In preclinical models, the development and optimization of protein-drug conjugates require accurate determination of the plasma and tissue profiles of both the protein and its conjugated drug. To ...this aim, we developed a bioanalytical strategy based on dual radiolabeling and ex vivo digital imaging. By combining enzymatic and chemical reactions, we obtained homogeneous dual-labeled anti-MMP-14 Fabs (antigen-binding fragments) conjugated to monomethyl auristatin E where the protein scaffold was labeled with carbon-14 (14C) and the conjugated drug with tritium (3H). These antibody-drug conjugates with either a noncleavable or a cleavable linker were then evaluated in vivo. By combining liquid scintillation counting and ex vivo dual-isotope radio-imaging, it was possible not only to monitor both components simultaneously during their circulation phase but also to quantify accurately their amount accumulated within the different organs.
Neuronal PET tracers for Alzheimer's disease Prem Kumar, Ashwini; Singh, Nivedita; Nair, Deepak ...
Biochemical and biophysical research communications,
01/2022, Letnik:
587
Journal Article
Recenzirano
Advancements in brain imaging techniques have emerged as a significant tool in detecting Alzheimer's disease (AD) progression. The complicated cascade of AD progression can be detected using radio ...imaging, especially with Positron emission tomography (PET). The review focus on recently introduced investigational PET tracers targeting neurofibrillary tau aggregates found typically in AD. Herein, we also address the use of different PET tracers and the clinical implementation of established and newer generation tracers. This review also intends to discuss the importance of several PET radiotracers and challenges in PET imaging.
•PET tracers play an important role in understanding AD progression.•Molecular PET tracers are a helpful tool to assess neuronal circuits.•PET tracers can be used to detect the alteration of toxic proteoforms in AD.•Engineering PET tracers would allow better adaptation in the early diagnosis of AD.
The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has ...increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their
behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.
The article presents the results of a study of groundwater contaminated with tritium in the vicinity of the 'Atomic Lake' - a crater filled with water as a result of a thermonuclear explosion on the ...territory of the former Semipalatinsk test site. This crater was created as part of an experimental thermonuclear explosion in 1965 with the aim of creating an artificial reservoir in arid areas. The study was carried out to identify the source of groundwater contamination near the crater formed from a thermonuclear test. There were two possible factors of pollution: the influence of contaminated water from the crater on the groundwater of the adjacent area, or groundwater polluting the water in the crater. It was necessary to find out the source of groundwater contamination and its connection with the water in the funnel. For this purpose, a study of the geological and lithological conditions of the territory adjacent to the funnel was carried out, which was carried out using drilling operations and hydrological measurements. Drilling work made it possible to study the depth of distribution of groundwater, hydrological work made it possible to determine the conditions of distribution of groundwater, as well as to take samples of groundwater. The assessment of the degree of groundwater contamination was carried out through water sampling and laboratory analysis. As a result, it was established that the geological and lithological conditions of the area limit the flow of contaminated groundwater to the water in the crater - the 'Atomic Lake'. Despite the fact that the waters in the crater from a thermonuclear explosion and the groundwater of the adjacent territory are contaminated with the radionuclide tritium, they have different sources of contamination and are not interconnected. Radionuclide analysis of groundwater showed that increased concentrations of tritium with a specific activity of up to 95 000 Bq/l are found in groundwater near the river bed. Shagan and this is due to the influence of the flow of groundwater coming from other parts of the landfill.
Natural and artificial radionuclide concentrations were determined and evaluated in 12 different medicinal plants used in Rize Province of Turkey. The levels of
226
Ra,
232
Th,
40
K and
137
Cs were ...specified in medicinal plants and a germanium detector with high-purity was used for these measurements. Mean activity values of
226
Ra,
232
Th,
40
K and
137
Cs in medicinal plants were obtained to be 4.48, 1.83, 259.2 and 0.70 Bq kg
‒1
, respectively. The obtained values were compared with the values reached in similar studies conducted in different countries. All activity values of
226
Ra,
232
Th and
40
K determined in the present study were found to be lower than the worldwide mean values. In addition, the following radiological parameters were determined in medicinal plants and compared with the recommended limits: radium equivalent activity (Ra
eq
), annual gonadal dose equivalent (AGDE), absorbed gamma dose rate (D), exposure rate (ER), gamma representative level index (RLI), annual effective dose (AED), and excess lifetime cancer risk (ELCR). Pearson correlation coefficients were determined to assess the correlations between radioactive variables in medicinal plants. The radiological values determined in this study are within the recommended safety limit and the medicinal plants do not pose any significant radiological risk to human health.
To determine the cut-off standardized uptake value (SUV) on (18)F fluoro-2-deoxy-glucose (FDG) positron emission tomography/computed tomography (FDG-PET/CT) images that generates the best volumetric ...match to pathologic gross tumor volume (GTV(path)) for non-small-cell lung cancer (NSCLC).
Fifteen patients with NSCLC who underwent FDG-PET/CT scans followed by lobectomy were enrolled. The surgical specimen was dissected into 5-7-mum sections at approximately 4-mm intervals and stained with hematoxylin and eosin. The tumor-containing area was outlined slice by slice and the GTV(path) determined by summing over all the slices, taking into account the interslice thickness and fixation-induced volume reduction. The gross tumor volume from the PET images, GTV(PET), was determined as a function of cut-off SUV. The optimal threshold or optimal absolute SUV was defined as the value at which the GTV(PET) was the same as the GTV(path).
The fixation process induced a volumetric reduction to 82% +/- 10% (range, 62-100%) of the original. The maximal SUV was 10.1 +/- 3.6 (range, 4.2-18.7). The optimal threshold and absolute SUV were 31% +/- 11% and 3.0 +/- 1.6, respectively. The optimal threshold was inversely correlated with GTV(path) and tumor diameter (p < 0.05), but the optimal absolute SUV had no significant correlation with GTV(path) or tumor diameter (p > 0.05).
This study evaluated the use of GTV(path) as a criterion for determining the optimal cut-off SUV for NSCLC target volume delineation. Confirmatory studies including more cases are being performed.
Purpose The availability of newly approved treatment options for metastatic castration resistant prostate cancer is not matched with conclusive data on optimal sequencing strategies and resistance ...patterns. A comprehensive review of efficacy and safety data for new agents and current knowledge regarding treatment sequencing would enable treating physicians to make rational drug selections in patients with metastatic castration resistant prostate cancer. Materials and Methods We searched MEDLINE® and relevant congresses for data on cabazitaxel, docetaxel,223 radium dichloride, abiraterone, enzalutamide and sipuleucel-T, focusing on sequencing strategies, resistance mechanisms and biomarkers of response. Results Abiraterone and enzalutamide target the androgen axis with different mechanisms of action. Abiraterone blocks cytochrome P450 17, inhibiting androgen synthesis, whereas enzalutamide inhibits androgen receptor, reducing nuclear translocation of the androgen receptor complex and subsequent DNA binding. Both agents provide improved overall survival in patients with metastatic castration resistant prostate cancer who received prior docetaxel treatment and in those who are chemotherapy naïve. Cabazitaxel provides improved overall survival in patients with metastatic castration resistant prostate cancer with prior docetaxel therapy. Sipuleucel-T provides improved overall survival in asymptomatic patients and223 radium provides improved overall survival in chemotherapy naïve and chemotherapy treated patients with symptomatic bone metastases. Selecting the correct treatment with metastatic castration resistant prostate cancer is complex as no head-to-head trials have been done and comparison between existing trials is difficult due to differences in study populations and a lack of validated biomarkers. Factors to consider include prior therapy, symptom burden, metastasis type, performance status, comorbidities, adverse event profiles and patient preference. Another consideration is treatment sequence since some agents affect responses to subsequent choices. For example, resistance to abiraterone or enzalutamide may result in limited responses to subsequent androgen targeted agents. Identifying factors predictive of resistance is an area of ongoing research with androgen receptor variants representing a good candidate. Prognostic factors for survival are also likely to be useful and are currently being studied. Conclusions New therapies for metastatic castration resistant prostate cancer have brought new challenges with regard to treatment selection and sequencing. While hormonal agents provide good therapeutic responses, resistance may be intrinsic without prior drug exposure. Identifying predictors of response and relevant biomarkers will allow therapies to be more precisely tailored to individual patient profiles.
Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy ...disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized 18Flansoprazole, 11CN-methyl lansoprazole, and 18FN-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that 18FN-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.
This study aimed to evaluate the radiological hazards of uranium (
U), thorium (
Th), and potassium (
K) in microgranitic rocks from the southeastern part of Wadi Baroud, a northeastern desert of ...Egypt. The activity concentrations of the measured radionuclides were determined by using a gamma-ray spectrometer (NaI-Tl-activated detector). The mean (
U), (
Th), and (
K) concentrations in the studied rocks were found to be 3680.3, 3635.2, and 822.76 Bq/kg, respectively. The contents in these rocks were elevated, reaching up to 6.3 wt%. This indicated the alkaline nature of these rocks. The high ratios of Th/U in the mineralized rocks could be related to late magmatic mineralization, suggesting the ascent of late magmatic fluids through weak planes such as faults and the contact of these rocks with older granites. The present data were higher than those of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) guideline limits. All the radiological hazard results indicated high human health risks. This confirmed that this area is not radiologically safe, and care must be taken when working in this area. This study showed that the area under investigation had high U content suitable for uranium extraction that could be used in the nuclear fuel cycle.
To date, glioblastoma treatments have only been palliative. In this context, locoregional drug delivery strategies, which allow for blood--brain barrier bypass and reduced systemic toxicity, are of ...major significance. Recent progress in nanotechnology has led to the development of colloidal carriers of radiopharmaceutics, such as lipid nanocapsules loaded with rhenium-188 (LNC(188)Re-SSS) that are implanted in the brain. In our study, we demonstrated that fractionated internal radiation using LNC(188)Re-SSS triggered remarkable survival responses in a rat orthotopic glioma model (cure rates of 83%). We also highlighted the importance of the radioactivity activity gradient obtained by combining a simple stereotactic injection (SI) with convection-enhanced delivery (CED).We assumed that the immune system played a role in the treatment's efficacy on account of the overproduction of peripheral cytokines, recruitment of immune cells to the tumor site, and memory response in long-term survivor animals. Hence, nanovectorized internal radiation therapy with activity gradients stimulating immune responses may represent a new and interesting alternative for the treatment of solid tumors such as glioblastomas.
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