Atherosclerosis is a chronic inflammatory disease of the blood vessels caused by elevated levels of lipoproteins. The hyperlipoproteinemia triggers a series of cellular changes, particularly the activation of the macrophages, which play a crucial role in the development and progression of atherosclerosis. The presence of free cholesterol (FC) in lipoproteins may contribute to macrophage stimulation. However, the mechanisms linking the accumulation of FC in macrophages to their pro-inflammatory activation remain poorly understood. Our research found a positive correlation between the number of pro-inflammatory macrophages (CD14 + CD16 + CD36high) in visceral adipose tissue and the levels of LDL-C and cholesterol remnant particles in 56 healthy people. In contrast, the proportion of anti-inflammatory, alternatively activated macrophages (CD14 + CD16-CD163+) correlated negatively with HDL-C. Additionally, our in vitro study demonstrated that macrophages accumulating FC promoted a pro-inflammatory response, activating the TNF-α and chemokine CCL3 genes. Furthermore, the accumulation of FC in macrophages alters the surface receptors on macrophages (CD206 and CD16) and increases cellular granularity. Notably, the CD36 surface receptor and the ACAT and CD36 genes did not show a response. These results suggest a link between excessive FC accumulation and systemic inflammation to underlie the development of atherosclerosis.
- MeSH
- Macrophage Activation MeSH
- CD36 Antigens metabolism MeSH
- Atherosclerosis metabolism MeSH
- Antigens, CD metabolism MeSH
- Cholesterol * metabolism MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Macrophages * metabolism immunology drug effects MeSH
- Intra-Abdominal Fat metabolism MeSH
- Tumor Necrosis Factor-alpha metabolism genetics MeSH
- Inflammation * metabolism MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Díky novým technologiím a vyššímu důrazu kladenému na bezpečnostní profil léčiv dochází k postupnému zlepšování lékových forem, což je také případ inhalačního kortikosteroidu beklometason dipropionátu, kdy jeho extra-fine formulace vede vklinické praxi ke snížení jeho nominální dávky až 2,5krát. Článek podrobněji popisuje dopady této transformace vefixních kombinovaných přípravcích, tj. depozici extra-fine částic vcentrální i periferní části plic, nižší systémovou expozici a v neposlední řadě taky pozitivní vliv u skupiny pacientů s astmatem, CHOPN a snížení rizika výskytu pneumonie.
Thanks to advancements and increased emphasis on the safety profile of medications, there is a gradual improvement in the development of pharmaceutical forms. One such change has been implemented in the inhaled corticosteroid beclomethasone dipropionate, resulting in a 2.5× reduction in its nominal clinical dose. The article provides a detailed description of the effects of this transformation in fixed combination preparations, i.e., the deposition of extra-fine particles in both the central and peripheral parts of the lungs, lower systemic exposure, and, last but not least, the positive impact on patients with asthma, COPD, and a reduced risk of pneumonia.
- MeSH
- Administration, Inhalation MeSH
- Beclomethasone * administration & dosage pharmacology therapeutic use MeSH
- Asthma * drug therapy MeSH
- Pulmonary Disease, Chronic Obstructive * drug therapy MeSH
- Drug Combinations MeSH
- Formoterol Fumarate administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Pneumonia prevention & control MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
An International Workshop on Standards and Measurements for Alpha-Emitting Radionuclides in Therapeutic Nuclear Medicine was held on 22-23 February 2024 at the Bureau International des Poids et Mesures (BIPM) and online. The workshop brought together members of the medical and metrology communities who play crucial roles in developing Targeted Alpha Therapy (TAT) radiopharmaceuticals. The workshop aimed to discuss ways to improve radioactivity measurements of alpha-emitting radionuclides for TAT. Through the presentations and discussions that took place over the two days of the workshop, information was exchanged, and recommendations for improvements that could lead to improved safety and effectiveness in TAT were proposed. This paper summarizes the topics and important ideas that were discussed at the workshop and presents recommendations for all the communities involved in the development of TAT radiopharmaceuticals to consider.
- MeSH
- Alpha Particles * therapeutic use MeSH
- Humans MeSH
- Nuclear Medicine MeSH
- Radiopharmaceuticals * therapeutic use MeSH
- Radioisotopes * therapeutic use standards MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.
- MeSH
- Antigens, Surface * metabolism MeSH
- Glutamate Carboxypeptidase II * metabolism MeSH
- Rats MeSH
- Kidney * diagnostic imaging metabolism MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Organophosphorus Compounds MeSH
- Salivary Glands * diagnostic imaging metabolism radiation effects MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Using an active targeting approach of chemotherapeutics-loaded nanocarriers (NCs) with monoclonal antibodies is a potential strategy to improve the specificity of the delivery systems and reduce adverse reactions of chemotherapeutic drugs. Specific targeting of the human epidermal growth factor receptor-2 (HER-2), expressed excessively in HER-2-positive breast cancer cells, can be achieved by conjugating NCs with an anti-HER-2 monoclonal antibody. We constructed trastuzumab-conjugated chitosan iodoacetamide-coated NCs containing doxorubicin (Tras-Dox-CHI-IA-NCs) as a tumor-targeted drug delivery system, during the study. Chitosan-iodoacetamide (CHI-IA) was synthesized and utilized to prepare trastuzumab-conjugated NCs (Tras-NCs). The morphology, physicochemical properties, drug loading, drug release, and biological activities of the NCs were elucidated. The Tras-NCs were spherical, with a particle size of approximately 76 nm, and had a positive zeta potential; after incorporating the drug, the size of the Tras-NC increased. A prolonged, 24-h drug release from the NCs was achieved. The Tras-NCs exhibited high cellular accumulation and significantly higher antitumor activity against HER-2-positive breast cancer cells than the unconjugated NCs and the drug solution. Therefore, Tras-Dox-CHI-IA-NCs could be a promising nanocarrier for HER-2-positive breast cancer.
- MeSH
- Chitosan * chemistry MeSH
- Doxorubicin chemistry MeSH
- Iodoacetamide MeSH
- Drug Delivery Systems MeSH
- Humans MeSH
- Antibodies, Monoclonal chemistry MeSH
- Breast Neoplasms * drug therapy MeSH
- Nanoparticles * chemistry MeSH
- Drug Carriers chemistry MeSH
- Trastuzumab MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
NASA has encouraged studies on 226Ra deposition in the human brain to investigate the effects of exposure to alpha particles with high linear energy transfer, which could mimic some of the exposure astronauts face during space travel. However, this approach was criticized, noting that radium is a bone-seeker and accumulates in the skull, which means that the radiation dose from alpha particles emitted by 226Ra would be heavily concentrated in areas close to cranial bones rather than uniformly distributed throughout the brain. In the high background radiation areas of Ramsar, Iran, extremely high levels of 226Ra in soil contribute to a large proportion of the inhabitants' radiation exposure. A prospective study on Ramsar residents with a calcium-rich diet was conducted to improve the dose uniformity due to 226Ra throughout the cerebral and cerebellar parenchyma. The study found that exposure of the human brain to alpha particles did not significantly affect working memory but was significantly associated with increased reaction times. This finding is crucial because astronauts on deep space missions may face similar cognitive impairments due to exposure to high charge and energy particles. The current study was aimed to evaluate the validity of the terrestrial model using the Geant4 Monte Carlo toolkit to simulate the interactions of alpha particles and representative cosmic ray particles, acknowledging that these radiation types are only a subset of the complete space radiation environment.
- MeSH
- DNA MeSH
- Humans MeSH
- Linear Energy Transfer MeSH
- Monte Carlo Method MeSH
- Brain MeSH
- Prospective Studies MeSH
- Radium * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
In intravenous immunoglobulins (IVIG), and some other immunoglobulin products, protein particles have been implicated in adverse events. Role and mechanisms of immunoglobulin particles in vascular adverse effects of blood components and manufactured biologics have not been elucidated. We have developed a model of spherical silica microparticles (SiMPs) of distinct sizes 200-2000 nm coated with different IVIG- or albumin (HSA)-coronas and investigated their effects on cultured human umbilical vein endothelial cells (HUVEC). IVIG products (1-20 mg/mL), bare SiMPs or SiMPs with IVIG-corona, did not display significant toxicity to unstimulated HUVEC. In contrast, in TNFα-stimulated HUVEC, IVIG-SiMPs induced decrease of HUVEC viability compared to HSA-SiMPs, while no toxicity of soluble IVIG was observed. 200 nm IVIG-SiMPs after 24 h treatment further increased ICAM1 (intercellular adhesion molecule 1) and tissue factor surface expression, apoptosis, mammalian target of rapamacin (mTOR)-dependent activation of autophagy, and release of extracellular vesicles, positive for mitophagy markers. Toxic effects of IVIG-SiMPs were most prominent for 200 nm SiMPs and decreased with larger SiMP size. Using blocking antibodies, toxicity of IVIG-SiMPs was found dependent on FcγRII receptor expression on HUVEC, which increased after TNFα-stimulation. Similar results were observed with different IVIG products and research grade IgG preparations. In conclusion, submicron particles with immunoglobulin corona induced size-dependent toxicity in TNFα-stimulated HUVEC via FcγRII receptors, associated with apoptosis and mTOR-dependent activation of autophagy. Testing of IVIG toxicity in endothelial cells prestimulated with proinflammatory cytokines is relevant to clinical conditions. Our results warrant further studies on endothelial toxicity of sub-visible immunoglobulin particles.
- MeSH
- Apoptosis drug effects MeSH
- Autophagy * drug effects MeSH
- Human Umbilical Vein Endothelial Cells * drug effects metabolism MeSH
- Immunoglobulins, Intravenous * MeSH
- Humans MeSH
- Intercellular Adhesion Molecule-1 metabolism MeSH
- Silicon Dioxide chemistry toxicity MeSH
- Protein Corona metabolism MeSH
- Receptors, IgG * metabolism MeSH
- Tumor Necrosis Factor-alpha * metabolism MeSH
- TOR Serine-Threonine Kinases metabolism MeSH
- Particle Size MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Boron has been suggested to enhance the biological effectiveness of proton beams in the Bragg peak region via the p + 11B → 3α nuclear capture reaction. However, a number of groups have observed no such enhancement in vitro or questioned its proposed mechanism recently. To help elucidate this phenomenon, we irradiated DU145 prostate cancer or U-87 MG glioblastoma cells by clinical 190 MeV proton beams in plateau or Bragg peak regions with or without 10B or 11B isotopes added as sodium mercaptododecaborate (BSH). The results demonstrate that 11B but not 10B or other components of the BSH molecule enhance cell killing by proton beams. The enhancement occurs selectively in the Bragg peak region, is present for boron concentrations as low as 40 ppm, and is not due to secondary neutrons. The enhancement is likely initiated by proton-boron capture reactions producing three alpha particles, which are rare events occurring in a few cells only, and their effects are amplified by intercellular communication to a population-level response. The observed up to 2-3-fold reductions in survival levels upon the presence of boron for the studied prostate cancer or glioblastoma cells suggest promising clinical applications for these tumour types.
- MeSH
- Boron chemistry MeSH
- Glioblastoma radiotherapy drug therapy MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Prostatic Neoplasms radiotherapy drug therapy MeSH
- Proton Therapy * methods MeSH
- Protons MeSH
- Boron Neutron Capture Therapy * methods MeSH
- Cell Survival drug effects radiation effects MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: Red blood cells (RBCs), also known as erythrocytes, are underestimated in their role in the immune system. In mammals, erythrocytes undergo maturation that involves the loss of nuclei, resulting in limited transcription and protein synthesis capabilities. However, the nucleated nature of non-mammalian RBCs is challenging this conventional understanding of RBCs. Notably, in bony fishes, research indicates that RBCs are not only susceptible to pathogen attacks but express immune receptors and effector molecules. However, given the abundance of RBCs and their interaction with every physiological system, we postulate that they act in surveillance as sentinels, rapid responders, and messengers. METHODS: We performed a series of in vitro experiments with Cyprinus carpio RBCs exposed to Aeromonas hydrophila, as well as in vivo laboratory infections using different concentrations of bacteria. RESULTS: qPCR revealed that RBCs express genes of several inflammatory cytokines. Using cyprinid-specific antibodies, we confirmed that RBCs secreted tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). In contrast to these indirect immune mechanisms, we observed that RBCs produce reactive oxygen species and, through transmission electron and confocal microscopy, that RBCs can engulf particles. Finally, RBCs expressed and upregulated several putative toll-like receptors, including tlr4 and tlr9, in response to A. hydrophila infection in vivo. DISCUSSION: Overall, the RBC repertoire of pattern recognition receptors, their secretion of effector molecules, and their swift response make them immune sentinels capable of rapidly detecting and signaling the presence of foreign pathogens. By studying the interaction between a bacterium and erythrocytes, we provide novel insights into how the latter may contribute to overall innate and adaptive immune responses of teleost fishes.
- MeSH
- Aeromonas hydrophila * immunology MeSH
- Cytokines * metabolism immunology MeSH
- Erythrocytes * immunology metabolism MeSH
- Phagocytosis immunology MeSH
- Gram-Negative Bacterial Infections * immunology MeSH
- Carps * immunology microbiology MeSH
- Fish Diseases * immunology microbiology MeSH
- Pathogen-Associated Molecular Pattern Molecules immunology MeSH
- Immunity, Innate MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Radioligand therapy using alpha emitters has gained more and more prominence in the last decade. Despite continued efforts to identify new appropriate radionuclides, the combination of 225Ac/213Bi remains among the most promising. Bismuth-213 has been employed in clinical trials in combination with appropriate vectors to treat patients with various forms of cancer, such as leukaemia, bladder cancer, neuroendocrine tumours, melanomas, gliomas, or lymphomas. However, the half-life of 213Bi (T1⁄2 = 46 min) implies that its availability for clinical use is limited to hospitals possessing a 225Ac/213Bi radionuclide generator, which is still predominantly scarce. We investigated a new Ac/Bi generator system based on using the composite sorbent α-ZrP-PAN (zirconium(IV) phosphate as active component and polyacrylonitrile as matrix). The developed 225Ac/213Bi generator was subjected to long-term testing after its development. The elution profile was determined and the elution yield, the contamination of the eluate with the parent 225Ac and the contamination of the eluate with the column material were monitored over time. RESULTS: The high activity (75 MBq of parent 225Ac) generator with a length of 75 mm and a diameter of 4 mm containing the composite sorbent α-ZrP-PAN with a particle size of 0.8 to 1.0 mm as the stationary phase, eluted with a mixture of 10 mM DTPA in 5 mM nitric acid, provided 213Bi with yields ranging from 77 % to 96 % in 2.8 mL of eluate, with parent 225Ac contamination in the order of 10-3 %, up to twenty days of use. CONCLUSION: All the results of the monitored parameters indicate that the composite sorbent α-ZrP-PAN based separation system for the elution of 213Bi is a very promising and functional solution.
