Blast injury to the brain is the predominant cause of neurotrauma in current military conflicts, and its etiology is largely undefined. Using a compression-driven shock tube to simulate blast ...effects, we assessed the physiological, neuropathological, and neurobehavioral consequences of airblast exposure, and also evaluated the effect of a Kevlar protective vest on acute mortality in rats and on the occurrence of traumatic brain injury (TBI) in those that survived. This approach provides survivable blast conditions under which TBI can be studied. Striking neuropathological changes were caused by both 126- and 147-kPa airblast exposures. The Kevlar vest, which encased the thorax and part of the abdomen, greatly reduced airblast mortality, and also ameliorated the widespread fiber degeneration that was prominent in brains of rats not protected by a vest during exposure to a 126-kPa airblast. This finding points to a significant contribution of the systemic effects of airblast to its brain injury pathophysiology. Airblast of this intensity also disrupted neurologic and neurobehavioral performance (e.g., beam walking and spatial navigation acquisition in the Morris water maze). When immediately followed by hemorrhagic hypotension, with MAP maintained at 30 mm Hg, airblast disrupted cardiocompensatory resilience, as reflected by reduced peak shed blood volume, time to peak shed blood volume, and time to death. These findings demonstrate that shock tube-generated airblast can cause TBI in rats, in part through systemic mediation, and that the resulting brain injury significantly impacts acute cardiovascular homeostatic mechanisms as well as neurobehavioral function.
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•Microbubble-assisted delivery of oxygen.•Lonidamine prolongs the elevated oxygen levels.•High intensity destructive ultrasound pulses.
Prior work has shown that microbubble-assisted ...delivery of oxygen improves tumor oxygenation and radiosensitivity, albeit over a limited duration. Lonidamine (LND) has been investigated because of its ability to stimulate glycolysis, lactate production, inhibit mitochondrial respiration, and inhibit oxygen consumption rates in tumors but suffers from poor bioavailability. The goal of this work was to characterize LND-loaded oxygen microbubbles and assess their ability to oxygenate a human head and neck squamous cell carcinoma (HNSCC) tumor model, while also assessing LND biodistribution. In tumors treated with surfactant-shelled microbubbles with oxygen core (SE61O2) and ultrasound, pO2 levels increased to a peak 19.5 ± 9.7 mmHg, 50 s after injection and returning to baseline after 120 s. In comparison, in tumors treated with SE61O2/LND and ultrasound, pO2 levels showed a peak increase of 29.0 ± 8.3 mmHg, which was achieved 70 s after injection returning to baseline after 300 s (p < 0.001). The co-delivery of O2andLNDvia SE61 also showed an improvement of LND biodistribution in both plasma and tumor tissues (p < 0.001). In summary, ultrasound-sensitive microbubbles loaded with O2 and LND provided prolonged oxygenation relative to oxygenated microbubbles alone, as well as provided an ability to locally deliver LND, making them more appropriate for clinical translation.
The objective of this study is to determine the diagnostic accuracy of the American College of Radiology Contrast-Enhanced Ultrasound (CEUS) Liver Imaging Reporting and Data System LR-5 ...characterization for HCC diagnosis in North American or European patients.
A prospective multinational cohort study was performed from January 2018 through November 2022 at 11 academic and nonacademic centers in North America and Europe. Patients at risk for HCC with at least 1 liver observation not previously treated, identified on ultrasound (US), or multiphase CT or MRI performed as a part of standard clinical care were eligible for the study. All participants were examined with CEUS of the liver within 4 weeks of CT/MRI or tissue diagnosis to characterize up to 2 liver nodules per participant using ACR CEUS Liver Imaging Reporting and Data System. Definite HCC diagnosis on the initial CT/MRI, imaging follow-up, or histology for CT/MRI-indeterminate nodules were used as reference standards. A total of 545 nodules had confirmed reference standards in 480 patients, 73.8% were HCC, 5.5% were other malignancies, and 20.7% were nonmalignant. The specificity of CEUS LR-5 for HCC was 95.1% (95% CI 90.1%-97.7%), sensitivity 62.9% (95% CI 57.9%-67.7%), positive predictive value 97.3% (95% CI 94.5%-98.7%), and negative predictive value 47.7% (95% CI 41.7%-53.8%). In addition, benign CEUS characterization (LR-1 or LR-2) had 100% specificity and 100% positive predictive value for nonmalignant liver nodules.
CEUS Liver Imaging Reporting and Data System provides an accurate categorization of liver nodules in participants at risk for HCC.
Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia ...locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O
and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O
and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (
< 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation.
Background & Aims: The objective of this study is to determine diagnostic accuracy of the American College of Radiology Contrast-Enhanced Ultrasound (CEUS) Liver Imaging Reporting and Data System ...(LI-RADS) LR-5 characterization for HCC diagnosis in North American or European patients. Approach & Results: Prospective multinational cohort study was performed from 01/2018 through 11/2022 at 11 academic and nonacademic centers in North America and Europe. Patients at risk for HCC with at least one liver observation not previously treated, identified on ultrasound (US) or multiphase CT or MRI performed as a part of standard clinical care were eligible for the study. All participants were examined with CEUS of the liver within 4 weeks of CT / MRI or tissue diagnosis to characterize up to 2 liver nodules per participant using ACR CEUS LI-RADS. Definite HCC diagnosis on the initial CT/MRI, imaging follow-up, or histology for CT/MRI-indeterminate nodules were used as reference standard. A total 545 nodules had confirmed reference standard in 480 patients, 73.8% were HCC, 5.5% other malignancy, and 20.7% were non-malignant. The specificity of CEUS LR-5 for HCC was 95.1% (95% CI 90.1% - 97.7%), sensitivity 62.9% (95% CI 57.9%-67.7%), Positive Predictive Value (PPV) 97.3% (95% CI 94.5% - 98.7%), and Negative Predictive Value (NPV) 47.7% (95% CI 41.7% - 53.8%). In addition, benign CEUS characterization (LR-1 or LR-2) had 100% specificity and 100% PPV for non-malignant liver nodules. Conclusions: CEUS LI-RADS characterization provides accurate categorization of liver nodules in participants at risk for HCC. ClinicalTrials.gov ID NCT03318380
Cathepsin K (CatK) inhibitors exhibited chondroprotective and pain-reducing effects in animal models, however, improvements were relatively modest at dose levels achieving maximal suppression of CatK ...biomarkers in urine. In this report, a previously characterized CatK inhibitor (MK-1256) is utilized to explore the potential of reduced target engagement and/or suboptimal exposure (free drug) as limiting factors to the pharmacological potential of CatK inhibitors in the knee joint. Following oral administration of MK-1256 at a dose level achieving maximal inhibition of urinary biomarker (helical peptide) in dogs, full suppression of the biomarker in synovial fluid was observed. Subsequent tissue distribution studies conducted in dogs and rabbits revealed that MK-1256 levels in synovial fluid and cartilage were consistent with the free-drug hypothesis. Reasonable projection (within twofold) of drug levels in these tissues can be made based on plasma drug concentration with adjustments for binding factors. These results indicate that the previously observed efficacies in the animal models were not limited by compound distribution or target engagement in the knee tissues.
Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and ...safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
J. Neurochem. (2011) 116, 82-92. ABSTRACT: Elevated plasma homocysteine, a risk factor for Alzheimer's disease, could result from increased production from methionine or by inefficient clearance by ...folate- and B-vitamin-dependent pathways. Understanding the relative contributions of these processes to pathogenesis is important for therapeutic strategies designed to lower homocysteine. To assess these alternatives, we elevated plasma homocysteine by feeding mutant amyloid precursor protein (APP)-expressing mice diets with either high methionine (HM) or deficient in B-vitamins and folate (B Def). Mutant APP mice fed HM demonstrated increased brain beta amyloid. Interestingly, this increase was not observed in mutant APP mice fed B Def diet, nor was it observed in C57Bl6 or YAC-APP mice fed HM. Furthermore, HM, but not B Def, produced a prolonged increase in brain homocysteine only in mutant APP mice but not wild-type mice. These changes were time-dependent over 10 weeks. Further, by 10 weeks HM increased brain cholesterol and phosphorylated tau in mutant APP mice. Transcriptional profiling experiments revealed robust differences in RNA expression between C57Bl6 and mutant APP mice. The HM diet in C57Bl6 mice transiently induced a transcriptional profile similar to mutant APP cortex, peaking at 2 weeks, following a time course comparable to brain homocysteine changes. Together, these data suggest a link between APP and methionine metabolism.
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