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Scientific Data Jun 2024Accurate differentiation between angina with no obstructive coronary arteries (ANOCA) and mental stress-induced myocardial ischemia (MSIMI) is crucial for tailored...
Accurate differentiation between angina with no obstructive coronary arteries (ANOCA) and mental stress-induced myocardial ischemia (MSIMI) is crucial for tailored treatment strategies, yet public data scarcity hampers understanding. Given the higher incidence of both conditions in women, this study prospectively enrolled 80 female ANOCA and 39 age-matched female controls, subjecting them to three types of mental stress tasks. ECGs were continuously monitored across Rest, Stress, and Recover stages of the mental stress tasks, with PET/CT imaging during the Stress stage to evaluate myocardial perfusion. With PET/CT serving as the gold standard for MSIMI diagnosis, 35 of the 80 ANOCA patients were diagnosed as MSIMI. Using ECG variables from different stages of mental stress tasks, we developed five machine learning models to diagnose MSIMI. The results showed that ECG data from different stages provide valuable information for MSIMI classification. Additionally, the dataset encompassed demographic details, physiological, and blood sample test results of the patients. We anticipate this new dataset will significantly push further progress in ANOCA and MSIMI research.
Topics: Humans; Female; Myocardial Ischemia; Stress, Psychological; Electrocardiography; Machine Learning; Positron Emission Tomography Computed Tomography; Middle Aged; Angina Pectoris; Prospective Studies
PubMed: 38937514
DOI: 10.1038/s41597-024-03462-2 -
Nature Communications Jun 2024Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods...
Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[F]fluoro-2-deoxytrehalose ([F]FDT) - is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [F]FDT from the most globally-abundant organic F-containing molecule, [F]FDG. The full, pre-clinical validation of both production method and [F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [F]FDT directly from the widely-available clinical reagent [F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.
Topics: Animals; Mycobacterium tuberculosis; Positron-Emission Tomography; Trehalose; Tuberculosis; Humans; Mice; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Radiopharmaceuticals; Disease Models, Animal; Female
PubMed: 38937448
DOI: 10.1038/s41467-024-48691-6 -
Diagnostic and Interventional Imaging Jun 2024
PubMed: 38937251
DOI: 10.1016/j.diii.2024.06.003 -
Neurobiology of Disease Jun 2024The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage....
BACKGROUND
The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical, supported by the electromyographic examination to reveal signs of lower motor neuron damage. Identifying reliable markers of upper motor neuron (UMN) involvement is challenging. On this regard, the role of transcranial magnetic stimulation-induced motor-evoked potentials (TMS-MEPs), and its relationship with UMN burden, is still under investigation.
OBJECTIVE
To evaluate the ability of TMS-MEPs in delineating the neurophysiological UMN damage, and to determine the relationship between TMS-MEPs and [F]FDG-PET measures of neural dysfunction.
METHODS
We retrospectively selected 13 ALS patients who underwent, during the diagnostic process, the TMS-MEPs and [F]FDG-PET scans. Demographic and clinical data were collected. For the MEP evaluation, we considered normal MEP, absent MEP, or significantly increased central-motor-conduction-time. For [F]FDG-PET, we conducted voxel-wise analyses, both at single-subject and group levels, exploring hypometabolism and hypermetabolism patterns in comparison with a large dataset of healthy controls (HC).
RESULTS
Based on TMS-MEPs, we identified 4/13 patients with normal MEP in all limbs (GROUP-NO), while 9/13 had an abnormal MEP in at least one limb (GROUP-AB). Despite the [F]FDG-PET single-subject analysis revealed heterogenous expression of regional hypo- and hyper-metabolism patterns in the patients, the group-level analysis revealed a common hypometabolism, involving the precentral gyrus and the supplementary motor area, the paracentral lobule and the anterior cingulate cortex in the GROUP-AB. Moreover, exclusively for the GROUP-AB compared with HC, a relative hypermetabolism was observed in the right cerebellum, right inferior and middle temporal gyrus. The GROUP-NO showed no specific cluster of hypo- and hyper-metabolism compared to HC.
CONCLUSION
This study showed altered brain metabolism only in the ALS group with abnormal MEPs, suggesting an association between the two biomarkers in defining the UMN damage.
PubMed: 38936435
DOI: 10.1016/j.nbd.2024.106579 -
Molecular Pharmaceutics Jun 2024Doxorubicin (DOX) is a common and highly effective chemotherapeutic. However, its use is limited by cardiotoxic effects and the lack of methods to detect these at early...
Doxorubicin (DOX) is a common and highly effective chemotherapeutic. However, its use is limited by cardiotoxic effects and the lack of methods to detect these at early time points. In the present study, we evaluated if [Cu]Cu-NODAGA-E[(cRGDyK)]2 positron emission tomography-computed tomography ([Cu]Cu-RGD PET/CT) could detect cardiotoxicity in a rat model of DOX-induced heart failure. Male Lewis rats were divided into two groups and treated with either a cumulative dose of 15 mg/kg of DOX or left untreated. Cardiac anatomy and function were assessed using magnetic resonance imaging at baseline and in week 8. [Cu]Cu-RGD PET/CT scans were performed in week 4. DOX treatment led to a decline in pump function as well as an increase in cardiac and thymic uptake of [Cu]Cu-RGD. In addition, DOX altered cardiac gene expression, led to infiltration of immune cells, reduced endothelial content, and increased interstitial fibrosis. Furthermore, concentrations of inflammatory plasma proteins were increased in the DOX group. In conclusion, DOX treatment resulted in the development of cardiotoxicity and heart failure, which could be detected using [Cu]Cu-RGD PET/CT at early time points. [Cu]Cu-RGD uptake in the myocardial septum and thymus predicted a low left ventricular ejection fraction in week 8.
PubMed: 38936409
DOI: 10.1021/acs.molpharmaceut.4c00272 -
Applied Radiation and Isotopes :... Jun 2024Radioisotopes are widely used in the fields of medicine, science, and industry. The growing demand for medical radioisotopes has driven research on alternative...
Radioisotopes are widely used in the fields of medicine, science, and industry. The growing demand for medical radioisotopes has driven research on alternative production methods. In particular, both isotopes of Cu and Ge play vital roles in the medical environment in many countries to be used in the radio-immunotherapy and the positron emission tomography imaging, respectively. This study designed a multi-target system consisting of two Zn and one GaO plates to enable simultaneous production of the medical radioisotopes Cu and Ge using 100 MeV proton beams. To understand the thermal effect on the multi-targets, we examined the distribution of energy absorbed in each solid plate target when exposed to an accelerated proton beam through the thermal-fluid analysis based on ANSYS simulation. For confirming thermal stability for two Zn targets and one GaO target, the modified water flow path inside the multi-target system was designed effectively with the controlled distribution of multiple sub-holes between main inlet and the following four channels. It was confirmed that the newly designed multi-target system of Zn and GaO solid plates shows higher thermal stability than the case of uniform distribution of water inlet, which means it could be exposed to a higher current beam of 7.57% to decrease the processing time.
PubMed: 38936285
DOI: 10.1016/j.apradiso.2024.111415 -
Sleep Medicine Reviews Jun 2024The quality of sleep plays a significant role in determining human well-being, and studying sleep and sleep disorders using various methods can aid in the prevention and... (Review)
Review
The quality of sleep plays a significant role in determining human well-being, and studying sleep and sleep disorders using various methods can aid in the prevention and treatment of diseases. Positron emission tomography (PET) is a noninvasive and highly sensitive medical imaging technique that has been widely adopted in the clinic. This review article provides data on research activity related to sleep and sleep apnea and discusses the use of PET in investigating sleep apnea and other sleep disorders. We conducted a statistical analysis of the number of original research articles published on sleep and sleep apnea between 1965 and 2021 and found that there has been a dramatic increase in publications since 1990. The distribution of contributing countries and regions has also undergone significant changes. Although there is an extensive body of literature on sleep research (256,399 original research articles during 1965-2021), PET has only been used in 54 of these published studies, indicating a largely untapped area of research. Nonetheless, PET is a useful tool for identifying connections between sleep disorders and pathological changes in various diseases, including neurological, metabolic, and cardiovascular disorders, as well as cancer. To facilitate the broader use of PET in sleep apnea research, further studies are needed in both clinical and preclinical settings.
PubMed: 38936220
DOI: 10.1016/j.smrv.2024.101967 -
Molecular Pharmaceutics Jun 2024Colony-stimulating factor 1 receptor (CSF1R) is a type III receptor tyrosine kinase that is crucial for immune cell activation, survival, proliferation, and...
Colony-stimulating factor 1 receptor (CSF1R) is a type III receptor tyrosine kinase that is crucial for immune cell activation, survival, proliferation, and differentiation. Its expression significantly increases in macrophages during inflammation, playing a crucial role in regulating inflammation resolution and termination. Consequently, CSF1R has emerged as a critical target for both therapeutic intervention and imaging of inflammatory diseases. Herein, we have developed a radiotracer, 1-[4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl]-3-(4-[F]fluorophenyl)urea ([F]), for positron emission tomography (PET) imaging of CSF1R. Compound exhibits a comparable inhibitory potency against CSF1R as the well-known CSF1R inhibitor PLX647. The radiosynthesis of [F] was successfully performed by radiofluorination of aryltrimethyltin precursor with a yield of approximately 12% at the end of synthesis, maintaining a purity exceeding 98%. stability and biodistribution studies demonstrate that [F] remains >90% intact at 30 min postinjection, with no defluorination observed even at 60 min postinjection. The PET/CT imaging study in lipopolysaccharide-induced pulmonary inflammation mice indicates that [F] offers a more sensitive characterization of pulmonary inflammation compared to traditional [F]FDG. Notably, [F] shows a higher discrepancy in uptake ratio between mice with pulmonary inflammation and the sham group. Furthermore, the variations in [F] uptake ratio observed on day 7 and day 14 correspond to lung density changes observed in CT imaging. Moreover, the expression levels of CSF1R on day 7 and day 14 follow a trend similar to the uptake pattern of [F], indicating its potential for accurately characterizing CSF1R expression levels and effectively monitoring the pulmonary inflammation progression. These results strongly suggest that [F] has promising prospects as a CSF1R PET tracer, providing diagnostic opportunities for pulmonary inflammatory diseases.
PubMed: 38935927
DOI: 10.1021/acs.molpharmaceut.4c00337 -
JCO Oncology Practice Jun 2024Patients with advanced, well-differentiated neuroendocrine tumors (WD-NETs) often require both peptide receptor radionuclide therapy (PRRT) and subsequent chemotherapy....
PURPOSE
Patients with advanced, well-differentiated neuroendocrine tumors (WD-NETs) often require both peptide receptor radionuclide therapy (PRRT) and subsequent chemotherapy. However, no mid-PRRT predictors are available to identify patients who will not benefit from subsequent PRRT to limit their radiation exposure. Our aim is to characterize patients for whom subsequent PRRT is less efficacious on the basis of mid-PRRT evaluation.
MATERIALS AND METHODS
A retrospective study of patients with WD-NET who underwent ≥four PRRT cycles. Data gathered included demographics, tumor grade, stage, and response (partial response [PR], stable disease [SD], and progressive disease [PD]) on the basis of RECIST 1.1 criteria and Ga-dotatate positron emission tomography-computerized tomography pretreatment, after second and fourth treatment cycle, 6 months after fourth cycle, and at last follow-up.
RESULTS
Fifty-one patients (51.6% women; age at diagnosis 66.0 ± 1.65 years), with pancreatic NET (PNET; n = 24), small intestine NET (n = 13), or other NET (n = 14), received PRRT, resulting in PR (n = 21), SD (n = 23), and PD (n = 3). Of the patients reaching PR after PRRT, most reached PR after two treatments (70.4%), with only 11.8% PR occurring between subsequent cycles ( = .001). Furthermore, patients with PR at mid-treatment had higher PR rates after PRRT completion than those with SD ( = .007). Patients harboring PNET who achieved PR had a more pronounced reduction of tumor burden in additional cycles than patients who did not (25.6% 1.5%; = .03, respectively). On the multivariable model, adjusted for grade and primary site, PR at mid-treatment evaluation was associated with a 20.9 adjusted odds ratio for additional PR at PRRT completion ( = .002).
CONCLUSION
Mid-PRRT assessment predicts subsequent PRRT response in patients with WD-NET, especially those with PNET, informing personalized management and consideration of reduced bone marrow radiation exposure in high-risk patients.
PubMed: 38935916
DOI: 10.1200/OP.23.00789 -
Journal of Medicinal Chemistry Jun 2024We report the [Mn/Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN...
We report the [Mn/Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN [(4,4,10,10)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane]. The X-ray crystal structures of Mn-PYAN and Mn-CHXPYAN evidence distorted octahedral geometries through coordination of the nitrogen atoms of the macrocycles. Cyclic voltammetry studies evidence reversible processes due to the Mn(II)/Mn(III) pair, indicating that the complexes are resistant to oxidation. CHXPYAN forms a more thermodynamically stable and kinetically inert Mn(II) complex than PYAN. Radiochemical studies with the radioactive isotope manganese-52 (Mn, = 5.6 days) evidenced better radiochemical yields for CHXPYAN than for PYAN. Both [Mn]Mn(II) complexes remained stable in mouse and human serum, so in vivo stability studies were carried out. Positron emission tomography/computed tomography scans and biodistribution assays indicated that [Mn]Mn-PYAN has a distribution pattern similar to that of [Mn]MnCl, showing persistent radioactivity accumulation in the kidneys. Conversely, [Mn]Mn-CHXPYAN remained stable in vivo, clearing quickly from the liver and kidneys.
PubMed: 38935616
DOI: 10.1021/acs.jmedchem.4c00812