Updates on the Applications of Spectral Computed Tomography for Musculoskeletal Imaging.

Spectral CT represents a novel imaging approach that can noninvasively visualize, quantify, and characterize many musculoskeletal pathologies. This modality has revolutionized the field of radiology by capturing CT attenuation data across multiple energy levels and offering superior tissue characterization while potentially minimizing radiation exposure compared to traditional enhanced CT scans. Despite MRI being the preferred imaging method for many musculoskeletal conditions, it is not viable for some patients. Moreover, this technique is time-consuming, costly, and has limited availability in many healthcare settings. Thus, spectral CT has a considerable role in improving the diagnosis, characterization, and treatment of gout, inflammatory arthropathies, degenerative disc disease, osteoporosis, occult fractures, malignancies, ligamentous injuries, and other bone-marrow pathologies. This comprehensive review will delve into the diverse capabilities of dual-energy CT, a subset of spectral CT, in addressing these musculoskeletal conditions and explore potential future avenues for its integration into clinical practice.

Clinical Applications of PET in Evaluating the Aging Spine.

Back pain is a common health complaint that contributes globally to medical burden and costs, particularly in elderly populations. Nuclear medicine techniques using PET tracers offer diagnostic information about various spine disorders, including malignant, degenerative, inflammatory, and infectious diseases. Herein, the authors briefly review applications of PET in the evaluation of spine disorders in elderly patients.

Imaging Approach to Disease of the Pleura.

Diseases of pleura are not only common but also have a significant impact on patients' outcomes. While early detection and treatment are imperative in reducing this burden, many pleural entities present similarly, thus posing a diagnostic dilemma for radiologists requiring critical further workup. While chest radiography, CT, and image-guided thoracentesis are primarily utilized as the initial imaging techniques for the workup of pleural diseases, MRI, and FDG-PET/CT are also frequently employed to investigate the root cause of pleural abnormalities. By elucidating the common imaging features of neoplastic, inflammatory, and infectious pleural pathologies, clinicians can quickly and easily differentiate the various pleural diseases, rapidly reach the correct diagnosis, and ultimately improve patient outcomes.

An Extra Set of Intelligent Eyes: Application of Artificial Intelligence in Imaging of Abdominopelvic Pathologies in Emergency Radiology.

Imaging in the emergent setting carries high stakes. With increased demand for dedicated on-site service, emergency radiologists face increasingly large image volumes that require rapid turnaround times. However, novel artificial intelligence (AI) algorithms may assist trauma and emergency radiologists with efficient and accurate medical image analysis, providing an opportunity to augment human decision making, including outcome prediction and treatment planning. While traditional radiology practice involves visual assessment of medical images for detection and characterization of pathologies, AI algorithms can automatically identify subtle disease states and provide quantitative characterization of disease severity based on morphologic image details, such as geometry and fluid flow. Taken together, the benefits provided by implementing AI in radiology have the potential to improve workflow efficiency, engender faster turnaround results for complex cases, and reduce heavy workloads. Although analysis of AI applications within abdominopelvic imaging has primarily focused on oncologic detection, localization, and treatment response, several promising algorithms have been developed for use in the emergency setting. This article aims to establish a general understanding of the AI algorithms used in emergent image-based tasks and to discuss the challenges associated with the implementation of AI into the clinical workflow.

Advantages and Applications of Total-Body PET Scanning.

Recent studies have focused on the development of total-body PET scanning in a variety of fields such as clinical oncology, cardiology, personalized medicine, drug development and toxicology, and inflammatory/infectious disease. Given its ultrahigh detection sensitivity, enhanced temporal resolution, and long scan range (1940 mm), total-body PET scanning can not only image faster than traditional techniques with less administered radioactivity but also perform total-body dynamic acquisition at a longer delayed time point. These unique characteristics create several opportunities to improve image quality and can provide a deeper understanding regarding disease detection, diagnosis, staging/restaging, response to treatment, and prognostication. By reviewing the advantages of total-body PET scanning and discussing the potential clinical applications for this innovative technology, we can address specific issues encountered in routine clinical practice and ultimately improve patient care.

TAK1 regulates the tumor microenvironment through inflammatory, angiogenetic and apoptotic signaling cascades.

Transforming growth factor beta-activated kinase 1 (TAK1) has been implicated for its role in inflammatory signaling and as an important mediator of cellular apoptosis and necroptosis in various cell types. Our recent discovery of a first-in-class, potent and selective TAK1 inhibitor, takinib, represents a novel pharmacological tool to evaluate TAK1's role in cancer. In this study we evaluated the potential therapeutic capacity of TAK1 inhibition on tumor growth and on tumor microenvironment remodeling. In a screen of 16 cancer cell lines, takinib in combination with tumor necrosis factor (TNF) was found to induce cell death (>20%) in 6 out of 16 cell lines. Furthermore, knocking out of TAK1 in MDA-MB-231 cells dramatically increased their sensitization to TNF-mediated apoptosis. In vivo xenographs of MDA-MB-231 TAK1KO tumors displayed delayed tumor growth and increased overall survival compared to TAK1WT controls. Histological and proteomic analysis of TAK1KO tumors showed altered angiogenic signaling and inflammatory signaling via immune cells. Overall, these findings suggest that the targeting of TAK1 in immune mediated cancers may be a novel therapeutic axis.

Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice.

OBJECTIVES: To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. METHODS: Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 µM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). RESULTS: Here, we show takinib's ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. CONCLUSION: Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion.

Immune challenge of invading macrophages at sites of infection is associated with release of TNF, which triggers a local cytokine storm as part of the normal inflammatory response. Whereas this response maybe beneficial in fighting off infections, similar responses triggered in autoimmune diseases contribute significantly to the underlying damaging pathology associated with these diseases. Here we show that Takinib, a highly discriminatory inhibitor of transforming growth factor Beta- activated kinase 1 (TAK1), selectively and potently reduces TNF production in pro-inflammatory THP-1 macrophages. A complete survey of 110 cytokines, showed robust loss of proinflammatory cytokine responsiveness to lipopolysaccharide (LPS) and interferon gamma (IFNγ) challenge in response to Takinib. The mechanisms of action of Takinib was recapitulated in TAK1 KO macrophages. TAK1 KO cells showed significant loss of TNF production as well as release of IL-6 in response to LPS challenge. Furthermore, Takinib blocked the ability of exogenously added LPS to promote phosphorylation of, c-Jun, p38 protein kinases as well as downstream transcription factors regulated by nuclear factor κ-light-chain-enhancer of activated B cells (NFκB). In a mouse LPS challenge model, Takinib significantly reduced TNF serum levels. Our findings demonstrate that Takinib has utility in the treatment inflammatory disease by locally suppressing TNF production from invading macrophages.

Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF-α Inhibition for Cancer and Autoimmune Disease.

Tumor necrosis factor alpha (TNF-α) has both positive and negative roles in human disease. In certain cancers, TNF-α is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-α antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-α-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-α stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-α-induced cell death, with general implications for cancer and autoimmune disease treatment.