Acoustic diffraction-resistant adaptive profile technology (ADAPT) for elasticity imaging.

Acoustic beam shaping with high degrees of freedom is critical for applications such as ultrasound imaging, acoustic manipulation, and stimulation. However, the ability to fully control the acoustic pressure profile over its propagation path has not yet been achieved. Here, we demonstrate an acoustic diffraction-resistant adaptive profile technology (ADAPT) that can generate a propagation-invariant beam with an arbitrarily desired profile. By leveraging wave number modulation and beam multiplexing, we develop a general framework for creating a highly flexible acoustic beam with a linear array ultrasonic transducer. The designed acoustic beam can also maintain the beam profile in lossy material by compensating for attenuation. We show that shear wave elasticity imaging is an important modality that can benefit from ADAPT for evaluating tissue mechanical properties. Together, ADAPT overcomes the existing limitation of acoustic beam shaping and can be applied to various fields, such as medicine, biology, and material science.

Comparison of Prospectively Generated Glioma Treatment Plans Clinically Delivered on Magnetic Resonance Imaging (MRI)-Linear Accelerator (MR-Linac) Versus Conventional Linac: Predicted and Measured Skin Dose.

Introduction: Magnetic resonance imaging-linear accelerator radiotherapy is an innovative technology that requires special consideration for secondary electron interactions within the magnetic field, which can alter dose deposition at air-tissue interfaces. As part of ongoing quality assurance and quality improvement of new radiotherapy technologies, the purpose of this study was to evaluate skin dose modelled from the treatment planning systems of a magnetic resonance imaging-linear accelerator and a conventional linear accelerator, and then correlate with in vivo measurements of delivered skin dose from each linear accelerator. Methods: In this prospective cohort study, 37 consecutive glioma patients had treatment planning completed and approved prior to radiotherapy initiation using commercial treatment planning systems: a Monte Carlo-based algorithm for magnetic resonance imaging-linear accelerator or a convolution-based algorithm for conventional linear accelerator. In vivo skin dose was measured using an optically stimulated luminescent dosimeter. Results: Monte Carlo-based magnetic resonance imaging-linear accelerator plans and convolution-based conventional linear accelerator plans had similar dosimetric parameters for target volumes and organs-at-risk. However, magnetic resonance imaging-linear accelerator plans had 1.52 Gy higher mean dose to air cavities (P < .0001) and 1.10 Gy higher mean dose to skin (P < .0001). In vivo skin dose was 14.5% greater for magnetic resonance imaging-linear accelerator treatments (P = .0027), and was more accurately predicted by Monte Carlo-based calculation (ρ = 0.95, P < .0001) versus convolution-based (ρ = 0.80, P = .0096). Conclusion: This is the first prospective dosimetric comparison of glioma patients clinically treated on both magnetic resonance imaging-linear accelerator and conventional linear accelerator. Our findings suggest that skin doses were significantly greater with magnetic resonance imaging-linear accelerator plans but correlated better with in vivo measurements of actual skin dose from delivered treatments. Future magnetic resonance imaging-linear accelerator planning processes are being designed to account for skin dosimetry and treatment delivery.

Early Metabolic Changes in 1H-MRSI Predictive for Survival in Patients With Newly Diagnosed High-grade Glioma.

BACKGROUND: The purpose of this study was to evaluate the association of specific threshold values for changes in metabolic metrics measured from 1H magnetic resonance spectroscopic imaging (MRSI) to survival of patients with high-grade glioma treated with multimodality therapy. PATIENTS AND METHODS: Forty-four patients with newly diagnosed high-grade glioma were prospectively enrolled. Serial MRI and MRSI scans provided measures of tumor choline, creatine, and N-acetylaspartate (NAA). Cox regression analyses adjusted for patient age, KPS, and delivery of concurrent chemotherapy were used to assess the association of changes in metabolic metrics with survival. RESULTS: Median follow-up time for patients at risk was 13.4 years. Overall survival (OS) was longer in patients with ≤20% increase (vs. >20%) in normalized choline (p=0.024) or choline/NAA (p=0.024) from baseline to week 4 of RT. During this period, progression-free survival (PFS) was longer in patients with ≤40% increase (vs. >40%) in normalized choline (p=0.013). Changes in normalized creatine, choline/creatine, and NAA/creatine from baseline to mid-RT were not associated with OS. From baseline to post-RT, changes in metabolic metrics were not associated with OS or PFS. CONCLUSION: Threshold values for serial changes in choline metrics on mid-RT MRSI associated with OS and PFS were identified. Metabolic metrics at post-RT did not predict for these survival endpoints. These findings suggest a potential clinical role for MRSI to provide an early assessment of treatment response and could enable risk-adapted therapy in clinical trial development and clinical practice.

Inter-fraction dynamics during post-operative 5 fraction cavity hypofractionated stereotactic radiotherapy with a MR LINAC: a prospective serial imaging study.

PURPOSE/OBJECTIVE(S): This study examined changes in the clinical target volume (CTV) and associated clinical implications on a magnetic resonance imaging linear accelerator (MR LINAC) during hypofractionated stereotactic radiotherapy (HSRT) to resected brain metastases. In addition, the suitability of using T2/FLAIR (T2f) sequence to define CTV was explored by assessing contouring variability between gadolinium-enhanced T1 (T1c) and T2f sequences. MATERIALS/METHODS: Fifteen patients treated to either 27.5 or 30 Gy with five fraction HSRT were imaged with T1c and T2f sequences during treatment; T1c was acquired at planning (FxSim), and fraction 3 (Fx3), and T2f was acquired at FxSim and all five fractions. The CTV were contoured on all acquired images. Inter-fraction cavity dynamics and CTV contouring variability were quantified using absolute volume, Dice similarity coefficient (DSC), and Hausdorff distance (HD) metrics. RESULTS: The median CTV on T1c and T2f sequences at FxSim were 12.0cm3 (range, 1.2-30.1) and 10.2cm3 (range, 2.9-27.9), respectively. At Fx3, the median CTV decreased in both sequences to 9.3cm3 (range, 3.7-25.9) and 8.6cm3 (range, 3.3-22.5), translating to a median % relative reduction of - 11.4% on T1c (p = 0.009) and - 8.4% on T2f (p = 0.032). We observed a median % relative reduction in CTV between T1c and T2f at FxSim of - 6.0% (p = 0.040). The mean DSC was 0.85 ± 0.10, and the mean HD was 5.3 ± 2.7 mm when comparing CTV on T1c and T2f at FxSim. CONCLUSION: Statistically significant reductions in cavity CTV was observed during HSRT, supporting the use of MR image guided radiation therapy and treatment adaptation to mitigate toxicity. Significant CTV contouring variability was seen between T1c and T2f sequences. Trial registration NCT04075305 - August 30, 2019.

Clinical Learning, Didactic Education, and Research Experiences of Radiation Oncology Resident Physicians in Canada.

Changes in the field of radiation oncology (RO) impacts residency training. Assessing trainee experiences is essential to inform curriculum development. We aim to explore gaps and strengths in current Canadian RO training, as we move towards competency-based medical education (CBME). An online survey was distributed to residents at all Canadian RO training programs. Surveys consisted of 66 open-ended, Likert-scale, matrix-style, and multiple-choice questions, and assessed clinical exposure, didactic teaching, professional relationships, and research experiences. Statistics were calculated from anonymized, aggregate responses. Out of 128 eligible residents, 53 responded (41% response rate). Of these, 57% were male, and 77% were Canadian medical graduates. Senior residents (PGY-4 to PGY-5) perceived insufficient exposure to lymphoma and ocular malignancies, brachytherapy for breast and esophagus malignancies, and stereotactic radiotherapy of the pancreas, prostate, and adrenal gland. Half (51%) had training on image-guided radiotherapy (IGRT) challenges, and 43% had a formal staff mentor. Most residents presented at least one research project at conferences (77%) and authored ≥ 1 publications (66%) during residency. Canadian RO residents are satisfied with their clinical training and educational experience in high-volume tumor sites and high-volume brachytherapy procedures. Areas identified for potential improvement are (1) low-volume tumor sites; (2) low-volume brachytherapy procedures; (3) low-volume stereotactic radiotherapy sites; (4) IGRT challenges; and (5) mentorship opportunities. These findings will inform future CBME curriculum revisions.

Glycosylation of Siglec15 promotes immunoescape and tumor growth.

Siglec15 is a recently characterized immunosuppressive transmembrane protein, which expresses in various types of solid tumors and promotes cancer development. Several studies reported that Siglec15 is a prognostic biomarker of cancer patients, and targeting Siglec15 may be a promising strategy for cancer therapy. However, the regulation of Siglec15 function remains unclear. Here we show that the immunosuppression activity of Siglec15 is largely modulated by N-glycosylation. Through mass spectrum and site mutation analysis, we identified that Siglec15 was extensively glycosylated at N172 (N173 for mouse) in cancer cells. Meanwhile, Siglec15 N172Q had a similar molecular weight with PNGase-F-treated Siglec15, suggesting N172 as the only one glycosylation residue. In xenograft model, glycosylation deficiency of Siglec15 reduced tumor growth in C57BL/6 mice, but had no impact in nude mice, indicating the requirement of N-glycosylation for immunosuppressive function of Siglec15. Furthermore, colorectal cancer patients with high Siglec15 expression had a poor response to neoadjuvant chemo-radiotherapy and short survival time. Interestingly, removal of N-glycosylation enhances the detection of Siglec15, which may be employed in the prediction of immunotherapy response. Together, our results disclose a pivotal role of glycosylated Siglec15 in tumor immune escape, which may be a therapeutic target for cancer immunotherapy.

Clinical Outcomes of the CHIRP Trial: A Phase II Prospective Randomized Trial of Conventionally Fractionated Versus Moderately Hypofractionated Prostate and Pelvic Nodal Radiation Therapy in Patients With High-Risk Prostate Cancer.

PURPOSE: Hypofractionated radiation therapy (HFRT) may offer treatment advantages for patients with prostate cancer. However, HFRT may also increase the risk of gastrointestinal (GI) or genitourinary (GU) toxicity compared with conventionally fractionated radiation therapy (CFRT). Several large trials have found that HFRT is well tolerated in mixed risk population studies. Here, we report on a phase II, randomized controlled study conducted to evaluate these endpoints in exclusively high-risk patients with prostate cancer treated with prostate and pelvic nodal radiation. METHODS AND MATERIALS: After giving informed consent, patients with high-risk prostate cancer were randomly assigned to prostate plus pelvic nodal radiation therapy with either HFRT (68 Gy in 25 fractions) or CFRT (78 Gy in 39 fractions) and 18 months of androgen suppression therapy. Toxicity was scored using the Common Terminology Criteria for Adverse Events (version 4.0). Biochemical failure was determined by the Phoenix definition. Patients were analyzed on an intention-to-treat basis. RESULTS: From 2012 to 2018, 111 patients with high-risk prostate cancer were enrolled and 109 patients were treated. The cumulative incidence of grade 2 or higher acute GI toxicity was not significantly different between the arms (HFRT 18.9% vs CFRT 21.8%; P = .812). Similarly, acute GU (HFRT 30.2% vs CFRT 30.9%; P = 1.00), late GI (HFRT 16.0% vs CFRT 10.0%; P = .554), and late GU (HFRT 16.0% vs CFRT 6.0%; P = .200) were not significantly different between the arms. Median follow-up was 38.0 months (4.8-77.8 months). The 3-year biochemical recurrence-free survival was not significantly different between the 2 arms (97.3% for HFRT vs 91.0% for CFRT; P = .606). The 3-year overall survival was 94.8% in the HFRT arm and 100.0% in the CFRT arm (P = .116). CONCLUSIONS: HFRT and CFRT using intensity modulated radiation therapy were both well tolerated for patients with high-risk prostate cancer and resulted in similar 3-year biochemical recurrence-free survival and overall survival.

Motivations, Well-Being, and Career Aspirations of Radiation Oncology Resident Physicians in Canada.

Prior Pan-Canadian surveys of Radiation Oncology (RO) residents reveal a decrease in Canadian RO employment opportunities. Canadian RO resident levels increased from 130 in 2003, peaked at 209 in 2009, then decreased to 130 in 2017. Recognizing that RO has entered another period of transition, we re-examined resident motivations and perspectives on the job market and explored well-being and career aspirations among a contemporary cohort of Canadian RO residents. An online survey was distributed to residents at all Canadian RO training programs. Surveys consisted of 75 open-ended, Likert-scale, matrix-style, and multiple-choice questions. Student's t test compared subgroups, with statistical significance at p ≤ 0.05. Out of 128 eligible residents, 84 completed the survey (66% response rate) with representative sampling from each training year. Demographics reveal 53% male, and 85% Canadian registry-funded. Top training-related stressors were exam performance, job prospects, and physical/psychological demands of residency. Most intend to pursue fellowship post-residency (80%) and practice in Canada (88%). Few believe they can obtain staff positions treating preferred tumor sites (38%) or at preferred geographic locations (28%). Residents view job market being less competitive than 5 years ago (40%) and predict it will be less competitive in 5 years (60%). Canadian RO residents feel adequately trained, and most pursue post-residency fellowships. Current perceptions of the Canadian job market remain guarded, but appear more optimistic about the future. This update provides insights into current RO training and identifies areas that could be addressed by incoming competency-based medical education models for RO.

Catalytic, Enantioselective ß-Protonation through a Cooperative Activation Strategy.

The NHC-catalyzed transformation of unsaturated aldehydes into saturated esters through an organocatalytic homoenolate process has been thoroughly studied. Leveraging a unique "Umpolung"-mediated ß-protonation, this process has evolved from a test bed for homoenolate reactivity to a broader platform for asymmetric catalysis. Inspired by our success in using the ß-protonation process to generate enals from ynals with good E/Z selectivity, our early studies found that an asymmetric variation of this reaction was not only feasible, but also adaptable to a kinetic resolution of secondary alcohols through NHC-catalyzed acylation. In-depth analysis of this process determined that careful catalyst and solvent pairing is critical for optimal yield and selectivity; proper choice of nonpolar solvent provided improved yield through suppression of an oxidative side reaction, while employment of a cooperative catalytic approach through inclusion of a hydrogen bond donor cocatalyst significantly improved enantioselectivity.

Spine labeling in axial magnetic resonance imaging via integral kernels.

This study investigates a fast integral-kernel algorithm for classifying (labeling) the vertebra and disc structures in axial magnetic resonance images (MRI). The method is based on a hierarchy of feature levels, where pixel classifications via non-linear probability product kernels (PPKs) are followed by classifications of 2D slices, individual 3D structures and groups of 3D structures. The algorithm further embeds geometric priors based on anatomical measurements of the spine. Our classifier requires evaluations of computationally expensive integrals at each pixel, and direct evaluations of such integrals would be prohibitively time consuming. We propose an efficient computation of kernel density estimates and PPK evaluations for large images and arbitrary local window sizes via integral kernels. Our method requires a single user click for a whole 3D MRI volume, runs nearly in real-time, and does not require an intensive external training. Comprehensive evaluations over T1-weighted axial lumbar spine data sets from 32 patients demonstrate a competitive structure classification accuracy of 99%, along with a 2D slice classification accuracy of 88%. To the best of our knowledge, such a structure classification accuracy has not been reached by the existing spine labeling algorithms. Furthermore, we believe our work is the first to use integral kernels in the context of medical images.

Cooperative Catalysis and Activation with N-Heterocyclic Carbenes.

N-Heterocyclic carbene (NHC) catalysis has emerged as a powerful stratagem in organic synthesis to construct complex molecules primarily by polarity reversal (umpolung) approaches. These unique Lewis bases have been used to generate acyl anions, enolates, and homoenolates in catalytic fashion. Recently, a new strategy has emerged that dramatically expands the synthetic utility of carbene catalysis by leveraging additional activation modes: cooperative catalysis. The careful selection and balance of cocatalysts have led to enhanced reactivity, increased yields, and improved stereoselectivity. In certain cases, these catalytic additives have changed the regioselectivity or diastereoselectivity. This Minireview highlights new advances in NHC cooperative catalysis and surveys the evolution of this field.

Enantioselective ß-Protonation by a Cooperative Catalysis Strategy.

An enantioselective N-heterocyclic carbene (NHC)-catalyzed ß-protonation through the orchestration of three distinct organocatalysts has been developed. This cooperative catalyst system enhances both yield and selectivity, compared to only the NHC-catalyzed process. This new method allows for the efficient conversion of a large scope of aryl-oxobutenoates to highly enantioenriched succinate derivatives and demonstrates the benefits of combining different activation modes in organocatalysis.

Derivation and analysis of viscoelastic properties in human liver: impact of frequency on fibrosis and steatosis staging.

Commercially-available shear wave imaging systems measure group shear wave speed (SWS) and often report stiffness parameters applying purely elastic material models. Soft tissues, however, are viscoelastic, and higher-order material models are necessary to characterize the dispersion associated with broadband shear waves. In this paper, we describe a robust, model-based algorithm and use a linear dispersion model to perform shear wave dispersion analysis in traditionally difficult-to-image subjects. In a cohort of 135 non-alcoholic fatty liver disease patients, we compare the performance of group SWS with dispersion analysis-derived phase velocity c(200 Hz) and dispersion slope dc/df parameters to stage hepatic fibrosis and steatosis. Area under the ROC curve (AUROC) analysis demonstrates correlation between all parameters [group SWS, c(200 Hz), and, to a lesser extent dc/df ] and fibrosis stage, whereas no correlation was observed between steatosis stage and any of the material parameters. Interestingly, optimal AUROC threshold SWS values separating advanced liver fibrosis (≥F3) from mild-to-moderate fibrosis (≤F2) were shown to be frequency-dependent, and to increase from 1.8 to 3.3 m/s over the 0 to 400 Hz shear wave frequency range.

Ferrocene-based planar chiral imidazopyridinium salts for catalysis.

Planar chirality remains an underutilized control element in asymmetric catalysis. Factors that have limited its broader application in catalysis include poor catalyst performance and difficulties associated with the economical production of enantiopure planar chiral compounds. The construction of planar chiral azolium salts that incorporate a sterically demanding iron sandwich complex is now reported. Applications of this new N-heterocyclic carbene as both an organocatalyst and a ligand for transition-metal catalysis demonstrate its unprecedented versatility and potential broad utility in asymmetric catalysis.

Finite element modeling of impulsive excitation and shear wave propagation in an incompressible, transversely isotropic medium.

Elastic properties of materials can be measured by observing shear wave propagation following localized, impulsive excitations and relating the propagation velocity to a model of the material. However, characterization of anisotropic materials is difficult because of the number of elasticity constants in the material model and the complex dependence of propagation velocity relative to the excitation axis, material symmetries, and propagation directions. In this study, we develop a model of wave propagation following impulsive excitation in an incompressible, transversely isotropic (TI) material such as muscle. Wave motion is described in terms of three propagation modes identified by their polarization relative to the material symmetry axis and propagation direction. Phase velocities for these propagation modes are expressed in terms of five elasticity constants needed to describe a general TI material, and also in terms of three constants after the application of two constraints that hold in the limit of an incompressible material. Group propagation velocities are derived from the phase velocities to describe the propagation of wave packets away from the excitation region following localized excitation. The theoretical model is compared to the results of finite element (FE) simulations performed using a nearly incompressible material model with the five elasticity constants chosen to preserve the essential properties of the material in the incompressible limit. Propagation velocities calculated from the FE displacement data show complex structure that agrees quantitatively with the theoretical model and demonstrates the possibility of measuring all three elasticity constants needed to characterize an incompressible, TI material.

Parameters affecting the resolution and accuracy of 2-D quantitative shear wave images.

Time-of-flight methods allow quantitative measurement of shear wave speed (SWS) from ultrasonically tracked displacements following impulsive acoustic radiation force excitation in tissue. In heterogeneous materials, reflections at boundaries can distort the wave shape and confound determination of the wave arrival time. The magnitude of these effects depends on the shear wavelength of the excitation, the kernel size used to calculate the SWS, and the method used to determine the wave arrival time. In this study, we perform a parametric analysis of these factors using finite element modeling of the tissue response and simulated ultrasonic tracking. Two geometries are used, a stiff vertical layer and a stiff spherical inclusion, each in a uniform background. Wave arrival times are estimated using the peak displacement, peak slope of the leading edge, and cross-correlation methods. Results are evaluated in terms of reconstruction accuracy, resolution, contrast, and contrast-to-noise ratio of reconstructed SWS images. Superior results are obtained using narrower excitation widths and arrival time estimators which identify the leading edge of the propagating wave. The optimal kernel size is determined by a tradeoff between improved accuracy for larger kernels at the expense of spatial resolution.

Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease in developed countries, may progress to nonalcoholic steatohepatitis (NASH) in a minority of people. Those with NASH are at increased risk for cirrhosis and hepatocellular carcinoma. The potential risk and economic burden of utilizing liver biopsy to stage NAFLD in an overwhelmingly large at-risk population are enormous; thus, the discovery of sensitive, inexpensive, and reliable noninvasive diagnostic modalities is essential for population-based screening. METHODS: Acoustic Radiation Force Impulse (ARFI) shear wave imaging, a noninvasive method of assessing tissue stiffness, was used to evaluate liver fibrosis in 172 patients diagnosed with NAFLD. Liver shear stiffness measures in three different imaging locations were reconstructed and compared to the histologic features of NAFLD and AST-to-platelet ratio indices (APRI). RESULTS: Reconstructed shear stiffnesses were not associated with ballooned hepatocytes (p=0.11), inflammation (p=0.69), nor imaging location (p=0.11). Using a predictive shear stiffness threshold of 4.24kPa, shear stiffness distinguished low (fibrosis stage 0-2) from high (fibrosis stage 3-4) fibrosis stages with a sensitivity of 90% and a specificity of 90% (AUC of 0.90). Shear stiffness had a mild correlation with APRI (R(2)=0.22). BMI>40kg/m(2) was not a limiting factor for ARFI imaging, and no correlation was noted between BMI and shear stiffness (R(2)=0.05). CONCLUSIONS: ARFI imaging is a promising imaging modality for assessing the presence or absence of advanced fibrosis in patients with obesity-related liver disease.

Robust estimation of time-of-flight shear wave speed using a radon sum transformation.

Time-of-flight methods allow quantitative measurement of shear wave speed (SWS) from ultrasonically tracked displacements following impulsive excitation in tissue. However, application of these methods to in vivo data are challenging because of the presence of gross outlier data resulting from sources such as physiological motion or spatial inhomogeneities. This paper describes a new method for estimating SWS by considering a solution space of trajectories and evaluating each trajectory using a metric that characterizes wave motion along the entire trajectory. The metric used here is found by summing displacement data along the trajectory as in the calculation of projection data in the Radon transformation. The algorithm is evaluated using data acquired in calibrated phantoms and in vivo human liver. Results are compared with SWS estimates using a random sample consensus (RANSAC) algorithm described by Wang et al. Good agreement is found between the Radon sum and RANSAC SWS estimates with a correlation coefficient of greater than 0.99 for phantom data and 0.91 for in vivo liver data. The Radon sum transformation is suitable for use in situations requiring real-time feedback and is comparably robust to the RANSAC algorithm with respect to outlier data.

Improving the robustness of time-of-flight based shear wave speed reconstruction methods using RANSAC in human liver in vivo.

The stiffness of tissue can be quantified by measuring the shear wave speed (SWS) within the medium. Ultrasound is a real-time imaging modality capable of tracking the propagation of shear waves in soft tissue. Time-of-flight (TOF) methods have previously been shown to be effective for quantifying SWS from ultrasonically tracked displacements. However, the application of these methods to in vivo data is challenging due to the presence of additional sources of error, such as physiologic motion or spatial inhomogeneities in tissue. This article introduces the use of random sample consensus (RANSAC), a model fitting paradigm robust to the presence of gross outlier data, for estimating the SWS from ultrasonically tracked tissue displacements in vivo. SWS reconstruction is posed as a parameter estimation problem and the RANSAC solution to this problem is described. Simulations using synthetic TOF data show that RANSAC is capable of good stiffness reconstruction accuracy (mean error 0.5 kPa) and precision (standard deviation 0.6 kPa) over a range of shear stiffness (0.6-10 kPa) and proportion of inlier data (50%-95%). As with all TOF SWS estimation methods, the accuracy and precision of the RANSAC reconstructed shear modulus decreases with increasing tissue stiffness. The RANSAC SWS estimator was applied to radiation force induced shear wave data from 123 human patient livers acquired with a modified SONOLINE Antares ultrasound system (Siemens Healthcare, Ultrasound Business Unit, Mountain View, CA, USA) in a clinical setting before liver biopsy was performed. Stiffness measurements were not possible in 19 patients due to the absence of shear wave propagation inside the liver. The mean liver stiffness for the remaining 104 patients ranged from 1.3 to 24.2 kPa and the proportion of inliers for the successful reconstructions ranged between 42% to 99%. Using RANSAC for SWS estimation improved the diagnostic accuracy of liver stiffness for delineating fibrosis stage compared with ordinary least squares (OLS) without outlier removal (AUROC = 0.94 for F >or= 3 and AUROC = 0.98 for F = 4). These results show that RANSAC is a suitable method for estimating the SWS from noisy in vivo shear wave displacements tracked by ultrasound.

RNAi-mediated CD40-CD154 interruption promotes tolerance in autoimmune arthritis.

INTRODUCTION: We have previously demonstrated that ex vivo inhibition of costimulatory molecules on antigen-pulsed dendritic cells (DCs) can be useful for induction of antigen-specific immune deviation and suppression of autoimmune arthritis in the collagen induced arthritis (CIA) model. The current study evaluated a practical method of immune modulation through temporary systemic inhibition of the costimulatory molecule CD40. METHODS: Mice with collagen II (CII)-induced arthritis (CIA) were administered siRNA targeting the CD40 molecule. Therapeutic effects were evaluated by clinical symptoms, histopathology, Ag-specific T cell and B cell immune responses. RESULTS: Systemic administration of CD40-targeting siRNA can inhibit antigen-specific T cell response to collagen II, as well as prevent pathogenesis of disease in both a pre- and post-immunization manner in the CIA model. Disease amelioration was associated with suppression of Th1 cytokines, attenuation of antibody production, and upregulation of T regulatory cells. CONCLUSIONS: These studies support the feasibility of transient gene silencing at a systemic level as a mechanism of resetting autoreactive immunity.