in all living organisms. They function as molecular machines by coupling ATP binding, hydrolysis, and phosphate release to translocation of diverse substrates across membranes. The substrates range from vitamins, steroids, lipids, and ions to peptides, proteins, polysaccharides, and xenobiotics. ABC transporters undergo substantial conformational changes during substrate translocation. A comprehensive understanding of their inner workings thus requires linking these structural rearrangements to the different functional state transitions. Recent advances in single-particle cryogenic electron microscopy have not only delivered crucial information on the architecture of several medically relevant ABC transporters and their supramolecular assemblies, including the ATP-sensitive potassium channel and the peptide-loading complex, but also made it possible to explore the entire conformational space of these nanomachines under turnover conditions and thereby gain detailed mechanistic insights into their mode of action.

Structural linkage between ligand discrimination and receptor activation by type I interferons.

Type I Interferons (IFNs) are important cytokines for innate immunity against viruses and cancer. Sixteen human type I IFN variants signal through the same cell-surface receptors, IFNAR1 and IFNAR2, yet they can evoke markedly different physiological effects. The crystal structures of two human type I IFN ternary signaling complexes containing IFNα2 and IFNω reveal recognition modes and heterotrimeric architectures that are unique among the cytokine receptor superfamily but conserved between different type I IFNs. Receptor-ligand cross-reactivity is enabled by conserved receptor-ligand "anchor points" interspersed among ligand-specific interactions that "tune" the relative IFN-binding affinities, in an apparent extracellular "ligand proofreading" mechanism that modulates biological activity. Functional differences between IFNs are linked to their respective receptor recognition chemistries, in concert with a ligand-induced conformational change in IFNAR1, that collectively control signal initiation and complex stability, ultimately regulating differential STAT phosphorylation profiles, receptor internalization rates, and downstream gene expression patterns.

Conformation space of a heterodimeric ABC exporter under turnover conditions.

Cryo-electron microscopy (cryo-EM) has the capacity to capture molecular machines in action1-3. ATP-binding cassette (ABC) exporters are highly dynamic membrane proteins that extrude a wide range of substances from the cytosol4-6 and thereby contribute to essential cellular processes, adaptive immunity and multidrug resistance7,8. Despite their importance, the coupling of nucleotide binding, hydrolysis and release to the conformational dynamics of these proteins remains poorly resolved, especially for heterodimeric and/or asymmetric ABC exporters that are abundant in humans. Here we present eight high-resolution cryo-EM structures that delineate the full functional cycle of an asymmetric ABC exporter in a lipid environment. Cryo-EM analysis under active turnover conditions reveals distinct inward-facing (IF) conformations-one of them with a bound peptide substrate-and previously undescribed asymmetric post-hydrolysis states with dimerized nucleotide-binding domains and a closed extracellular gate. By decreasing the rate of ATP hydrolysis, we could capture an outward-facing (OF) open conformation-an otherwise transient state vulnerable to substrate re-entry. The ATP-bound pre-hydrolysis and vanadate-trapped states are conformationally equivalent; both comprise co-existing OF conformations with open and closed extracellular gates. By contrast, the post-hydrolysis states from the turnover experiment exhibit asymmetric ATP and ADP occlusion after phosphate release from the canonical site and display a progressive separation of the nucleotide-binding domains and unlocking of the intracellular gate. Our findings reveal that phosphate release, not ATP hydrolysis, triggers the return of the exporter to the IF conformation. By mapping the conformational landscape during active turnover, aided by mutational and chemical modulation of kinetic rates to trap the key intermediates, we resolved fundamental steps of the substrate translocation cycle of asymmetric ABC transporters.

CT in Patients With External Fixation for Complex Lower Extremity Fractures: Impact of Iterative Metal Artifact Reduction Techniques on Metal Artifact Burden and Subjective Quality.

BACKGROUND. Lower extremity external fixators have complex geometries that induce pronounced metal artifact on CT. Iterative metal artifact reduction (iMAR) algorithms help reduce such artifact, although no dedicated iMAR preset exists for external fixators. OBJECTIVE. The purpose of our study was to compare iMAR presets for CT examinations in terms of quantitative metal artifact burden and subjective image quality in patients with external fixators for complex lower extremity fractures. METHODS. This retrospective study included 72 CT examinations in 56 patients (20 women, 36 men; mean age, 56 ± 18 [SD] years) with lower extremity external fixators (regular, hybrid, or monotube). Examinations were reconstructed without iMAR (hereafter referred to as "noMAR") and with three iMAR presets (iMARspine, iMARhip, iMARextremity). A radiology resident quantified metal artifact burden using software. Two radiology residents independently assessed overall image quality and diagnostic confidence using 4-point scales (4 = excellent [highest quality or highest confidence]). Techniques were compared using Bonferroni-corrected post hoc tests. Interreader agreement was assessed by intraclass correlation coefficients (ICCs). A post hoc multinomial regression model was used for predicting overall image quality. RESULTS. Mean quantitative metal artifact burden was 100,816 ± 45,558 for noMAR, 88,889 ± 44,028 for iMARspine, 82,295 ± 41,983 for iMARhip, and 81,956 ± 41,890 for iMARextremity. Overall image quality yielded an ICC of 0.94 or greater. Using pooled reader data, median overall image quality score for the regular fixator was 2 (noMAR), 3 (iMARspine and iMARhip), and 4 (iMARextremity); for the hybrid fixator, 1 (noMAR), 2 (iMARspine), and 3 (iMARhip and iMARextremity); and for the monotube fixator, 2 (noMAR), 3 (iMARspine and iMARhip), and 4 (iMARextremity). Metal artifact burden was lower and overall image quality was higher (p < .05) for iMARhip and iMARextremity than noMAR and iMARspine for all fixators (aside from image quality of iMARhip and iMARextremity vs iMARspine for regular fixators) but were not different (all, p > .05) between iMARhip and iMARextremity. Median diagnostic confidence was 4 for all fixators and reconstructions. Independent predictors of overall quality relative to noMAR were iMARspine (odds ratio [OR] = 1.92-5.51), iMARhip (OR = 5.56-31.10), and iMARextremity (OR = 7.07-38.21). All iMAR presets introduced new reconstruction artifacts for all examinations for both readers. CONCLUSION. For the three fixator types, iMARhip and iMARextremity achieved greatest metal artifact burden reduction and highest subjective image quality, although both introduced new reconstruction artifacts. CLINICAL IMPACT. CT using the two identified iMAR presets may facilitate perioperative management of external fixators.

Solid-Phase Reference Baths for Fiber-Optic Distributed Sensing.

Observations from Raman backscatter-based Fiber-Optic Distributed Sensing (FODS) require reference sections of the fiber-optic cable sensor of known temperature to translate the primary measured intensities of Stokes and anti-Stokes photons to the secondary desired temperature signal, which also commonly forms the basis for other derived quantities. Here, we present the design and the results from laboratory and field evaluations of a novel Solid-Phase Bath (SoPhaB) using ultrafine copper instead of the traditional mechanically stirred liquid-phase water bath. This novel type is suitable for all FODS applications in geosciences and industry when high accuracy and precision are needed. The SoPhaB fully encloses the fiber-optic cable which is coiled around the inner core and surrounded by tightly interlocking parts with a total weight of 22 kg. The SoPhaB is thermoelectrically heated and/or cooled using Peltier elements to control the copper body temperature within ±0.04 K using commercially available electronic components. It features two built-in reference platinum wire thermometers which can be connected to the distributed temperature sensing instrument and/or external measurement and logging devices. The SoPhaB is enclosed in an insulated carrying case, which limits the heat loss to or gains from the outside environment and allows for mobile applications. For thermally stationary outside conditions the measured spatial temperature differences across SoPhaB parts touching the fiber-optic cable are <0.05 K even for stark contrasting temperatures of ΔT> 40 K between the SoPhaB's setpoint and outside conditions. The uniform, stationary known temperature of the SoPhaB allows for substantially shorter sections of the fiber-optic cable sensors of less than <5 bins at spatial measurement resolution to achieve an even much reduced calibration bias and spatiotemporal uncertainty compared to traditional water baths. Field evaluations include deployments in contrasting environments including the Arctic polar night as well as peak summertime conditions to showcase the wide range of the SoPhaB's applicability.

Typical doses and typical values for fluoroscopic diagnostic and interventional procedures.

To implement typical doses (TD) and typical values (TV) for fluoroscopic diagnostic and interventional procedures. A total of 3811 fluoroscopic procedures performed within 34 months on three devices were included in this retrospective study. Dose-, patient- and procedure-related information were extracted using the institutional dose management system (DMS). TD/TV were defined as median dose and calculated for the five most frequent procedures per device for dose area product (DAP), cumulative air kerma (CAK) and fluoroscopy time (FT). National diagnostic reference levels and other single facility studies were compared to our results. Additionally, the five procedures with the highest doses of each device were analysed. To evaluate the data coverage of the DMS compared to the picture archiving and communication system (PACS), procedure lists were extracted from the PACS and compared to the procedure information extracted from the DMS. TD/TV for 15 procedures were implemented. Among all devices, TD for DAP ranged between 0.6 Gycm2for port catheter control (n= 64) and 145.9 Gycm2for transarterial chemoembolisation (n= 84). TD for CAK ranged between 5 mGy for port catheter control and 1397 mGy for aneurysm treatment (n= 129) and TV for FT ranged between 0.3 min for upper cavography (n= 67) and 51.4 min for aneurysm treatment. TD for DAP and CAK were lower or within the range of other single facility studies. The five procedures with the highest median DAP per device were identified, 6 of 15 procedures were also found to be among the most frequent procedures. Data coverage of the DMS compared to the PACS ranged between 71% (device 2, stroke treatment) and 78% (device 1, lower limb angiography) for the most common procedure per device. Thus, in 22%-29% of cases dose data of the performed procedure was not transferred into the DMS. We implemented TD/TV for fluoroscopic diagnostic and interventional procedures which enable a comprehensive dose analysis and comparison with previously published values.

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP.

ABC transporters form one of the largest protein superfamilies in all domains of life, catalyzing the movement of diverse substrates across membranes. In this key position, ABC transporters can mediate multidrug resistance in cancer therapy and their dysfunction is linked to various diseases. Here, we describe the 2.7-Å X-ray structure of heterodimeric Thermus thermophilus multidrug resistance proteins A and B (TmrAB), which not only shares structural homology with the antigen translocation complex TAP, but is also able to restore antigen processing in human TAP-deficient cells. TmrAB exhibits a broad peptide specificity and can concentrate substrates several thousandfold, using only one single active ATP-binding site. In our structure, TmrAB adopts an asymmetric inward-facing state, and we show that the C-terminal helices, arranged in a zipper-like fashion, play a crucial role in guiding the conformational changes associated with substrate transport. In conclusion, TmrAB can be regarded as a model system for asymmetric ABC exporters in general, and for TAP in particular.

Development of size-specific institutional diagnostic reference levels for computed tomography protocols in neck imaging.

PURPOSE: To develop size-specific institutional diagnostic reference levels (DRLs) for computed tomography (CT) protocols used in neck CT imaging (cervical spine CT, cervical CT angiography (CTA) and cervical staging CT) and to compare institutional to national DRLs. MATERIALS AND METHODS: Cervical CT examinations (spine, n = 609; CTA, n = 505 and staging CT, n = 184) performed between 01/2016 and 06/2017 were included in this retrospective study. For each region and examination, the volumetric CT dose index (CTDIvol) and dose-length product (DLP) were determined and binned into size bins according to patient water-equivalent diameter (dw). Linear regression analysis was performed to calculate size-specific institutional DRLs for CTDIvol and DLP, applying the 75th percentile as the upper limit for institutional DRLs. The mean institutional CTDIvol and DLP were compared to national DRLs (CTDIvol 20 mGy for cervical spine CT (DLP 300 mGycm) and cervical CTA (DLP 600 mGycm), and CTDIvol 15 mGy for cervical staging CT (DLP 330 mGycm)). RESULTS: The mean CTDIvol and DLP (±standard deviation) were 15.2 ± 4.1 mGy and 181.5 ± 88.3 mGycm for cervical spine CT; 8.1 ± 4.3 mGy and 280.2 ± 164.3 mGycm for cervical CTA; 8.6 ± 1.9 mGy and 162.8 ± 85.0 mGycm for cervical staging CT. For all CT protocols, there was a linear increase in CTDIvol and DLP with increasing dw. For the CTDIvol, size-specific institutional DRLs increased with dw from 14 to 29 mGy for cervical spine CT, from 5 to 17 mGy for cervical CTA and from 8 to 13 mGy for cervical staging CT. For the DLP, size-specific institutional DRLs increased with dw from 130 to 510 mGycm for cervical spine CT, from 140 to 640 mGycm for cervical CTA and from 140 to 320 mGycm for cervical staging CT. Institutional DRLs were lower than national DRLs by 81% and 67% for cervical spine CT (dw = 17.8 cm), 43% and 51% for cervical CTA (dw = 19.5 cm) and 59% and 53% for cervical staging CT (dw = 18.8 cm) for CTDIvol and DLP, respectively. CONCLUSION: Size-specific institutional DRLs were generated for neck CT examinations. The mean institutional CTDIvol and DLP values were well below national DRLs.

Potential of a machine-learning model for dose optimization in CT quality assurance.

OBJECTIVES: To evaluate machine learning (ML) to detect chest CT examinations with dose optimization potential for quality assurance in a retrospective, cross-sectional study. METHODS: Three thousand one hundred ninety-nine CT chest examinations were used for training and testing of the feed-forward, single hidden layer neural network (January 2016-December 2017, 60% male, 62 ± 15 years, 80/20 split). The model was optimized and trained to predict the volumetric computed tomography dose index (CTDIvol) based on scan patient metrics (scanner, study description, protocol, patient age, sex, and water-equivalent diameter (DW)). The root mean-squared error (RMSE) was calculated as performance measurement. One hundred separate, consecutive chest CTs were used for validation (January 2018, 60% male, 63 ± 16 years), independently reviewed by two blinded radiologists with regard to dose optimization, and used to define an optimal cutoff for the model. RESULTS: RMSE was 1.71, 1.45, and 1.52 for the training, test, and validation dataset, respectively. The scanner and DW were the most important features. The radiologists found dose optimization potential in 7/100 of the validation cases. A percentage deviation of 18.3% between predicted and actual CTDIvol was found to be the optimal cutoff: 8/100 cases were flagged as suboptimal by the model (range 18.3-53.2%). All of the cases found by the radiologists were identified. One examination was flagged only by the model. CONCLUSIONS: ML can comprehensively detect CT examinations with dose optimization potential. It may be a helpful tool to simplify CT quality assurance. CT scanner and DW were most important. Final human review remains necessary. A threshold of 18.3% between the predicted and actual CTDIvol seems adequate for CT quality assurance. KEY POINTS: • Machine learning can be integrated into CT quality assurance to improve retrospective analysis of CT dose data. • Machine learning may help to comprehensively detect dose optimization potential in chest CT, but an individual review of the results by an experienced radiologist or radiation physicist is required to exclude false-positive findings.

Heparin-bonded stent graft treatment for major visceral arterial injury after upper abdominal surgery.

PURPOSE: To analyse technical success, complications, and short- and intermediate-term outcomes after heparin-bonded stent graft implantation for the treatment of major abdominal vessel injury after upper abdominal surgery. METHODS: This retrospective, IRB-approved analysis included 29 consecutive patients (female: n = 6, male: n = 23, mean age 65.9 ± 11.2 years). All patients underwent angiography and attempted heparin-bonded stent-graft implantation because of a major visceral arterial injury after upper abdominal surgery. Electronic clinical records, angiographic reports and imaging datasets were reviewed to assess technical success and complications. Telephone interviews were performed to obtain follow-up information and to estimate short- (> 30 days) and intermediate-term (> 90 days) outcomes. RESULTS: Successful stent graft placement was achieved in 82.8% (24/29). Peri-interventional complications were observed in 20.7% (6/29) and delayed, angiography-associated complications were observed in 34.5% (10/29) of the patients. Symptomatic re-bleeding occurred in 24.1% (7/29). Short-term survival (> 30 days) was 72.4% (21/29). Intermediate survival (> 90 days) was 37.9% (11/29). CONCLUSION: Treatment of major vascular injuries with heparin-bonded stent grafts is feasible with a high technical success rate. However, survival depends on the underlying surgical condition, making interdisciplinary patient management mandatory. KEY POINTS: • Stent graft implantation is challenging, but has a high technical success rate. • Complications are frequent but surgical conversion is rarely necessary. • Survival depends on the underlying surgical condition causing the vascular injury. • Interdisciplinary management is crucial for the survival of these patients.

Institutional computed tomography diagnostic reference levels based on water-equivalent diameter and size-specific dose estimates.

Size-specific institutional diagnostic reference levels (DRLs) were generated for chest and abdominopelvic computed tomography (CT) based on size-specific dose estimates (SSDEs) and depending on patients' water-equivalent diameter (Dw). 1690 CT examinations were included in the IRB-approved retrospective study. SSDEs based on the mean water-equivalent diameter of the entire scan volume were calculated automatically. SSDEs were analyzed for different patient sizes and institutional DRLs (iDRLS; 75% percentiles) based on Dw and SSDEs were generated. iDRLs were compared to the national DRLs. Mean volumetric computed tomography dose index (CTDIvol), Dw and SSDEs for all 1690 CT examinations were 7.2 ± 4.0 mGy (0.84-47.9 mGy), 29.0 ± 3.4 cm and 8.5 ± 3.8 mGy (1.2-37.7 mGy), respectively. Overall, the mean SSDEs of all CT examinations were higher than the CTDIvol in chest CT, abdominopelvic CT and upper abdominal CT, respectively (p < 0.001 for all). There was a strong linear correlation between Dw and SSDEs in chest (R2 = 0.66), abdominopelvic (R2 = 0.98) and upper abdominal CT (R2 = 0.96) allowing for the implementation of size-specific institutional DRLs based on SSDEs and patients' Dw. We generated size-specific, Dw-dependent institutional DRLs based on SSDEs, which allow for easier and more comprehensive analyses of CT radiation exposure. Our results indicate that implementation of SSDEs into national DRLs may be beneficial.

Mechanistic Basis for Epitope Proofreading in the Peptide-Loading Complex.

The peptide-loading complex plays a pivotal role in Ag processing and is thus central to the efficient immune recognition of virally and malignantly transformed cells. The underlying mechanism by which MHC class I (MHC I) molecules sample immunodominant peptide epitopes, however, remains poorly understood. In this article, we delineate the interaction between tapasin (Tsn) and MHC I molecules. We followed the process of peptide editing in real time after ultra-fast photoconversion to pseudoempty MHC I molecules. Tsn discriminates between MHC I loaded with optimal and MHC I bound to suboptimal cargo. This differential interaction is key to understanding the kinetics of epitope proofreading. To elucidate the underlying mechanism at the atomic level, we modeled the Tsn/MHC I complex using all-atom molecular dynamics simulations. We present a catalytic working cycle, in which Tsn binds to MHC I with suboptimal cargo and thereby adjusts the energy landscape in favor of MHC I complexes with immunodominant epitopes.

Metal artifact reduction (MAR) based on two-compartment physical modeling: evaluation in patients with hip implants.

BACKGROUND: Artifacts from metallic implants can hinder image interpretation in computed tomography (CT). Image quality can be improved using metal artifact reduction (MAR) techniques. PURPOSE: To evaluate the impact of a MAR algorithm on image quality of CT examinations in comparison to filtered back projection (FBP) in patients with hip prostheses. MATERIAL AND METHODS: Twenty-two patients with 25 hip prostheses who underwent clinical abdominopelvic CT on a 64-row CT were included in this retrospective study. Axial images were reconstructed with FBP and five increasing MAR levels (M30-34). Objective artifact strength (OAS) (SIart-SInorm) was assessed by region of interest (ROI) measurements in position of the strongest artifact (SIart) and in an osseous structure without artifact (SInorm) (in Hounsfield units [HU]). Two independent readers evaluated subjective image quality regarding metallic hardware, delineation of bone, adjacent muscle, and pelvic organs on a 5-point scale (1, non-diagnostic; 5, excellent image quality). Artifacts in the near field, far field, and newly induced artifacts due to the MAR technique were analyzed. RESULTS: OAS values were: M34: 243.8 ± 155.4 HU; M33: 294.3 ± 197.8 HU; M32: 340.5 ± 210.1 HU; M31: 393.6 ± 225.2 HU; M30: 446.8 ± 224.2 HU and FBP: 528.9 ± 227.7 HU. OAS values were significantly lower for M32-34 compared to FBP (P < 0.01). For overall subjective image quality, results were: FBP, 2.0 ± 0.2; M30, 2.3 ± 0.8; M31, 2.6 ± 0.5; M32, 3.0 ± 0.6; M33, 3.5 ± 0.6; and M34, 3.8 ± 0.4 (P < 0.001 for M30-M34 vs. FBP, respectively). Increasing MAR levels resulted in new artifacts in 17% of reconstructions. CONCLUSION: The investigated MAR algorithm led to a significant reduction of artifacts from metallic hip implants. The highest MAR level provided the least severe artifacts and the best overall image quality.

Optimizing radiation exposure in screening of body packing: image quality and diagnostic acceptability of an 80 kVp protocol with automated tube current modulation.

The aim of this study was to evaluate the objective and subjective image quality of a novel computed tomography (CT) protocol with reduced radiation dose for body packing with 80 kVp and automated tube current modulation (ATCM) compared to a standard body packing CT protocol. 80 individuals who were examined between March 2012 and July 2015 in suspicion of ingested drug packets were retrospectively included in this study. Thirty-one CT examinations were performed using ATCM and a fixed tube voltage of 80 kVp (group A). Forty-nine CT examinations were performed using a standard protocol with a tube voltage of 120 kVp and a fixed tube current time product of 40 mAs (group B). Subjective and objective image quality and visibility of drug packets were assessed. Radiation exposure of both protocols was compared. Contrast-to-noise ratio (group A: 0.56 ± 0.36; group B: 1.13 ± 0.91) and Signal-to-noise ratio (group A: 3.69 ± 0.98; group B: 7.08 ± 2.67) were significantly lower for group A compared to group B (p < 0.001). Subjectively, image quality was decreased for group A compared to group B (2.5 ± 0.8 vs. 1.2 ± 0.4; p < 0.001). Attenuation of body packets was higher with the new protocol (group A: 362.2 ± 70.3 Hounsfield Units (HU); group B: 210.6 ± 60.2 HU; p = 0.005). Volumetric Computed Tomography Dose Index (CTDIvol) and Dose Length Product (DLP) were significantly lower in group A (CTDIvol 2.2 ± 0.9 mGy, DLP 105.7 ± 52.3 mGycm) as compared to group B (CTDIvol 2.7 ± 0.1 mGy, DLP 126.0 ± 9.7 mGycm, p = 0.002 and p = 0.01). The novel 80 kVp CT protocol with ATCM leads to a significant dose reduction compared to a standard CT body packing protocol. The novel protocol led to a diagnostic image quality and cocaine body packets were reliably detected due to the high attenuation.

Iodine concentration as a perfusion surrogate marker in oncology: Further elucidation of the underlying mechanisms using Volume Perfusion CT with 80 kVp.

OBJECTIVES: To assess the value of iodine concentration (IC) in computed tomography data acquired with 80 kVp, as a surrogate for perfusion imaging in hepatocellular carcinoma (HCC) and lymphoma by comparing iodine related attenuation (IRA) with quantitative Volume Perfusion CT (VPCT)-parameters. METHODS: VPCT-parameters were compared with intra-tumoral IC at 5 time points after the aortic peak enhancement (APE) with a temporal resolution of 3.5 sec in untreated 30 HCC and 30 lymphoma patients. RESULTS: Intra-tumoral perfusion parameters for HCC showed a blood flow (BF) of 52.7 ± 17.0 mL/100 mL/min, blood volume (BV) 12.6 ± 4.3 mL/100 mL, arterial liver perfusion (ALP) 44.4 ± 12.8 mL/100 mL/min. Lesion IC 7 sec after APE was 133.4 ± 57.3 mg/100 mL. Lymphoma showed a BF of 36.8 ± 13.4 mL/100 mL/min, BV of 8.8 ± 2.8 mL/100 mL and IC of 118.2 ± 64.5 mg/100 mL 3.5 sec after APE. Strongest correlations exist for VPCT-derived BF and ALP with IC in HCC 7 sec after APE (r = 0.71 and r = 0.84) and 3.5 sec after APE in lymphoma lesions (r = 0.77). Significant correlations are also present for BV (r = 0.60 and r = 0.65 for HCC and lymphoma, respectively). CONCLUSIONS: We identified a good, time-dependent agreement between VPCT-derived flow values and IC in HCC and lymphoma. Thus, CT-derived ICs 7 sec after APE in HCC and 3.5 sec in lymphoma may be used as surrogate imaging biomarkers for tumor perfusion with 80 kVp. KEY POINTS: • Iodine concentration derived from low kVp CT is regarded as perfusion surrogate • Correlation with Perfusion CT was performed to elucidate timing and histology dependencies • Highest correlation was present 7 sec after aortic peak enhancement in hepatocellular carcinoma • In lymphoma, highest correlation was calculated 3.5 sec after aortic peak enhancement • With these results, further optimization of Dual energy CT protocols is possible.

Design of a superior cytokine antagonist for topical ophthalmic use.

IL-1 is a key inflammatory and immune mediator in many diseases, including dry-eye disease, and its inhibition is clinically efficacious in rheumatoid arthritis and cryopyrin-associated periodic syndromes. To treat ocular surface disease with a topical biotherapeutic, the uniqueness of the site necessitates consideration of the agent's size, target location, binding kinetics, and thermal stability. Here we chimerized two IL-1 receptor ligands, IL-1ß and IL-1Ra, to create an optimized receptor antagonist, EBI-005, for topical ocular administration. EBI-005 binds its target, IL-1R1, 85-fold more tightly than IL-1Ra, and this increase translates to an ∼100-fold increase in potency in vivo. EBI-005 preserves the affinity bias of IL-1Ra for IL-1R1 over the decoy receptor (IL-1R2), and, surprisingly, is also more thermally stable than either parental molecule. This rationally designed antagonist represents a unique approach to therapeutic design that can potentially be exploited for other ß-trefoil family proteins in the IL-1 and FGF families.

Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation.

Type I interferons (IFNs) form a network of homologous cytokines that bind to a shared, heterodimeric cell surface receptor and engage signaling pathways that activate innate and adaptive immune responses. The ability of IFNs to mediate differential responses through the same cell surface receptor has been subject of a controversial debate and has important medical implications. During the past decade, a comprehensive insight into the structure, energetics, and dynamics of IFN recognition by its two-receptor subunits, as well as detailed correlations with their functional properties on the level of signal activation, gene expression, and biological responses were obtained. All type I IFNs bind the two-receptor subunits at the same sites and form structurally very similar ternary complexes. Differential IFN activities were found to be determined by different lifetimes and ligand affinities toward the receptor subunits, which dictate assembly and dynamics of the signaling complex in the plasma membrane. We present a simple model, which explains differential IFN activities based on rapid endocytosis of signaling complexes and negative feedback mechanisms interfering with ternary complex assembly. More insight into signaling pathways as well as endosomal signaling and trafficking will be required for a comprehensive understanding, which will eventually lead to therapeutic applications of IFNs with increased efficacy.

Noise-optimized virtual monoenergetic images and iodine maps for the detection of venous thrombosis in second-generation dual-energy CT (DECT): an ex vivo phantom study.

AIMS AND OBJECTIVES: Deep venous thrombosis (DVT) can be difficult to detect using CT due to poor and heterogeneous contrast. Dual-energy CT (DECT) allows iodine contrast optimization using noise-optimized monoenergetic extrapolations (MEIs) and iodine maps (IMs). Our aim was to assess whether MEI and IM could improve the delineation of thrombotic material within iodine-enhanced blood compared to single-energy CT (SECT). MATERIALS AND METHODS: Six vessel phantoms, including human thrombus and contrast media-enhanced blood and one phantom without contrast, were placed in an attenuation phantom and scanned with DECT 100/140 kV and SECT 120 kV. IM, virtual non-contrast images (VNC), mixed images, and MEI were calculated. Attenuation of thrombi and blood were measured. Contrast and contrast-to-noise-ratios (CNRs) were calculated and compared among IM, VNC, mixed images, MEI, and SECT using paired t tests. RESULTS: MEI40keV and IM showed significantly higher contrast and CNR than SE120kV from high to intermediate iodine concentrations (contrast:pMEI40keV < 0.002,pIM < 0.005;CNR:pMEI40keV < 0.002,pIM < 0.004). At low iodine concentrations, MEI190keV and VNC images showed significantly higher contrast and CNR than SE120kV with inverted contrasts (contrast:pMEI190keV < 0.008,pVNC < 0.002;CNR:pMEI190keV < 0.003,pVNC < 0.002). CONCLUSIONS: Noise-optimized MEI and IM provide significantly higher contrast and CNR in the delineation of thrombosis compared to SECT, which may facilitate the detection of DVT in difficult cases. KEY POINTS: • Poor contrast makes it difficult to detect thrombosis in CT. • Dual-energy-CT allows contrast optimization using monoenergetic extrapolations (MEI) and iodine maps (IM). • Noise-optimized-MEI and IM are significantly superior to single-energy-CT in delineation of thrombosis. • Noise-optimized-MEI and IM may facilitate the detection of deep vein thrombosis.