Radioactive Counts Research Articles

Metabolic Study of Tetra-PEG-Based Hydrogel after Pelvic Implantation in Rats.

In vivo metabolism of polyethylene glycol (PEG) hydrogels has rarely been studied. In this study, we prepared a chemically crosslinked hydrogel formulation using 14C-labeled tetra-armed poly (ethylene glycol) succinimidyl succinate (Tetra-PEG-SS) and 3H-labeled crosslinking agent for implantation into the pelvis of Sprague-Dawley (SD) rats. This radioactive labeling technique was used to investigate the radioactivity excretion rates in of feces and urine, the blood exposure time curve, and the radioactivity recovery rate in each tissue over time. We showed that the primary excretion route of the hydrogel was via urine (3H: about 86.4%, 14C: about 90.0%), with fewer portion through feces (3H: about 6.922%, 14C: about 8.16%). The hydrogel metabolites exhibited the highest distribution in the kidney, followed by the jejunal contents; The 3H and 14C radioactivity exposures in the remaining tissues were low. We also showed that the 3H and 14C radioactivity recovery rates in the blood were usually low (<0.10% g−1 at 12 h after implantation), even though, in theory, the hydrogel could be absorbed into the blood through the adjacent tissues. By using a combination of HPLC-MS/MS and offline radioactivity counting method, we established that the tetra-PEG-based hydrogel was mainly metabolized to lower-order PEG polymers and other low-molecular-weight substances in vivo.

Usefulness of Liver Uptake Rate Constant in 99mTc-GSA Scintigraphy for the Risk Stratification of Patients Undergoing Hepatectomy: A New Method for Calculation

Introduction: The use of technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin (^99mTc-GSA) scintigraphy parameters, HH15 and LHL15, in assessing the future liver remnant function is not expedient because of their nonlinear behaviour against liver volume. Uptake rate constant for the binding of ^99mTc-GSA to asialoglycoprotein receptors is probably more favourable, but the reported calculation methods are complex. We devised a simple method to calculate the uptake rate constant, KrGSA. Methods: Radioactivity counts for the entire liver and heart regions were extracted at 10, 20, and 30 min. Using whole liver and heart volumes measured from single-photon emission computed tomography images, free radioactivity corresponding to the liver blood pool was subtracted. The time activity curve was fitted to the equation L(t) = L(∞) × [1 − Exp (−kt)] using Microsoft Office Excel (add-in free programme Solver)®, where L(∞) is the count at plateau level and k denotes KrGSA. Results: KrGSA values accurately identified liver cirrhosis and were similar to the KICG. The areas under the curve for KrGSA and KICG in the receiver operating characteristic analysis were 0.808 and 0.795, respectively, and a good correlation was seen between KrGSA and KICG. Discussion/Conclusion: KrGSA can be utilized as an alternative to KICG in assessing the future liver remnant function.

Radiolabeling Methods.

In vivo measurements of the deposition of an inhaled radiolabeled pharmaceutic have provided useful information related to the inhaler efficiency for depositing drug in the lung. A number of labeling techniques have been developed and applied to pharmaceutical aerosols delivered by pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers; the choice of radiotracer depends on the type of imaging study being performed and the equipment used to image the lung. Preparation, validation and calibration of the radiolabeled pharmaceutical product is key to successful interpretation of the imaging study. When imaging a subject after inhalation of a radiolabeled formulation, it is the radioactivity that is detected and measured by the scanner; absolute amounts of deposited drug are inferred from the counts of radioactivity in the lung and other regions, based on the assumption that there is a 1:1 relationship between the two components-drug and radioactivity. This relationship holds true for direct-labeled PET products or for those formulations where a firm bond can be demonstrated between the drug and radiotracer for the time taken to acquire all the images. This chapter will discuss radiolabeling methods applied to therapeutic aerosols for the purpose of determining the deposition efficiency of these aerosols in the lung. The techniques apply to both in vivo studies in man and in animal models, and to some extent to in vitro models.

Mass Spectrometry-Based Method for the Determination of the Biodistribution of Tumor-Targeting Small Molecule-Metal Conjugates.

Nuclear medicine plays a key role in modern diagnosis and cancer therapy. The development of tumor-targeting radionuclide conjugates (also named small molecule-radio conjugates (SMRCs)) represents a significant improvement over the clinical use of metabolic radiotracers (e.g., [18F]-fluorodeoxyglucose) for imaging and over the application of biocidal external beam radiations for therapy. During the discovery of SMRCs, molecular candidates must be carefully evaluated typically by performing biodistribution assays in preclinical tumor models. Quantification methodologies based on radioactive counts are typically demanding due to safety concerns, availability of radioactive materials, and infrastructures. In this article, we report the development of a mass spectrometry (MS)-based method for the detection and quantification of small molecule-metal conjugates (SMMCs) as cold surrogates of SMRCs. We applied this methodology for the evaluation of the biodistribution of a particular class of tumor-targeting drug candidates based on natLu, natGa, and natF and directed against fibroblast activation protein (FAP). The reliability of the liquid chromatography-MS (LC-MS) analysis was validated by a direct comparison of MS-based and radioactivity-based biodistribution data. The results show that MS biodistribution of stable isotope metal conjugates is an orthogonal tool for the preclinical characterization of different classes of radiopharmaceuticals.

Deep regression using 99mTc-DTPA dynamic renal imaging for automatic calculation of the glomerular filtration rate.

To develop and evaluate an artificial intelligence (AI) system that can automatically calculate the glomerular filtration rate (GFR) from dynamic renal imaging without manually delineating the regions of interest (ROIs) of kidneys and the corresponding background. This study was a single-center retrospective analysis of the data of 14,634 patients who underwent 99mTc-DTPA dynamic renal imaging. Two systems based on convolutional neural networks (CNN) were developed and evaluated: sGFRa predicts the radioactive counts of ROIs and calculates GFR using the Gates equation and sGFRb directly predicts GFR from dynamic renal imaging without using other information. The root-mean-square error (RMSE), mean absolute error (MAE), mean absolute percentage error (MAPE), and R2 were used to evaluate the performance of our approach. sGFRa achieved an RMSE of 5.05, MAE of 4.03, MAPE of 6.07%, and R2 of 0.93 for total GFR while sGFRb achieved an RMSE of 7.61, MAE of 5.92, MAPE of 8.92%, and R2 of 0.85 for total GFR. The accuracy of sGFRa and sGFRb in determining the stage of chronic kidney disease was 87.41% and 82.44%, respectively. The findings of sGFRa show that automatic GFR calculation based on CNN and using dynamic renal imaging is feasible and efficient and, additionally, can aid clinical diagnosis. Furthermore, the promising results of sGFRb demonstrate that CNN can predict GFR from dynamic renal imaging without additional information. • Our CNN-based AI systems can automatically calculate GFR from dynamic renal imaging without manually delineating the ROIs of kidneys and the corresponding background. • sGFRa accurately predicted the radioactive counts of ROIs and calculated GFR using the Gates method. • sGFRb-predicted GFR directly without any parameters related to the Gates equation.

Uptake of lipid core nanoparticles by fragments of tissues collected during cerebral tumor excision surgeries: hypotheses for use in drug targeting therapy.

Malignant cerebral tumors have poor prognosis and the blood-brain barrier is a major hindrance for most drugs to reach those tumors. Lipid nanoparticles (LDE) that bind to lipoprotein receptors may carry anticancer drugs and penetrate the cells through those receptors that are overexpressed in gliomas. The aim was to investigate the in vivo uptake of LDE by human cerebral tumors. Twelve consecutive patients (4 with glioblastomas, 1 meduloblastoma, 1 primary lymphoma, 2 with non-cerebral metastases and 4 with benign tumors) scheduled for tumor excision surgery were injected intravenously, 12h before surgery, with LDE labeled 14C-cholesterol oleate. Fragments of tumors and of normal head tissues (muscle, periosteum, dura mater) discarded by the surgeon were submitted to lipid extraction and radioactive counting. Tumor LDE uptake (range: 10-283 d.p.m./g of tissue) was not lower than that of normal tissues (range: 20-263 d.p.m./g). Malignant tumor uptake was threefold greater than benign tumor uptake (140 ± 93 vs 46 ± 18 d.p.m./g, p < 0.05). Results show that LDE can concentrate in brain malignant tumors and may be used to carry drugs directed against those tumors. As LDE was previously shown to markedly decrease drug toxicity this new therapeutic strategy should be tested in future trials.

The ultra high sensitivity blood counter: a compact, MRI-compatible, radioactivity counter for pharmacokinetic studies in μl volumes

Quantification of physiological parameters in preclinical pharmacokinetic studies based on nuclear imaging requires the monitoring of arterial radioactivity over time, known as the arterial input function (AIF). Continuous derivation of the AIF in rodent models is very challenging because of the limited blood volume available for sampling. To address this challenge, an Ultra High Sensitivity Blood Counter (UHS-BC) was developed. The device detects beta particles in real-time using silicon photodiodes, custom low-noise electronics, and 3D-printed plastic cartridges to hold standard catheters. Two prototypes were built and characterized in two facilities. Sensitivities up to 39% for 18F and 58% for 11C-based positron emission tomography (PET) tracers were demonstrated. 99mTc and 125I based Single Photon Emission Computed Tomography (SPECT) tracers were detected with greater than 3% and 10% sensitivity, respectively, opening new applications in nuclear imaging and fundamental biology research. Measured energy spectra show all relevant peaks down to a minimum detectable energy of 20 keV. The UHS-BC was shown to be highly reliable, robust towards parasitic background radiation and electromagnetic interference in the PET or MRI environment. The UHS-BC provides reproducible results under various experimental conditions and was demonstrated to be stable over days of continuous operation. Animal experiments showed that the UHS-BC performs accurate AIF measurements using low detection volumes suitable for small animal models in PET, SPECT and PET/MRI investigations. This tool will help to reduce the time and number of animals required for pharmacokinetic studies, thus increasing the throughput of new drug development.

Value of Quantitative SPECT/CT Lymphoscintigraphy in Improving Sentinel Lymph Node Biopsy in Breast Cancer.

Methods We retrospectively enrolled breast cancer patients who underwent SPECT/CT prior to sentinel lymph node biopsy. Quantification of radiotracer uptake from SPECT/CT data was performed. A radioactivity count threshold (RSPECT) using SPECT/CT was calculated for detecting metastatic sentinel lymph nodes. To localize sentinel lymph nodes exactly, we compared the positions of sentinel lymph nodes localized using SPECT/CT with positions localized surgically using an intraoperative γ-probe. Results 491 patients were included, with a median of 3 sentinel lymph nodes/patient detected by the γ-probe and 2 sentinel lymph nodes/patient detected by SPECT/CT. As the number of sentinel lymph nodes visualized on SPECT/CT images, the metastasis incidence of lymph nodes in the ≤2 SLNs group was significantly higher than that in the >2 SLNs group (35% vs. 15%, P < 0.001). No metastasis was found in lymph nodes with RSPECT ≤ 30% in the >2 SLNs group, and thus, 30% (157/526) of SPECT/CT-identified nodes would avoid unnecessary removal. The positions of sentinel lymph nodes localized by SPECT/CT and γ-probe were identical in 42% (39/93) of patients. Conclusions Quantitative Tc-99 m SC SPECT/CT imaging has the potential to preoperatively locate sentinel lymph nodes and intraoperatively avoid unnecessary sentinel lymph node biopsy.

Design, synthesis, and preclinical evaluation of a novel bifunctional macrocyclic chelator for theranostics of cancers.

This study was to design and synthesize a novel bifunctional chelator, named Dar, primarily validated by conjugating to tumor targeting motifs, labeled with radiometals, and performed preclinical evaluation of tumor imaging and cancer therapy in murine tumor models. The designed Dar was synthesized and characterized by X-ray crystallography, 1H/13C NMR, and mass spectrometry. Dar-PSMA-617 was conjugated and radiolabeled with 68Ga, 177Lu, and 89Zr. The in vivo behavior of 68Ga/89Zr-labeled Dar-PSMA-617 were evaluated using micro-PET imaging and biodistribution from image quantitation and tissue radioactivity counting, with 68Ga/89Zr-labeled NOTA/DOTA/DFO-PSMA-617 analogs as controls, respectively. The [177Lu]-Dar-PSMA-617, with [177Lu]-DOTA-PSMA-617 as control, was evaluated in competitive cell uptake, tumor cell internalization, and efflux studies. The treatment efficacy of [177Lu]Lu-Dar-PSMA-617, with [177Lu]Lu-DOTA-PSMA-617 as control, was evaluated in PSMA-positive LNCaP tumor-bearing mice. In addition, the ability of Dar for radiolabeling nanobody was tested by conjugating Dar to KN035 nanobody. The resultant [89Zr]Zr-Dar-KN035 nanobody, with [89Zr]Zr-DFO-KN035 as control, was evaluated by micro-PET imaging and biodistribution in a mouse model bearing MC38&MC38-hPD-L1 colon cancer. 68Ga, 89Zr, and 177Lu-radiolabeled Dar-PSMA-617 complexes were able to be produced under mild condition with high radiochemical yield and purity successfully. [177Lu]Lu-Dar-PSMA-617 had higher cellular uptake yet similar internalization and efflux properties in LNCaP cells, as compared to [177Lu]Lu-DOTA-PSMA-617. Micro-PET images demonstrated significantly higher tumor uptake of [68Ga]Ga-Dar-PSMA-617, than that of the analog [68Ga]Ga-DOTA-PSMA-617. The tumor uptake values of [68Ga]Ga-Dar-PSMA-617 at multiple time points are comparable to that of [68Ga]Ga-NOTA-PSMA-617, although a higher and persistently prolonged kidney retention was resulted in during the study period. The Dar chelator can also successfully mediate the radiolabeling with 89Zr, while the resultant [89Zr]Zr-Dar-PSMA-617 demonstrated a similar biodistribution with [89Zr]Zr-DFO-PSMA-617 measured at 96h p.i. The treatment with [177Lu]Lu-Dar-PSMA-617 significantly inhibited the tumor growth, showing much better efficacy than that of [177Lu]Lu-DOTA-PSMA-617 at the same injected radioactivity and mass dose. Dar was covalently linked to KN035 nanobody and enabled radiolabeling with 89Zr in high yield and radiochemical purity at room temperature. The resultant [89Zr]Zr-Dar-KN035, with [89Zr]Zr-DFO-KN035 as control, demonstrated superior tumor uptake and detection capability in PET imaging studies. The Dar, as a novel bifunctional chelator for medicating the labeling of radiometals onto tumor targeting carriers, was successfully synthesized and chemically characterized. Test radiolabeling, on PSMA-617 and a nanobody as tool targeting molecule carriers, demonstrated the Dar has potential as a universal bifunctional chelator for radiolabeling various radiometals (at least 68Ga, 177Lu, and 89Zr tested) commonly used for clinical imaging and therapy. Using a novel Dar chelator results in altered in vivo behavior of the carriers even though labeled with the same nuclide. This capability makes Dar an alternative to the existing choices for radiolabeling new carrier molecules with various radiometals, especially the radiometals with large radius.

Gaussian Filter for Brain SPECT Imaging

Background. The presence of a noise component on 3D images of single-photon emission computed tomo­graphy (SPECT) of a brain significantly distorts the probability distribution function (PD) of the radioactive count rate in the images. The presence of noise and further filtering of the data, based on a subjective assessment of image quality, have a significant impact on the calculation of volumetric cerebral blood flow and the values of the uptake asymmetry of the radiopharmaceutical in a brain. Objective. We are aimed to develop a method for optimal SPECT filtering of brain images with lipophilic radiopharmaceuticals, based on a Gaussian filter (GF), for subsequent image segmentation by the threshold method. Methods. SPECT images of the water phantom and the brain of patients with 99mTc-HMPAO were used. We have developed a technique for artificial addition of speckle noise to conditionally flawless data in order to determine the optimal parameters for smoothing SPECT, based on a GF. The quantitative criterion for optimal smoothing was the standard deviation between the PD of radioactive count rate of the smoothed image and conditionally ideal one. Results. It was shown that the maximum radioactive count rate of the SPECT image has an extremum by changing the standard deviation of the GF in the range of 0.3–0.4 pixels. The greater the noise component in the SPECT image, the more quasi-linearly the corresponding rate changes. This dependence allows determining the optimal smoothing parameters. The application of the developed smoothing technique allows restoring the probability distribution function of the radioactive count rate (distribution histogram) with an accuracy up to 5–10%. This provides the possibility to standardize SPECT images of brain. Conclusions. The research results of work solve a specific applied problem: restoration of the histogram of a radiopharmaceuticals distribution in a brain for correct quantitative assessment of regional cerebral blood flow. In contrast to the well-known publications on the filtration of SPECT data, the work takes into account that the initial tomographic data are 3D, rather than 2D slices, and contain not only uniform random Gaussian noise, but also a pronounced speckle component.

Novel VHH-Based Tracers with Variable Plasma Half-Lives for Imaging of CAIX-Expressing Hypoxic Tumor Cells.

Hypoxic areas are present in the majority of solid tumors, and hypoxia is associated with resistance to therapies and poor outcomes. A transmembrane protein that is upregulated by tumor cells that have adapted to hypoxic conditions is carbonic anhydrase IX (CAIX). Therefore, noninvasive imaging of CAIX could be of prognostic value, and it could steer treatment strategies. The aim of this study was to compare variants of CAIX-binding VHH B9, with and without a C-terminal albumin-binding domain with varying affinity (ABDlow and ABDhigh), for SPECT imaging of CAIX expression. The binding affinity and internalization of the various B9-variants were analyzed using SK-RC-52 cells. Biodistribution studies were performed in mice with subcutaneous SCCNij153 human head and neck cancer xenografts. Tracer uptake was determined by ex vivo radioactivity counting and visualized by SPECT/CT imaging. Furthermore, autoradiography images of tumor sections were spatially correlated with CAIX immunohistochemistry. B9-variants demonstrated a similar moderate affinity for CAIX in vitro. Maximal tumor uptake and acceptable tumor-to-blood ratios were found in the SCCNij153 model at 4 h post injection for [111In]In-DTPA-B9 (0.51 ± 0.08%ID/g and 8.1 ± 0.85, respectively), 24 h post injection for [111In]In-DTPA-B9-ABDlow (2.39 ± 0.44%ID/g and 3.66 ± 0.81, respectively) and at 72 h post injection for [111In]In-DTPA-B9-ABDhigh (8.7 ± 1.34%ID/g and 2.43 ± 0.15, respectively). An excess of unlabeled monoclonal anti-CAIX antibody efficiently inhibited tumor uptake of [111In]In-DTPA-B9, while only a partial reduction of [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh uptake was found. Immunohistochemistry and autoradiography images showed colocalization of all B9-variants with CAIX expression; however, [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh also accumulated in non-CAIX expressing regions. Tumor uptake of [111In]In-DTPA-B9-ABDlow and [111In]In-DTPA-B9-ABDhigh, but not of [111In]In-DTPA-B9, could be visualized with SPECT/CT imaging. In conclusion, [111In]In-DTPA-B9 has a high affinity to CAIX and shows specific targeting to CAIX in head and neck cancer xenografts. The addition of ABD prolonged plasma half-life, increased tumor uptake, and enabled SPECT/CT imaging. This uptake was, however, partly CAIX- independent, precluding the ABD-tracers for use in hypoxia quantification in this tumor type.

Evaluation of [18F]tetrafluoroborate as a Potential PET Imaging Agent in a Sodium Iodide Symporter-Transfected Cell Line A549 and Endogenous NIS-Expressing Cell Lines MKN45 and K1.

[18F]tetrafluoroborate (TFB) has been introduced as the 18F-labeled PET imaging probe for the human sodium iodide symporter (NIS). Noninvasive NIS imaging using [18F]TFB has received much interest in recent years for evaluating various NIS-expressing tumors. Cancers are a global concern with enormous implications; therefore, improving diagnostic methods for accurate detection of cancer is extremely important. Our aim was to investigate the PET imaging capabilities of [18F]TFB in NIS-transfected lung cell line A549 and endogenous NIS-expressing tumor cells, such as thyroid cancer K1 and gastric cancer MKN45, and broaden its application in the medical field. Western blot and flow cytometry were used to assess the NIS expression level. Radioactivity counts of [18F]TFB, in vitro, in the three tumor cells were substantially higher than those in the KI inhibition group in the uptake experiment. In vivo PET imaging clearly delineated the three tumors based on the specific accumulation of [18F]TFB in a mouse model. Ex vivo biodistribution investigation showed high [18F]TFB absorption in the tumor location, which was consistent with the PET imaging results. These results support the use of NIS-transfected lung cell line A549 and NIS-expressing tumor cells MKN45 and K1, to investigate probing capabilities of [18F]TFB. We also demonstrate, for the first time, the feasibility of [18F]TFB in diagnosing stomach cancer. In conclusion, this study illustrates the promising future of [18F]TFB for tumor diagnosis and NIS reporter imaging.

Splenic, hepatic, renal and pulmonary clearance dysfunction associated with high-energy X-rays

Purpose To verify the high-energy X-rays effects on the blood clearance of colloidal particles by the spleen, liver, kidneys, and lungs. Materials and methods Seventeen male Wistar rats were distributed into three groups. Group 1 (n = 5) – control – non-irradiated animals, group 2 (n = 6) – irradiated animals studied 24 h after irradiation, and group 3 (n = 6) – irradiated animals studied 48 h after irradiation. The animals were anesthetized and irradiated with a non-fractionated 8 Gy dose in the abdominal region divided in two parallel and opposite fields, 4 Gy was given to the anteroposterior and 4 Gy to the posteroanterior. This high dose of high-energy X-rays causes extensive cell killing, tissue disorganization and break down cell to cell communication. According to the groups, 50 µCi of technetium-phytate were injected into the right internal jugular vein. After thirty minutes, the liver, spleen, kidneys, and lungs were removed. The clot was harvested from the abdominal cavity two minutes after the sectioning of the abdominal aorta and cava vein. The organs and clot were placed into plastic flasks to be weighed and studied for the emission of radioactivity in a gamma radiation detector. The uptake function of each organ was calculated based on the count of gamma rays emitted per minute and normalized with the organ mass, having as a reference the radioactivity count of a standard sample. The arithmetic mean of each organ uptake was calculated and compared among the groups. Results After irradiation, the spleen uptake of colloidal radiopharmaceutical was greater, while the hepatic, renal, and pulmonary uptake were lower. The renal uptake decreased slower than the hepatic and pulmonary uptake. Conclusion A single high dose of high-energy X-rays enhances the splenic clearance function, while it reduces the hepatic, renal, and pulmonary clearance until 48 h after irradiation, with a rapid deterioration of the hepatic and pulmonary uptake function.

Pelvic sentinel lymph nodes have minimal impact on survival in melanoma patients.

BackgroundLower limb or trunk melanoma often presents with femoral and pelvic sentinel lymph nodes (SLNs). The benefits of harvesting pelvic lymph nodes remain controversial. In this retrospective study, the frequency and predictors of pelvic SLNs (PSLNs), and the impact of PSLNs on survival and staging was investigated.MethodsAltogether 285 patients with cutaneous melanoma located in the lower limb or trunk underwent sentinel lymph node biopsy of the inguinal/iliac lymph node basin at Helsinki University Hospital from 2009–2013. Patient characteristics, detailed pathology reports and follow-up data were retrieved from hospital files. Subgroups of patients categorized by presence of PSLNs were compared for outcome parameters including progression-free survival, melanoma-specific survival and groin recurrence.ResultsSuperficial femoral/inguinal SLNs were present in all patients and 199 (69.8 per cent) also had PSLNs removed. Median number of SLNs per patient was five and median number of PSLNs was two. Sixty-three patients (22.1 per cent) had metastases in their SLNs and seven (2.5 per cent) had metastases in PSLNs. A single patient had metastases solely in PSLNs, while superficial SLNs remained negative. Harvesting PSLNs or the number of PSLNs retrieved had no impact on progression-free survival or overall survival. The removal of PSLNs did not affect the risk of postoperative seroma or lymphoedema. The only predictor of positive PSLNs was radioactivity count equal to or more than that of the hottest superficial SLNs.ConclusionPelvic SLNs have minimal clinical impact on the outcome of melanoma patients especially in cases with negative superficial femoral/inguinal SLNs. Removal of PSLNs should be considered when they are the most radioactive nodes or equal to the hottest superficial femoral/inguinal SLNs in lymphoscintigraphy or during surgery.Preliminary results were presented in part at the International Sentinel Node Society Biennial Meeting, Tokyo, Japan, 11–13 October 2018.

An analysis of the biopharmaceutical behaviour of proton pump inhibitors with different physicochemical properties

At present, little information on the biopharmaceutical behaviour of proton pump inhibitors (PPIs) describing their absorption and biodistribution in vivo has been reported because the extreme instability of PPIs in the gastrointestinal environment makes it difficult to analyze such behaviour. In this work, a modified rat in situ intestinal perfusion model was employed to investigate absorption in the gastrointestinal tract and subsequent biodistribution of several PPIs (ilaprazole, esomeprazole and rabeprazole), which have different physicochemical properties. Our data indicated that PPIs exhibited significantly enhanced absorption rates in the whole intestine, including the duodenum, jejunum, ileum and colon, corresponding to the increase in the oil-water partition coefficient (LogP). PPIs and corresponding salt types showed no obvious differences in absorption, implying that solubility changes in the PPI have little effect on its absorption in the gastrointestinal tract. Among these PPIs, ilaprazole presented a more stable intestinal absorption behaviour, as well as more distribution and longer residence time in the stomach by HPLC-MS/MS analysis and radioactivity counts after 14C radiolabelling. These results may be useful information for PPI optimization and oral formulation design.

Factors predicting one or two sentinel lymph nodes to be accepted for sentinel lymph node biopsy alone after neoadjuvant therapy in initially node-positive breast cancer patients

BackgroundCurrent guidelines recommend harvesting ≥3 sentinel nodes if sentinel lymph node biopsy (SLNB) alone is considered after neoadjuvant therapy (NAT) for initially node-positive (cN+) breast cancer. We attempted to investigate factors predicting one or two sentinel lymph nodes harvested to be accepted for SLNB alone after NAT in initially cN + patients. MethodsOverall, 157 patients who received NAT (clinically T1–3/N1–2/M0) and underwent SLNB were identified from a prospectively maintained database. Significant factors were identified using a multiple logistic regression model. ResultsThe overall SLN identification rate was 83.4%. Failed SLN identification was associated with a 2-day protocol using a single tracer (odds ratio: 0.331 [95% confidence interval {CI}: 0.132–0.830], p = 0.018), age >52 years (0.345 [0.131–0.913], p = 0.032), and lobular histology (0.156 [0.026–0.944], p = 0.043). The overall false-negative SLNB rate was 14.7%. Its increased risk was associated with radioactivity count >530 for any SLN during SLNB (96.4 [4.00–2320], p = 0.005), age ≥57 years (34.2 [1.92–610], p = 0.016), and taxane use (105 [1.02–10700], p = 0.049); its decreased risk was associated with more harvested SLNs (0.191 [0.054–0.669], p = 0.01) and dual tracers (0.101 [0.012–0.843], p = 0.034). A predictive model using these factors achieved an area under the curve of 0.935 (95% CI: 0.878–0.991). ConclusionWhen taxane was administered during NAT, the false-negative rate was predicted at <5% for patients aged <57 years, if 1–2 SLNs were harvested using dual tracers, and when the count of every SLN was lower than 530 after NAT in cN + breast cancer.

Artificial neural network for the prediction model of glomerular filtration rate to estimate the normal or abnormal stages of kidney using gamma camera.

Chronic kidney disease (CKD) is evaluated based on glomerular filtration rate (GFR) using a gamma camera in the nuclear medicine center or hospital in a routine procedure, but the gamma camera does not provide the accurate stages of the diseases. Therefore, this research aimed to find out the normal or abnormal stages of CKD based on the value of GFR using an artificial neural network (ANN). Two hundred fifty (Training 188, Testing 62) kidney patients who underwent the ultrasonography test to diagnose the renal test in our nuclear medical centre were scanned using gamma camera. The patients were injected with 99mTc-DTPA before the scanning procedure. After pushing the syringe into the patient's vein, the pre-syringe and post syringe radioactive counts were calculated using the gamma camera. The artificial neural network uses the softmax function with cross-entropy loss to diagnose CKD normal or abnormal labels depending on the value of GFR in the output layer. The results showed that the accuracy of the proposed ANN model was 99.20% for K-fold cross-validation. The sensitivity and specificity were 99.10% and 99.20%, respectively. The Area under the curve (AUC) was 0.9994. The proposed model using an artificial neural network can classify the normal or abnormal stages of CKD. After implementing the proposed model clinically, it may upgrade the gamma camera to diagnose the normal or abnormal stages of the CKD with an appropriate GFR value.

Disturbances of the transfer of cholesterol to high-density lipoprotein (HDL) in patients with peripheral artery disease with or without type 2 diabetes mellitus.

Low high-density lipoprotein (HDL)-cholesterol is frequent in patients with peripheral artery disease (PAD) and also in type 2 diabetes mellitus (T2DM), the major risk factor for PAD. The transfer of cholesterol from the other lipoproteins to HDL is an important aspect of HDL metabolism and function, and may contribute to atherogenic mechanisms that lead to PAD development. The aim of this study was to investigate the status of cholesterol transfers in patients with PAD without or with T2DM. Patients with PAD (n = 19), with PAD and T2DM (PAD + DM, n = 19), and healthy controls (n = 20), all paired for age, sex, and BMI were studied. Transfer of both forms of cholesterol, unesterified (UC) and esterified (EC), was performed by incubating plasma with a donor nanoemulsion containing radioactive UC and EC, followed by chemical precipitation and HDL radioactive counting. Low-density lipoprotein (LDL)-cholesterol and triglycerides were similar in the three groups. Compared to controls, HDL-C was lower in PAD + DM (p < 0.05), but not in PAD. Transfer of UC was lower in PAD + DM than in PAD and controls (4.18 ± 1.17%, 5.13 ± 1.44%, 6.59 ± 1.25%, respectively, p < 0.001). EC transfer tended to be lower in PAD + DM than in controls (2.96 ± 0.60 vs 4.12 ± 0.89%, p = 0.05). Concentrations of cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT), both involved in HDL metabolism, were not different among the three groups. Deficient cholesterol transfer to HDL may play a role in PAD pathogenesis. Since UC transfer to HDL was lower in PAD + DM compared to PAD alone, it is possible that defective HDL metabolism may contribute to the higher PAD incidence in patients with T2DM.Keywords.

The suitability of smartphone camera sensors for detecting radiation

The advanced image sensors installed on now-ubiquitous smartphones can be used to detect ionising radiation in addition to visible light. Radiation incidents on a smartphone camera’s Complementary Metal Oxide Semiconductor (CMOS) sensor creates a signal which can be isolated from a visible light signal to turn the smartphone into a radiation detector. This work aims to report a detailed investigation of a well-reviewed smartphone application for radiation dosimetry that is available for popular smartphone devices under a calibration protocol that is typically used for the commercial calibration of radiation detectors. The iPhone 6s smartphone, which has a CMOS camera sensor, was used in this study. Black tape was utilized to block visible light. The Radioactivity counter app developed by Rolf-Dieter Klein and available on Apple’s App Store was installed on the device and tested using a calibrated radioactive source, calibration concrete pads with a range of known concentrations of radioactive elements, and in direct sunlight. The smartphone CMOS sensor is sensitive to radiation doses as low as 10 µGy/h, with a linear dose response and an angular dependence. The RadioactivityCounter app is limited in that it requires 4–10 min to offer a stable measurement. The precision of the measurement is also affected by heat and a smartphone’s battery level. Although the smartphone is not as accurate as a conventional detector, it is useful enough to detect radiation before the radiation reaches hazardous levels. It can also be used for personal dose assessments and as an alarm for the presence of high radiation levels.

Lipid transfer to high-density lipoprotein is greater in elderly individuals with higher predictive cardiorespiratory fitness for age

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): FAPESP and CNPq Background Elderly individuals have higher coronary artery disease (CAD) risk. Triggering factors include diminished peak of oxygen consumption (VO2peak), commonly referred as cardiorespiratory fitness (CF), and increase in atherogenic lipid profile: non high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). The effect of aging on HDL-C is yet not clear, however, evaluating only the concentrations do not represent all HDL anti-atherosclerosis potential, aspects related to HDL metabolism and function can be more accurate to understand atherosclerosis process. Beyond that, elderly individuals also show reduced lipid transfer to HDL, an important assessment of HDL metabolism and function reported to be lower in CAD patients. Additionally, higher CF level is associated with longevity and lower hospitalizations rates and higher lipid transfer, independently of HDL-C. Data about different ages and absolute values of CF on lipids transfer are nonexistent. Purpose: To analyze the effect of paired CF absolute values and BMI in a healthy population of different ages on lipid transfer to HDL. Methods: 61 healthy individuals, enrolled in two groups: 30 young (27 ± 4 years, 21 females, BMI: 24.6 ± 2.6 kg/m², VO2peak: 33.9 ± 5.0 ml/kg/min) and 31 elderly (67 ± 5 years, 15 females, BMI: 23.9 ± 3.3 kg/m², VO2peak: 33.2 ± 4.5 ml/kg/min) that do not use any medication for chronic disease. Anthropometric data were collected. All participants performed treadmill cardiopulmonary test and the CF predictive value for age was calculated, according to each sex. Plasma lipids and cholesterol ester transfer protein (CETP) concentrations were determined. Lipid transfer was performed by incubating plasma with a donor lipoprotein-like nanoparticle containing radioactively labeled unesterified cholesterol (UC) and esterified cholesterol (EC), followed by chemical precipitation and radioactive count. Cholesterol transfers from the donor nanoparticle to HDL are expressed as %. For the statistical analysis Student"s t and Mann-Whitney tests were used according to data distribution. Results: Waist circumference (p = 0.0291) and waist-hip ratio (p &amp;lt; 0.0001) were higher in elderly. LDL-C (p = 0.0005) and non HDL-C (p = 0.0003) were higher in elderly, as well apolipoprotein A-I, B, and CETP concentration. HDL-C and triglycerides were equal between groups. EC (p = 0.0268) and UC (p = 0.0348) transfers to HDL were higher in elderly. VO2peak predictive by age expressed in percentage was higher in elderly (90 ± 13 vs. 120 ±18; p &amp;lt; 0.0001). Conclusion: Elderly individuals show higher anthropometric data and concentrations of atherogenic cholesterol lipoproteins; however, HDL-C was equal. When paired by absolute CF values and BMI with young adults, elderly subjects with high CF predicted by age, have higher cholesterol transfer to HDL which demonstrates greater HDL metabolism.