Advancements in the development of radiopharmaceuticals for nuclear medicine applications in the treatment of bone metastases.

Bone metastases are a painful and complex condition that overwhelmingly impacts the prognosis and quality of life of cancer patients. Over the years, nuclear medicine has made remarkable progress in the diagnosis and management of bone metastases. This review aims to provide a comprehensive overview of the recent advancements in nuclear medicine for the diagnosis and management of bone metastases. Furthermore, the review explores the role of targeted radiopharmaceuticals in nuclear medicine for bone metastases, focusing on radiolabeled molecules that are designed to selectively target biomarkers associated with bone metastases, including osteocytes, osteoblasts, and metastatic cells. The applications of radionuclide-based therapies, such as strontium-89 (Sr-89) and radium-223 (Ra-223), are also discussed. This review also highlights the potential of theranostic approaches for bone metastases, enabling personalized treatment strategies based on individual patient characteristics. Importantly, the clinical applications and outcomes of nuclear medicine in osseous metastatic disease are discussed. This includes the assessment of treatment response, predictive and prognostic value of imaging biomarkers, and the impact of nuclear medicine on patient management and outcomes. The review identifies current challenges and future perspectives on the role of nuclear medicine in treating bone metastases. It addresses limitations in imaging resolution, radiotracer availability, radiation safety, and the need for standardized protocols. The review concludes by emphasizing the need for further research and advancements in imaging technology, radiopharmaceutical development, and integration of nuclear medicine with other treatment modalities. In summary, advancements in nuclear medicine have significantly improved the diagnosis and management of osseous metastatic disease and future developements in the integration of innovative imaging modalities, targeted radiopharmaceuticals, radionuclide production, theranostic approaches, and advanced image analysis techniques hold great promise in improving patient outcomes and enhancing personalized care for individuals with bone metastases.

Association of CT findings in patients with hemoperitoneum due to ruptured ovarian cysts with subsequent intervention.

PURPOSE: Hemoperitoneum caused by ovarian cyst rupture may necessitate intervention. The literature is lacking in descriptions of CT findings that help guide patient management. The purpose of this study is to consider CT findings associated with a need for intervention (surgical or interventional radiology management) versus conservative treatment (observation, pain management, and blood transfusions). METHODS: Two radiologists retrospectively and independently reviewed 103 CTs of pre-menopausal women who presented with acute hemoperitoneum related to ruptured ovarian cysts between January 2010 and January 2019. The following imaging features were assessed: ovarian cyst characteristics, sentinel clot, contrast extravasation, and hemoperitoneum size. Findings were correlated with patient demographics, clinical parameters, and management with surgery/interventional radiology procedure (intervention group) versus conservative management (conservative group). RESULTS: Of the 103 patients with hemoperitoneum from cyst rupture, 16% (n = 16) required intervention, and 84% underwent conservative treatment (n = 87). Length of stay (p = .008) was higher in the intervention group. Statistically significant CT findings in the intervention versus conservative group included (p-value reader 1/p-value reader 2) greatest AP dimension of hemoperitoneum (p = .001/p = 0.02), posterior cul-de-sac AP dimension (p = 0.03/p = .006), total cul-de-sac AP dimension (p = .002/p = .007), and number of spaces with hemoperitoneum (p = .01/p = .02). There was good to excellent inter-reader agreement for these findings (ICC 0.68-0.91). Active contrast extravasation was significant for one reader (p = .02) with poor inter-reader agreement (ICC 0.36). In utilizing ROC curves, thresholds of 107 mm (greatest axial AP dimension of hemoperitoneum) yielded a sensitivity and specificity of 0.81 and 0.62 for reader 1 and 0.69 and 0.55 for reader 2; 45 mm (posterior cul-de-sac AP dimension) yielded a sensitivity and specificity of 0.75 and 0.63 for reader 1 and 0.94 and 0.49 for reader 2; 70 mm (total cul-de-sac AP dimension) yielded a sensitivity and specificity of 0.75 and 0.64 for reader 1 and 0.75 and 0.50 for reader 2; and greater than 5 spaces yielded a sensitivity and specificity of 0.75 and 0.58 for reader 1 and 0.69 and 0.70 for reader 2. CONCLUSION: CT findings associated with intervention in hemoperitoneum due to ovarian cyst rupture include size of hemoperitoneum, number of abdominopelvic spaces with hemoperitoneum, and contrast extravasation.

Hydrogen Bonding Stiffens Peptide Amphiphile Supramolecular Filaments by Aza-Glycine Residues.

Peptide amphiphiles (PAs) are a class of molecules comprised of short amino acid sequences conjugated to hydrophobic moieties that may exhibit self-assembly in water into supramolecular structures. We investigate here how mechanical properties of hydrogels formed by PA supramolecular nanofibers are affected by hydrogen bond densities within their internal structure by substituting glycine for aza-glycine (azaG) residues. We found that increasing the number of PA molecules that contain azaG up to 5 mol% in PA supramolecular nanofibers increases their persistence length fivefold and decreases their diffusion coefficients as measured by fluorescence recovery after photobleaching. When these PAs are used to create hydrogels, their bulk storage modulus (G') was found to increase as azaG PA content in the supramolecular assemblies increases up to a value of 10 mol% and beyond this value a decrease was observed, likely due to diminished levels of nanofiber entanglement in the hydrogels as a direct result of increased supramolecular rigidity. Interestingly, we found that the bioactivity of the scaffolds toward dopaminergic neurons derived from induced pluripotent stem cells can be enhanced directly by persistence length independently of storage modulus. We hypothesize that this is due to interactions between the cells and the extracellular environment across different size scales: from filopodia adhering to individual nanofiber bundles to cell adhesion sites that interact with the hydrogel as a bulk substrate. Fine tuning of hydrogen bond density in self-assembling peptide biomaterials such as PAs provides an approach to control nanoscale stiffness as part of an overall strategy to optimize bioactivity in these supramolecular systems. supramolecular biomaterials. STATEMENT OF SIGNIFICANCE: Hydrogen bonding is an important driving force for the self-assembly of peptides in both biological and artificial systems. Here, we increase the amount of hydrogen bonding within self-assembled peptide amphiphile (PA) nanofibers by substituting glycine for an aza-glycine (azaG). We show that increasing the molar concentration of azaG increases the internal order of individual nanofibers and increases their persistence length. We also show that these changes are sufficient to increase survival and tyrosine hydroxylase expression in induced pluripotent stem cell-derived dopaminergic neurons cultured in 3D gels made of these materials. Our strategy of tuning the number of hydrogen bonds in a supramolecular assembly provides mechanical customization for 3D cell culture and tissue engineering.

Chest radiograph at admission predicts early intubation among inpatient COVID-19 patients.

OBJECTIVE: The 2019 Coronavirus (COVID-19) results in a wide range of clinical severity and there remains a need for prognostic tools which identify patients at risk of rapid deterioration and who require critical care. Chest radiography (CXR) is routinely obtained at admission of COVID-19 patients. However, little is known regarding correlates between CXR severity and time to intubation. We hypothesize that the degree of opacification on CXR at time of admission independently predicts need and time to intubation. METHODS: In this retrospective cohort study, we reviewed COVID-19 patients who were admitted to an urban medical center during March 2020 that had a CXR performed on the day of admission. CXRs were divided into 12 lung zones and were assessed by two blinded thoracic radiologists. A COVID-19 opacification rating score (CORS) was generated by assigning one point for each lung zone in which an opacity was observed. Underlying comorbidities were abstracted and assessed for association. RESULTS: One hundred forty patients were included in this study and 47 (34%) patients required intubation during the admission. Patients with CORS ≥ 6 demonstrated significantly higher rates of early intubation within 48 h of admission and during the hospital stay (ORs 24 h, 19.8, p < 0.001; 48 h, 28.1, p < 0.001; intubation during hospital stay, 6.1, p < 0.0001). There was no significant correlation between CORS ≥ 6 and age, sex, BMI, or any underlying cardiac or pulmonary comorbidities. CONCLUSIONS: CORS ≥ 6 at the time of admission predicts need for intubation, with significant increases in intubation at 24 and 48 h, independent of comorbidities. KEY POINTS: • Chest radiography at the time of admission independently predicts time to intubation within 48 h and during the hospital stay in COVID-19 patients. • More opacities on chest radiography are associated with several fold increases in early mechanical ventilation among COVID-19 patients. • Chest radiography is useful in identifying COVID-19 patients whom may rapidly deteriorate and help inform clinical management as well as hospital bed and ventilation allocation.

Gelator length precisely tunes supramolecular hydrogel stiffness and neuronal phenotype in 3D culture.

The brain is one of the softest tissues in the body with storage moduli (G') that range from hundreds to thousands of pascals (Pa) depending upon the anatomic region. Furthermore, pathological processes such as injury, aging and disease can cause subtle changes in the mechanical properties throughout the central nervous system. However, these changes in mechanical properties lie within an extremely narrow range of moduli and there is great interest in understanding their effect on neuron biology. We report here the design of supramolecular hydrogels based on anionic peptide amphiphile nanofibers using oligo-L-lysines of different molecular lengths to precisely tune gel stiffness over the range of interest and found that G' increases by 10.5 Pa for each additional lysine monomer in the oligo-L-lysine chain. We found that small changes in storage modulus on the order of 70 Pa significantly affect survival, neurite growth and tyrosine hydroxylase-positive population in dopaminergic neurons derived from induced pluripotent stem cells. The work reported here offers a strategy to tune mechanical stiffness of hydrogels for use in 3D neuronal cell cultures and transplantation matrices for neural regeneration.

DNA-Peptide Amphiphile Nanofibers Enhance Aptamer Function.

The single stranded DNA oligonucleotides known as aptamers have the capacity to bind proteins and other molecules and offer great therapeutic potential. Further work is required to optimize their function and to diminish their susceptibility to nuclease degradation. We report here on the synthesis and supramolecular self-assembly of DNA-peptide amphiphiles that form high aspect ratio nanofibers and display aptamers for platelet-derived growth factor. The nanofibers were found to bind the growth factor with an affinity that was fivefold greater than the free aptamer. We also observed that the aptamer displayed by the supramolecular nanostructures was eight times more nuclease resistant than free aptamer. In order to highlight the therapeutic potential of these supramolecular systems, we demonstrated the improved inhibition of proliferation when the growth factor was bound to aptamers displayed by the nanofibers.

Reversible self-assembly of superstructured networks.

Soft structures in nature, such as protein assemblies, can organize reversibly into functional and often hierarchical architectures through noncovalent interactions. Molecularly encoding this dynamic capability in synthetic materials has remained an elusive goal. We report on hydrogels of peptide-DNA conjugates and peptides that organize into superstructures of intertwined filaments that disassemble upon the addition of molecules or changes in charge density. Experiments and simulations demonstrate that this response requires large-scale spatial redistribution of molecules directed by strong noncovalent interactions among them. Simulations also suggest that the chemically reversible structures can only occur within a limited range of supramolecular cohesive energies. Storage moduli of the hydrogels change reversibly as superstructures form and disappear, as does the phenotype of neural cells in contact with these materials.