Citations

Abstract CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of a series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers, and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity was tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded JAKs and potently killed CRLF2r cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1 and suppressed proliferation of CRLF2r ALL in vivo, e.g. compound 7 (SJ988497). Although dual JAK/GSPT1-degrading PROTACs were the most potent, the development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading, GSPT1-sparing PROTAC that demonstrated efficacy in the majority of kinase-driven xenografts that were otherwise unresponsive to type I JAK inhibitors, e.g. compound 8 (SJ1008030). Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT–driven ALL and highlight the interplay of JAK and GSPT1 degradation activity in this context.

ObjectiveTo use probe oscillation shear wave elastography (PROSE) with two vibration sources to generate two shear waves in the imaging plane to quantitatively assess the shear wave speeds (SWSs) of muscles with and without the diagnosis of taut bands (TB) and/or myofascial trigger points (MTrPs).MethodsThirty‐three patients were scanned with the PROSE technique. Shear waves were generated through continuous vibration of the ultrasound probe, while the shear wave motions were detected using the same probe. SWSs for the sides with and without TBs and/or MTrPs were computed and compared. The pressure pain thresholds (PPTs) were measured as an indicator of maximum pain tolerance of patients. The statistical differences between the SWSs with and without TBs and/or MTrPs with different PPT values were analyzed using the nonparametric Wilcoxon rank‐sum test.ResultsThe mean SWSs for the sides with TBs and/or MTrPs are faster than that of the contralateral side without TBs and/or MTrPs. A significant difference was observed between mean SWSs with and without TBs and/or MTrPs without any information of PPT, with rank‐sum test P < .005. Additionally, with the information of PPT, a significant difference was observed between mean SWSs for the sides with and without TBs and/or MTrPs, for PPT values between 0 and 50 N/cm2 (P < .005), but for PPT values between 50 and 90 N/cm2, it was difficult to differentiate mean SWSs with and without TBs and/or MTrPs.ConclusionOur preliminary results show that SWSs measured from patients had a significant difference between the mean SWSs with and without TBs and/or MTrPs.

Abstract Non-invasive detection of microvascular alterations in deep tissues in vivo provides critical information for clinical diagnosis and evaluation of a broad-spectrum of pathologies. Recently, the emergence of super-resolution ultrasound localization microscopy (ULM) offers new possibilities for clinical imaging of microvasculature at capillary level. Currently, the clinical utility of ULM on clinical ultrasound scanners is hindered by the technical limitations, such as long data acquisition time, high microbubble (MB) concentration, and compromised tracking performance associated with low imaging frame-rate. Here we present a robust in-human ULM on a high frame-rate (HFR) clinical ultrasound scanner to achieve super-resolution microvessel imaging using a short acquisition time (<10 s). Ultrasound MB data were acquired from different human tissues, including a healthy liver and a diseased liver with acute-on-chronic liver failure, a kidney, a pancreatic tumor, and a breast mass using an HFR clinical scanner. By leveraging the HFR and advanced processing techniques including sub-pixel motion registration, MB signal separation, and Kalman filter-based tracking, MBs can be robustly localized and tracked for ULM under the circumstances of relatively high MB concentration associated with standard clinical MB administration and limited data acquisition time in humans. Subtle morphological and hemodynamic information in microvasculature were shown based on data acquired with single breath-hold and free-hand scanning. Compared with contrast-enhanced power Doppler generated based on the same MB dataset, ULM showed a 5.7-fold resolution improvement in a vessel based on a linear transducer, and provided a wide-range blood flow speed measurement that is Doppler angle-independent. Microvasculatures with complex hemodynamics can be well-differentiated at super-resolution in both normal and pathological tissues. This preliminary study implemented the ultrafast in-human ULM in various human tissues based on a clinical scanner that supports HFR imaging, indicating the potentials of the technique for various clinical applications. However, rigorous validation of the technique in imaging human microvasculature (especially for those tiny vessel structure), preferably with a gold standard, is still required.

Abstract Ultrasound localization microscopy (ULM) has been proposed to image microvasculature beyond the ultrasound diffraction limit. Although ULM can attain microvascular images with a sub-diffraction resolution, long data acquisition time and processing time are the critical limitations. Deep learning-based ULM (deep-ULM) has been proposed to mitigate these limitations. However, microbubble (MB) localization used in deep-ULMs is currently based on spatial information without the use of temporal information. The highly spatiotemporally coherent MB signals provide a strong feature that can be used to differentiate MB signals from background artifacts. In this study, a deep neural network was employed and trained with spatiotemporal ultrasound datasets to better identify the MB signals by leveraging both the spatial and temporal information of the MB signals. Training, validation and testing datasets were acquired from MB suspension to mimic the realistic intensity-varying and moving MB signals. The performance of the proposed network was first demonstrated in the chicken embryo chorioallantoic membrane dataset with an optical microscopic image as the reference standard. Substantial improvement in spatial resolution was shown for the reconstructed super-resolved images compared with power Doppler images. The full-width-half-maximum (FWHM) of a microvessel was improved from 133 μ m to 35 μ m, which is smaller than the ultrasound wavelength (73 μ m). The proposed method was further tested in an in vivo human liver data. Results showed the reconstructed super-resolved images could resolve a microvessel of nearly 170 μ m (FWHM). Adjacent microvessels with a distance of 670 μ m, which cannot be resolved with power Doppler imaging, can be well-separated with the proposed method. Improved contrast ratios using the proposed method were shown compared with that of the conventional deep-ULM method. Additionally, the processing time to reconstruct a high-resolution ultrasound frame with an image size of 1024 × 512 pixels was around 16 ms, comparable to state-of-the-art deep-ULMs.

AbstractBackground and AimLiraglutide, a long‐acting GLP‐1 analog, is approved for the treatment of obesity with improvements in fasting blood glucose, hemoglobin A1c, and cardiovascular health. Our aim was to measure the impact of liraglutide dose for obesity on hepatic steatosis measured by ultrasound.MethodsA single‐center, randomized, double‐blind, placebo‐controlled pilot trial was undertaken in nondiabetic obese, otherwise healthy patients aged 18–65 years. Participants were randomly assigned to receive subcutaneous liraglutide (3.0 mg) or placebo over 16 weeks with dose escalation following US Food and Drug Administration guidelines. Both groups received standardized nutritional and behavioral counseling during the 16 weeks. Hepatic fat content was measured by ultrasound at baseline, 8 weeks, and 16 weeks as an attenuation coefficient (ACE). Effects of treatment were assessed using t‐test for the entire groups and for patient subgroup with baseline ACE >0.66 (indicating significant steatosis).ResultsAmong 30 patients (93% female) enrolled, 16 were randomized to placebo and 14 to liraglutide. Baseline body mass indices (BMIs) and average age were similar in the two groups. After 16 weeks, the liraglutide group had a significant improvement in steatosis ACE scores (−0.068 ± 0.02 vs −0.0077 ± 0.02 placebo, P = 0.05). Change in steatosis was positively correlated with change in BMI (R2 = 0.402, P = 0.0007). Within the liraglutide group, patients with baseline ACE >0.66 had improvement in ACE (−0.134 ± 0.03) compared to those without significant steatosis (−0.041 ± 0.02, P = 0.05).ConclusionsIn this pilot trial, liraglutide, 3.0 mg over 16 weeks, reduced hepatic steatosis; a reduction in hepatic steatosis is correlated with BMI reduction, and effects are particularly evident in those with a significant degree of steatosis by ultrasound imaging.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Abstract Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation, including epigenetic decoration of chromatin structure and functional modulation of bioactive components. Here we report that expression of the histone H3-specific demethylase KDM4 is upregulated in human stromal cells upon cellular senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation are correlated with adverse survival of cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq and expression profiling through RNA-seq reveal extensive reorganization of chromosomes and spatiotemporal reprogramming of the transcriptomic landscape, events responsible for development of the senescence-associated secretory phenotype (SASP). Selectively targeting KDM4 dampens the SASP of senescent stromal cells and enhances the apoptotic index of cancer cells in the treatment-damaged tumor microenvironment (TME), together prolonging overall survival of experimental animals. Our study supports the dynamic change of H3K9/H3K36 methylation marks during cellular senescence, identifies an unusually permissive chromatin state, unmasks KDM4 as a key modulator of the SASP, and presents a novel therapeutic avenue to manipulate cellular senescence and curtail age-related pathologies.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

ObjectivesCrohn disease (CD) is a chronic inflammation in the digestive tract that affects millions of Americans. Bowel vascularity has important diagnostic information because inflammation is associated with blood flow changes. We recently developed an ultrasensitive ultrasound microvessel imaging (UMI) technique with high vessel sensitivity. This study aimed to evaluate the feasibility of UMI to assist CD detection and staging.MethodsUltrasound microvessel imaging was performed on 76 bowel wall segments from 48 symptomatic patients with CD. Clinically indicated computed tomographic/magnetic resonance enterography was used as the reference standard. The vessel‐length ratio (VLR, the number of vessel pixels in the bowel wall segment normalized to the segment length) was derived in both conventional color flow imaging (CFI) and UMI to quantitatively stage disease activity. Receiver operating characteristic curves were then analyzed between different disease groups.ResultsThe VLR‐CFI and VLR‐UMI detected similar correlations between vascularization and disease activity: severe inflammation had a higher VLR than normal/mildly inflamed bowels (P < .05). No significant difference was found between quiescent and mild CD due to the small sample size. The VLR‐CFI had more difficulties in distinguishing quiescent versus mild CD compared to the VLR‐UMI. After combining the VLR‐UMI with thickness, in the receiver operating characteristic curve analysis, the areas under the curves (AUCs) improved to AUC1 = 0.996 for active versus quiescent CD, AUC2 = 0.978 for quiescent versus mild CD, and AUC3 = 0.931 for mild versus severe CD, respectively, compared to those using thickness alone (AUC1 = 0.968; P = .04; AUC2 = 0.919; P = .16; AUC3 = 0.857; P = .01).ConclusionsUltrasound microvessel imaging offers a safe and cost‐effective tool for CD diagnosis and staging, which may potentially assist disease activity classification and therapy efficacy evaluation.

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.