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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 -
Alzheimer's & Dementia : the Journal of... Jun 2024Motor function has correlated with longevity and functionality; however, there is limited research on those with Alzheimer's disease (AD). We studied the association...
INTRODUCTION
Motor function has correlated with longevity and functionality; however, there is limited research on those with Alzheimer's disease (AD). We studied the association between motor functionality and AD pathology in primary motor and medial temporal cortices.
METHODS
A total of 206 participants with a clinical diagnosis of cognitively healthy, AD, or mild cognitive impairment (MCI) underwent imaging and motor assessment. Linear regressions and analyses of variance were applied to test the prediction from AD imaging biomarkers to motor performance and the diagnosis group differences in motor performance.
RESULTS
Increased neurodegeneration was associated with worsening dexterity and lower walking speed, and increased amyloid and tau were associated with worsening dexterity. AD and MCI participants had lower motor performance than the cognitively healthy participants.
DISCUSSION
Increased AD pathology is associated with worsening dexterity performance. The decline in dexterity in those with AD pathology may offer an opportunity for non-pharmacological therapy intervention.
HIGHLIGHTS
Noted worsening dexterity performance was associated with greater Alzheimer's disease (AD) pathology (tau, amyloid beta, and neurodegeneration) in primary motor cortices. Similarly, increased neurodegeneration and tau pathology in parahippocampal, hippocampal, and entorhinal cortices is associated with worsening dexterity performance. Motor performance declined in those with clinical and preclinical AD among an array of motor assessments.
PubMed: 38934641
DOI: 10.1002/alz.13899 -
Archivio Italiano Di Urologia,... Jun 2024To evaluate the accuracy of PSMA PET/CT in men with mpMRI PI-RADS score 5 negative biopsy histology.
INTRODUCTION
To evaluate the accuracy of PSMA PET/CT in men with mpMRI PI-RADS score 5 negative biopsy histology.
MATERIALS AND METHODS
From January 2011 to January 2023, 180 men with PI-RADS score 5 underwent systematic plus mpMRI/TRUS biopsy; 25/180 (13.9%) patients had absence of cancer and six months from biopsy were submitted to: digital rectal examination, PSA and PSA density exams, mpMRI and 68GaPSMA PET/CT evaluation (standardized uptake value "SUVmax" was reported).
RESULTS
In 24/25 (96%) patients PSA and PSA density significantly decreased, moreover, the PI-RADS score was downgraded resulting < 3; in addition, median SUVmax was 7.5. Only 1/25 (4%) man had an increased PSA value (from 10.5 to 31 ng/ml) with a confirmed PI-RADS score 5, SUVmax of 32 and repeated prostate biopsy demonstrating a Gleason score 9/ISUP Grade Group 5 PCa.
CONCLUSIONS
The strict follow up of men with PI-RADS score 5 and negative histology reduce the risk of missing csPCa especially if PSMA PET/CT evaluation is in agreement with downgrading of mpMRI (PI-RADS score < 3).
Topics: Humans; Male; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Aged; Middle Aged; Biopsy; Prostate-Specific Antigen; Prostate; Retrospective Studies; Multiparametric Magnetic Resonance Imaging
PubMed: 38934527
DOI: 10.4081/aiua.2024.12358 -
Alzheimer's & Dementia : the Journal of... Jun 2024The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create...
The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 and single work groups in 2012 and 2018 to create recommendations for the diagnosis and characterization of Alzheimer's disease (AD). The present document updates the 2018 research framework in response to several recent developments. Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine (e.g., oncology), and is becoming a unifying concept common to all neurodegenerative diseases, not just AD. The present document is consistent with this principle. Our intent is to present objective criteria for diagnosis and staging AD, incorporating recent advances in biomarkers, to serve as a bridge between research and clinical care. These criteria are not intended to provide step-by-step clinical practice guidelines for clinical workflow or specific treatment protocols, but rather serve as general principles to inform diagnosis and staging of AD that reflect current science. HIGHLIGHTS: We define Alzheimer's disease (AD) to be a biological process that begins with the appearance of AD neuropathologic change (ADNPC) while people are asymptomatic. Progression of the neuropathologic burden leads to the later appearance and progression of clinical symptoms. Early-changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid biomarkers, and accurate plasma biomarkers [especially phosphorylated tau 217]) map onto either the amyloid beta or AD tauopathy pathway; however, these reflect the presence of ADNPC more generally (i.e., both neuritic plaques and tangles). An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of AD and to inform clinical decision making throughout the disease continuum. Later-changing Core 2 biomarkers (biofluid and tau PET) can provide prognostic information, and when abnormal, will increase confidence that AD is contributing to symptoms. An integrated biological and clinical staging scheme is described that accommodates the fact that common copathologies, cognitive reserve, and resistance may modify relationships between clinical and biological AD stages.
PubMed: 38934362
DOI: 10.1002/alz.13859 -
Frontiers in Aging Neuroscience 2024Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday...
Amyloid and tau burden relate to longitudinal changes in the performance of complex everyday activities among cognitively unimpaired older adults: results from the performance-based Harvard Automated Phone Task.
BACKGROUND
Changes in everyday functioning constitute a clinically meaningful outcome, even in the early stages of Alzheimer's disease. Performance-based assessments of everyday functioning might help uncover these early changes. We aimed to investigate how changes over time in everyday functioning relate to tau and amyloid in cognitively unimpaired older adults.
METHODS
Seventy-six cognitively unimpaired participants (72 ± 6 years old, 61% female) completed multiple Harvard Automated Phone Task (APT) assessments over 2.0 ± 0.9 years. The Harvard APT consists of three tasks, performed through an automated phone system, in which participants refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and transfer money to pay a bill (APT-Bank). Participants underwent Pittsburgh compound-B and flortaucipir positron emission tomography scans at baseline. We computed distribution volume ratios for a cortical amyloid aggregate and standardized uptake volume ratios for medial temporal and neocortical tau regions. In separate linear mixed models, baseline amyloid by time and tau by time interactions were used to predict longitudinal changes in performance on the Harvard APT tasks. Three-way amyloid by tau by time interactions were also investigated. Lastly, we examined associations between tau and change in Harvard APT scores in exploratory voxel-wise whole-brain analyses. All models were adjusted for age, sex, and education.
RESULTS
Amyloid [unstandardized partial regression coefficient estimate (β) = -0.007, 95% confidence interval (95% CI) = (-0.013, -0.001)], and medial temporal tau [β = -0.013, 95% CI = (-0.022, -0.004)] were associated with change over time in years on APT-PCP only, i.e., higher baseline amyloid and higher baseline tau were associated with steeper rate of decline of APT-PCP. Voxel-wise analyses showed widespread associations between tau and change in APT-PCP scores over time.
CONCLUSION
Even among cognitively unimpaired older adults, changes over time in the performance of cognitively complex everyday activities relate to cortical amyloid and widespread cerebral tau burden at baseline. These findings support the link between Alzheimer's disease pathology and function and highlight the importance of measuring everyday functioning in preclinical disease stages.
PubMed: 38934017
DOI: 10.3389/fnagi.2024.1420290