Novel technetium-99m-labeled bivalent PSMA-targeting probe based on hydroxamamide chelate for diagnosis of prostate cancer.

OBJECTIVE: Prostate-specific membrane antigen (PSMA) is a well-known biomarker of prostate cancer. Previously, our group reported that the succinimidyl-cystatin-urea-glutamate (SCUE) moiety has a high affinity for PSMA. In this study, we developed the novel technetium-99m-labeled PSMA-targeting probe "[99mTc]Tc-(Ham-SCUE)2" based on a hydroxamamide chelate with a bivalent SCUE and evaluated its potential as a SPECT imaging probe for the diagnosis of PSMA-expressing prostate cancer. METHODS: Ham-SCUE was synthesized by a one-step reaction with Ham-Mal and cysteine-urea-glutamine. Then, Ham-SCUE was reacted with [99mTc]NaTcO4 for 10 min at room temperature to obtain [99mTc]Tc-(Ham-SCUE)2. [99mTc]Tc-(Ham-SCUE)2 was added to LNCaP (high PSMA expression) cells or PC3 (low PSMA expression) cells, and their radioactivity was measured 60 min after administration. The blocking study was performed by co-incubation of LNCaP cells with various concentrations of 2-PMPA (a PSMA inhibitor) for 15 min before adding [99mTc]Tc-(Ham-SCUE)2. The biodistribution of [99mTc]Tc-(Ham-SCUE)2 in LNCaP/PC3 dual xenografted C.B.-17/Icr scid/scid Jcl mice was evaluated for 120 min after intravenous injection. The blocking study was performed by pretreatment of mice with 2-PMPA (10 mg/kg weight). RESULTS: [99mTc]Tc-(Ham-SCUE)2 was acquired at radiochemical yields of 56% with a radiochemical purity of over 95%. The cellular uptake level of [99mTc]Tc-(Ham-SCUE)2 by LNCaP cells was significantly higher than that by PC3 cells (LNCaP: 11.12 ± 0.71 vs. PC3: 1.40 ± 0.13%uptake/mg protein, p < 0.01), and the uptake was significantly suppressed by pretreatment with 2-PMPA (2.56 ± 0.37%uptake/mg protein, p < 0.05). IC50 of 2-PMPA was 245 ± 47 nM. In the in vivo study, the radioactivity of LNCaP tumor tissue was significantly higher than that of PC3 tumor tissue at 120 min after the administration of [99mTc]Tc-(Ham-SCUE)2 (LNCaP: 9.97 ± 2.79, PC3: 1.16 ± 0.23%ID/g, p < 0.01), and was suppressed by pretreatment with 2-PMPA (2.50 ± 0.45%ID/g, p < 0.01). CONCLUSION: [99mTc]Tc-(Ham-SCUE)2 has the potential to be a SPECT imaging agent for diagnosing high PSMA-expressing prostate cancer.

Deep learning-based measurement of split glomerular filtration rate with 99mTc-diethylenetriamine pentaacetic acid renal scan.

PURPOSE: To develop a deep learning (DL) model for generating automated regions of interest (ROIs) on 99mTc-diethylenetriamine pentaacetic acid (DTPA) renal scans for glomerular filtration rate (GFR) measurement. METHODS: Manually-drawn ROIs retrieved from a Picture Archiving and Communications System were used as ground-truth (GT) labels. A two-dimensional U-Net convolutional neural network architecture with multichannel input was trained to generate DL ROIs. The agreement between GFR values from GT and DL ROIs was evaluated using Lin's concordance correlation coefficient (CCC) and slope coefficients for linear regression analyses. Bias and 95% limits of agreement (LOA) were assessed using Bland-Altman plots. RESULTS: A total of 24,364 scans (12,822 patients) were included. Excellent concordance between GT and DL GFR was found for left (CCC 0.982, 95% confidence interval [CI] 0.981-0.982; slope 1.004, 95% CI 1.003-1.004), right (CCC 0.969, 95% CI 0.968-0.969; slope 0.954, 95% CI 0.953-0.955) and both kidneys (CCC 0.978, 95% CI 0.978-0.979; slope 0.979, 95% CI 0.978-0.979). Bland-Altman analysis revealed minimal bias between GT and DL GFR, with mean differences of - 0.2 (95% LOA - 4.4-4.0), 1.4 (95% LOA - 3.5-6.3) and 1.2 (95% LOA - 6.5-8.8) mL/min/1.73 m² for left, right and both kidneys, respectively. Notably, 19,960 scans (81.9%) showed an absolute difference in GFR of less than 5 mL/min/1.73 m². CONCLUSION: Our DL model exhibited excellent performance in the generation of ROIs on 99mTc-DTPA renal scans. This automated approach could potentially reduce manual effort and enhance the precision of GFR measurement in clinical practice.

Design and in vitro evaluation of 223Ra/99mTc-loaded spherical nano-hydroxyapatite in bone tumor therapy.

Aim: Nano-hydroxyapatite (nHA) is a good nanocarrier to load 223Ra, but the low specific activity (sp.act.) of 223Ra@nHA limits its application in medicine. Methods: We proposed a method for preparing nHA using PEG as a template, which significantly increases the sp.act of 223Ra@nHA and a new method to loaded 99mTc for in vivo tracking. Results: The nHA synthesized using PEG as a template was associated with higher sp.act for 223Ra in comparison to nHA with identical particle size and without PEG. The nHA load 99mTc-MDP was associated with higher labeling rate and stability in comparison to 99mTc. Conclusion: All these findings suggest that using PEG as a template and 99mTc-MDP could be the most effective of synthetic 223Ra/99mTc@nHA.

[Box: see text].

BRAF Detection in FNAC Combined with Semi-Quantitative 99mTc-MIBI Technique and AI Model, an Economic and Efficient Predicting Tool for Malignancy in Thyroid Nodules.

BACKGROUND: Technology allows us to predict a histopathological diagnosis, but the high costs prevent the large-scale use of these possibilities. The current liberal indication for surgery in benign thyroid conditions led to a rising frequency of incidental thyroid carcinoma, especially low-risk papillary micro-carcinomas. METHODS: We selected a cohort of 148 patients with thyroid nodules by ultrasound characteristics and investigated them by fine needle aspiration cytology (FNAC)and prospective BRAF collection for 70 patients. Also, we selected 44 patients with thyroid nodules using semi-quantitative functional imaging with an oncological, 99mTc-methoxy-isobutyl-isonitrile (99mTc-MIBI) radiotracer. RESULTS: Following a correlation with final histopathological reports in patients who underwent thyroidectomy, we introduced the results in a machine learning program (AI) in order to obtain a pattern. For semi-quantitative functional visual pattern imaging, we found a sensitivity of 33%, a specificity of 66.67%, an accuracy of 60% and a negative predicting value (NPV) of 88.6%. For the wash-out index (WOind), we found a sensitivity of 57.14%, a specificity of 50%, an accuracy of 70% and an NPV of 90.06%.The results of BRAF in FNAC included 87.50% sensitivity, 75.00% specificity, 83.33% accuracy, 75.00% NPV and 87.50% PPV. The prevalence of malignancy in our small cohort was 11.4%. CONCLUSIONS: We intend to continue combining preoperative investigations such as molecular detection in FNAC, 99mTc-MIBI scanning and AI training with the obtained results on a larger cohort. The combination of these investigations may generate an efficient and cost-effective diagnostic tool, but confirmation of the results on a larger scale is necessary.

Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF).

Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.

Odd Sites of Parathyroid Adenomas: 18F-fluorocholine PET/CT Pointing to the Right Place.

Primary hyperparathyroidism is mostly caused by parathyroid adenoma(s) which are generally localized using routine imaging modalities such as neck ultrasonography and 99mTc-SestaMIBI scintigraphy. However, these can miss ectopic parathyroid adenomas due to their limited sensitivities. These ectopic lesions can later lead to failure of surgical excision and necessitate the need for a re-exploration. 18F-fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) can help in the localization of these ectopic adenomas due to its superior detection rates and spatial resolution. Herein, we report a case of ectopic parathyroid adenomas that were localized on FCH PET/CT.

Self-supervised learning for denoising of multidimensional MRI data.

PURPOSE: To develop a fast denoising framework for high-dimensional MRI data based on a self-supervised learning scheme, which does not require ground truth clean image. THEORY AND METHODS: Quantitative MRI faces limitations in SNR, because the variation of signal amplitude in a large set of images is the key mechanism for quantification. In addition, the complex non-linear signal models make the fitting process vulnerable to noise. To address these issues, we propose a fast deep-learning framework for denoising, which efficiently exploits the redundancy in multidimensional MRI data. A self-supervised model was designed to use only noisy images for training, bypassing the challenge of clean data paucity in clinical practice. For validation, we used two different datasets of simulated magnetization transfer contrast MR fingerprinting (MTC-MRF) dataset and in vivo DWI image dataset to show the generalizability. RESULTS: The proposed method drastically improved denoising performance in the presence of mild-to-severe noise regardless of noise distributions compared to previous methods of the BM3D, tMPPCA, and Patch2self. The improvements were even pronounced in the following quantification results from the denoised images. CONCLUSION: The proposed MD-S2S (Multidimensional-Self2Self) denoising technique could be further applied to various multi-dimensional MRI data and improve the quantification accuracy of tissue parameter maps.

Molecular imaging of thyroid and parathyroid diseases.

INTRODUCTION: Molecular imaging of thyroid and parathyroid diseases has changed in recent years due to the introduction of new radiopharmaceuticals and new imaging techniques. Accordingly, we provided an clinicians-oriented overview of such techniques and their indications. AREAS COVERED: A review of the literature was performed in the PubMed, Web of Science, and Scopus without time or language restrictions through the use of one or more fitting search criteria and terms as well as through screening of references in relevant selected papers. Literature up to and including December 2023 was included. Screening of titles/abstracts and removal of duplicates was performed and the full texts of the remaining potentially relevant articles were retrieved and reviewed. EXPERT OPINION: Thyroid and parathyroid scintigraphy remains integral in patients with thyrotoxicosis, thyroid nodules, differentiated thyroid cancer and, respectively, hyperparathyroidism. In the last years positron-emission tomography with different tracers emerged as a more accurate alternative in evaluating indeterminate thyroid nodules [18F-fluorodeoxyglucose (FDG)], differentiated thyroid cancer [124I-iodide, 18F-tetrafluoroborate, 18F-FDG] and hyperparathyroidism [18F-fluorocholine]. Other PET tracers are useful in evaluating relapsing/advanced forms of medullary thyroid cancer (18F-FDOPA) and selecting patients with advanced follicular and medullary thyroid cancers for theranostic treatments (68Ga/177Ga-somatostatin analogues).

Evaluation of Ectopic Kidney Located at the Deep Subcutaneous Region of the Abdominal Wall: Role of Diuretic Renography with 99mTc-DTPA.

An ectopic kidney is often found inadvertently during CT, ultrasonography, MRI, or urologic physical examination. Ectopic kidneys usually occur in the pelvis. A pelvic ectopic kidney may be misinterpreted for a pelvic tumor by less experienced physicians and surgeons. We present an extremely rare case of ectopic kidney in the deep subcutaneous region of the abdominal wall and associated with the additional abnormality of spina bifida. MRI found an ectopic kidney but failed to identify ureteropelvic drainage. Diuretic renography with 99mTc-diethylenetriaminepentaacetic acid showed normal functioning and identified nonobstructive ureteropelvic drainage of the ectopic subcutaneous kidney.

Efficacy and safety of selpercatinib in treating RET-altered MTC: A single-arm meta-analysis.

Background: Selpercatinib is effective in the treatment of RET-altered medullary thyroid carcinoma (MTC). This study aimed to evaluate the efficacy and safety of selpercatinib in the treatment of patients with RET-altered MTC. Methods: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from their inception to April 5, 2024. Outcomes included complete response (CR), partial response (PR), stable disease (SD), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). We carried out a meta-analysis of these studies and exploratory subgroup analyses. The effect sizes for all pooled results were presented as 95% confidence intervals with upper and lower limits. Results: The pooled CR, PR, and SD rates for all patients were 10%, 59%, and 26%, respectively. The pooled ORR in all patients was 70%, while the pooled ORR in pre-treated and non-pre-treated groups were 67% and 70%, respectively. The pooled DCR in all patients was 95%, while the pooled DCR in pre-treated and non-pre-treated groups were 96% and 95%, respectively. The most common AEs associated with selpercatinib were hypertension, alanine aminotransferase (ALT) increased and aspartate aminotransferase (AST) increased. Conclusion: Selpercatinib offers significant benefits to patients with RET-altered MTC with assessable CR, PR, SD, ORR, and grade 3-4 AEs; however, treatment-related AEs should be considered.

A Review of Advances in Molecular Imaging of Rheumatoid Arthritis: From In Vitro to Clinic Applications Using Radiolabeled Targeting Vectors with Technetium-99m.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder caused by inflammation of cartilaginous diarthrodial joints that destroys joints and cartilage, resulting in synovitis and pannus formation. Timely detection and effective management of RA are pivotal for mitigating inflammatory arthritis consequences, potentially influencing disease progression. Nuclear medicine using radiolabeled targeted vectors presents a promising avenue for RA diagnosis and response to treatment assessment. Radiopharmaceutical such as technetium-99m (99mTc), combined with single photon emission computed tomography (SPECT) combined with CT (SPECT/CT), introduces a more refined diagnostic approach, enhancing accuracy through precise anatomical localization, representing a notable advancement in hybrid molecular imaging for RA evaluation. This comprehensive review discusses existing research, encompassing in vitro, in vivo, and clinical studies to explore the application of 99mTc radiolabeled targeting vectors with SPECT imaging for RA diagnosis. The purpose of this review is to highlight the potential of this strategy to enhance patient outcomes by improving the early detection and management of RA.

Non-contrast preoperative MRI for determining renal perfusion and visualizing renal arteries in potential living kidney donors at 1.5 Tesla.

Background: The aim of this work was to create and evaluate a preoperative non-contrast-enhanced (CE) magnetic resonance imaging (MRI)/angiography (MRA) protocol to assess renal function and visualize renal arteries and any abnormalities in potential living kidney donors. Methods: In total, 28 subjects were examined using scintigraphy to determine renal function. In addition, 3D-pseudocontinuous arterial spin labeling (pCASL), a 2D-non-CE electrocardiogram-triggered radial quiescent interval slice-selective (QISS-MRA), and 4D-CE time-resolved angiography with interleaved stochastic trajectories (CE-MRA) were performed to assess renal perfusion, visualize renal arteries and detect any abnormalities. Two glomerular filtration rates [described by Gates (GFRG) and according to the Chronic Kidney Disease Epidemiology Collaboration formula (GFRCKD-EPI)]. The renal volumes were determined using both MRA techniques. Results: The mean value of regional renal blood flow (rRBF) on the right side was significantly higher than that on the left. The agreements between QISS-MRA and CE-MRA concerning the assessment of absence or presence of an aberrant artery and renal arterial stenosis were perfect. The mean renal volumes measured in the right kidney with QISS-MRA were lower than the corresponding values of CE-MRA. In contrast, the mean renal volumes measured in the left kidney with both MRA techniques were similar. The correlation between the GFRG and rRBF was compared in the same manner as that between GFRCKD-EPI and rRBF. Conclusion: The combination of pCASL and QISS-MRA constitute a reliable preoperative protocol with a total measurement time of <10 min without the potential side effects of gadolinium-based contrast agents or radiation exposure.

MicroRNAs in thyroid cancer with focus on medullary thyroid carcinoma: potential therapeutic targets and diagnostic/prognostic markers and web based tools.

This review aimed to describe the inculpation of microRNAs (miRNAs) in thyroid cancer (TC) and its subtypes, mainly medullary thyroid carcinoma (MTC), and to outline web-based tools and databases for bioinformatics analysis of miRNAs in TC. Additionally, the capacity of miRNAs to serve as therapeutic targets and biomarkers in TC management will be discussed. This review is based on a literature search of relevant articles on the role of miRNAs in TC and its subtypes, mainly MTC. Additionally, web-based tools and databases for bioinformatics analysis of miRNAs in TC were identified and described. MiRNAs can perform as oncomiRs or antioncoges, relying on the target mRNAs they regulate. MiRNA replacement therapy using miRNA mimics or antimiRs that aim to suppress the function of certain miRNAs can be applied to correct miRNAs aberrantly expressed in diseases, particularly in cancer. MiRNAs are involved in the modulation of fundamental pathways related to cancer, resembling cell cycle checkpoints and DNA repair pathways. MiRNAs are also rather stable and can reliably be detected in different types of biological materials, rendering them favorable diagnosis and prognosis biomarkers as well. MiRNAs have emerged as promising tools for evaluating medical outcomes in TC and as possible therapeutic targets. The contribution of miRNAs in thyroid cancer, particularly MTC, is an active area of research, and the utility of web applications and databases for the biological data analysis of miRNAs in TC is becoming increasingly important.

Receptor-Targeted Peptide Conjugates Based on Diphosphines Enable Preparation of 99mTc and 188Re Theranostic Agents for Prostate Cancer.

Benchtop 99Mo/99mTc and 188W/188Re generators enable economical production of molecular theranostic 99mTc and 188Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates 99mTc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with 99mTc and 188Re for diagnostic imaging and systemic radiotherapy of prostate cancer. Methods: Two diphosphine-dipeptide bioconjugates, DP1-PSMAt and DP2-PSMAt, were formulated into kits for radiolabeling with 99mTc and 188Re. The resulting radiotracers were studied in vitro, in prostate cancer cells, and in vivo in mouse xenograft models, to assess similarity of uptake and biodistribution for each 99mTc/188Re pair of agents. Results: Both DP1-PSMAt and DP2-PSMAt could be efficiently radiolabeled with 99mTc and 188Re using kit-based methods to furnish the isostructural compounds M-DP1-PSMAt and M-DP2-PSMAt (M = [99mTc]Tc, [188Re]Re). All 99mTc/188Re radiotracers demonstrated specific uptake in PSMA-expressing prostate cancer cells, with negligible uptake in prostate cancer cells that did not express PSMA or in which PSMA uptake was blocked. M-DP1-PSMAt and M-DP2-PSMAt also exhibited high tumor uptake (18-30 percentage injected dose per gram at 2 h after injection), low retention in nontarget organs, fast blood clearance, and excretion predominantly via a renal pathway. Importantly, each pair of 99mTc/188Re radiotracers showed near-identical biologic behavior in these experiments. Conclusion: We have prepared and developed novel pairs of isostructural PSMA-targeting 99mTc/188Re theranostic agents. These generator-based theranostic agents have potential to provide access to the benefits of PSMA-targeted diagnostic imaging and systemic radiotherapy in health care settings that do not routinely have access to either reactor-produced 177Lu radiopharmaceuticals or PET/CT infrastructure.

Preparation and Evaluation of a Novel 99mTc-Labeled Niraparib Isonitrile Complex as a Potential PARP-1 Imaging Agent.

Poly ADP-ribose polymerase (PARP) plays an important role in the DNA repair process and has become an attractive target for cancer therapy in recent years. Given that niraparib has good clinical efficacy as a PARP inhibitor, this study aimed to develop radiolabeled niraparib derivatives for tumor imaging to detect PARP expression and improve the accuracy of stratified patient therapy. The niraparib isonitrile derivative (CNPN) was designed, synthesized, and radiolabeled to obtain the [99mTc]Tc-CNPN complex with high radiochemical purity (>95%). It was lipophilic and stable in vitro. In HeLa cell experiments, the uptake of [99mTc]Tc-CNPN was effectively inhibited by the ligand CNPN, indicating the binding affinity for PARP. According to the biodistribution studies of HeLa tumor-bearing mice, [99mTc]Tc-CNPN has moderate tumor uptake and can be effectively inhibited, demonstrating its specificity for targeting PARP. The SPECT imaging results showed that [99mTc]Tc-CNPN had tumor uptake at 2 h postinjection. All of the results of this study indicated that [99mTc]Tc-CNPN is a promising tumor imaging agent that targets PARP.

Role of a novel ER-resident glycoprotein Mtc6/Ehg2 in high-pressure growth: Stability of tryptophan permease Tat2 in Saccharomyces cerevisiae.

Deep-sea organisms are subjected to extreme conditions; therefore, understanding their adaptive strategies is crucial. We utilize Saccharomyces cerevisiae as a model to investigate pressure-dependent protein regulation and piezo-adaptation. Using yeast deletion library analysis, we identified six poorly characterized genes that are crucial for high-pressure growth, forming novel functional modules associated with cell growth. In this study, we aimed to unravel the molecular mechanisms of high-pressure adaptation in S. cerevisiae, focusing on the role of MTC6. MTC6, the gene encoding the novel glycoprotein Mtc6/Ehg2, was found to stabilize tryptophan permease Tat2, ensuring efficient tryptophan uptake and growth under high pressure at 25 MPa. The loss of MTC6 led to promoted vacuolar degradation of Tat2, depending on the Rsp5-Bul1 ubiquitin ligase complex. These findings enhance our understanding of deep-sea adaptations and stress biology, with broad implications for biotechnology, environmental microbiology, and evolutionary insights across species.

The Influence of N-Acetyl-selenomethionine on Two RONS-Generating Cancer Cell Lines Compared to N-Acetyl-methionine.

N-acetyl-selenomethionine (NASeLM), a representative of the selenium compounds, failed to convince in clinical studies and cell cultures that it neither inhibits cancer growth nor has a chemoprotective effect. This study aims to find out whether NASeLM shows a growth-inhibiting property compared to the carrier substance N-Acetyl-L-methionine (NALM) on two different cancer cells, namely Jurkat cells and MTC-SK cells. METHODS: Jurkat and MTC-SK cells were cultured in the absence or presence of varying concentrations (0-500 µg/mL) of NASeLM and NALM solutions. After 0, 24, 48, and 72 h, mitochondrial activity, cancer cell membrane CP levels, cell growth, and caspase-3 activity were assessed in aliquots of Jurkat and MTC-SK cells. RESULTS: Both substances, NASeLM and NALM, were similarly able to inhibit cell growth and mitochondrial activity of Jurkat cells in a concentration-dependent and time-dependent manner up to 70%. Only the determination of caspase activity showed that only NASeLM was able to increase this to almost 40% compared to the control as well as the same lack of NALM. However, the experiments on MTC-SK cells showed a clear difference in favor of NASeLM compared to NALM. While NASeLM was able to reduce cell growth to up to 55%, the same amount of NALM was only at around 15%, which turned out to be highly significant (p < 0.001). The same could also be measured for the reduction in MTC-SK mitochondrial activity. Time dependence could also be recognized: the longer both substances, NASeLM and NALM, were incubated, the higher the effect on cell growth and mitochondrial activity, in favour of NASeLM. Only NASeLM was able to increase caspase-3 activity in MTC-SK cells: at 250 µg/mL NASeLM, caspase-3 activity increased significantly to 28% after 24 and 48 h compared to the control (14%) or the same NALM concentration (14%). After 72 h, this could still increase to 37%. A further increase in the NASeLM concentration did not result in higher caspase-3 activity. CONCLUSION: NASeLM could clearly increase caspase-3 activity in both cell types, Jurkat or MTC-SK cells, and thus induce cell death. NALM and NASeLM showed a reduction in cell growth and mitochondrial activity in both cell lines: While NALM and NASeLM showed almost identical measurements on Jurkat cells, NASeLM was much more effective on MTC-SK than the non-selenium-containing carrier, indicating that it has additional anti-chemoprotective effects.

Inverse correlation between age of onset and myocardial amyloid deposition quantified by 99mTc-PYP scintigraphy in patients with wild-type transthyretin amyloid cardiomyopathy.

OBJECTIVE: Wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt-CM) is increasingly recognized as a contributing factor to cardiac insufficiency in the elderly population. We aimed to identify the factors affecting age of onset of ATTRwt-CM, encompassing the assessment of amyloid deposition in myocardial tissue through the use of 99mTc-pyrophosphate (PYP) and clinical parameters. METHODS: A retrospective investigation involving a consecutive cohort of 107 cases, each having been diagnosed with ATTRwt-CM confirmed through histopathological and genetic analysis, was performed. All patients underwent PYP scintigraphy, and the heart-to-contralateral (H/CL) ratio was calculated to measure amyloid deposition in the myocardium. Univariate and multivariate analyses were performed to identify independent predictors of the age of onset of ATTRwt-CM, considering the H/CL ratio and various clinical risk factors for heart failure. RESULTS: Gender (p = 0.03), Creatinine (Cr) (r = 0.32, p < 0.01), hemoglobin (Hb) (r = - 0.44, p < 0.01), albumin (Alb) (r = - 0.32, p < 0.01), brain natriuretic peptide (BNP) (r = 0.21, p = 0.03), low-density lipoprotein-cholesterol (LDL-C) (r = - 0.27, p < 0.01), and H/CL ratio (r = - 0.44, p < 0.01) were all significantly associated with the onset age. In multiple regression analysis, the independent predictive factors for the onset age of ATTRwt-CM were identified as the H/CL ratio (p < 0.01), Hb (p < 0.01), and Cr (p < 0.01). CONCLUSION: The H/CL ratio, Hb, and Cr independently affect age of onset in patients with ATTRwt-CM. The H/CL ratio is inversely correlated with age of onset, and may be the sole factor in the development of heart failure in early onset patients, while it may have a synergistic effect on heart failure with anemia and renal dysfunction in late-onset patients.