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Journal of Nuclear Medicine : Official... Dec 2023Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal...
Ovarian cancer (OC) is the most lethal gynecologic malignancy (5-y overall survival rate, 46%). OC is generally detected when it has already spread to the peritoneal cavity (peritoneal carcinomatosis). This study investigated whether gadolinium-based nanoparticles (Gd-NPs) increase the efficacy of targeted radionuclide therapy using [Lu]Lu-DOTA-trastuzumab (an antibody against human epidermal growth factor receptor 2). Gd-NPs have radiosensitizing effects in conventional external-beam radiotherapy and have been tested in clinical phase II trials. First, the optimal activity of [Lu]Lu-DOTA-trastuzumab (10, 5, or 2.5 MBq) combined or not with 10 mg of Gd-NPs (single injection) was investigated in athymic mice bearing intraperitoneal OC cell (human epidermal growth factor receptor 2-positive) tumor xenografts. Next, the therapeutic efficacy and toxicity of 5 MBq of [Lu]Lu-DOTA-trastuzumab with Gd-NPs (3 administration regimens) were evaluated. NaCl, trastuzumab plus Gd-NPs, and [Lu]Lu-DOTA-trastuzumab alone were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Lastly, Gd-NPs' subcellular localization and uptake, and the cytotoxic effects of the combination, were investigated in 3 cancer cell lines to obtain insights into the involved mechanisms. The optimal [Lu]Lu-DOTA-trastuzumab activity when combined with Gd-NPs was 5 MBq. Moreover, compared with [Lu]Lu-DOTA-trastuzumab alone, the strongest therapeutic efficacy (tumor mass reduction) was obtained with 2 injections of 5 mg of Gd-NPs/d (separated by 6 h) at 24 and 72 h after injection of 5 MBq of [Lu]Lu-DOTA-trastuzumab. In vitro experiments showed that Gd-NPs colocalized with lysosomes and that their radiosensitizing effect was mediated by oxidative stress and inhibited by deferiprone, an iron chelator. Exposure of Gd-NPs to Lu increased the Auger electron yield but not the absorbed dose. Targeted radionuclide therapy can be combined with Gd-NPs to increase the therapeutic effect and reduce the injected activities. As Gd-NPs are already used in the clinic, this combination could be a new therapeutic approach for patients with ovarian peritoneal carcinomatosis.
Topics: Mice; Animals; Humans; Female; Radioisotopes; Gadolinium; Peritoneal Neoplasms; Tissue Distribution; Trastuzumab; Radioimmunotherapy; Ovarian Neoplasms; Nanoparticles; Lutetium; Cell Line, Tumor
PubMed: 37857502
DOI: 10.2967/jnumed.123.265418 -
Medicine Oct 2023This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209...
This century has seen a revolution the management of beta-thalassemia major. Over a 12-year period to 2016, we aimed to analyze the benefits of such advances. In 209 patients, independent of the chelation regimen, ferritin, cardiac T2* and liver iron concentration changes were evaluated. We defined chelation success (ChS) as no iron load in the heart and acceptable levels in the liver. Over 3 early magnetic resonance imagings, the same parameters were assessed in 2 subgroups, the only 2 that had sufficient patients continuing on 1 regimen and for a significant period of time, 1 on deferrioxamine (low iron load patients n = 41, Group A) and 1 on deferoxamine-deferiprone (iron overloaded n = 60, Group B). Finally, 28 deaths and causes were compared to those of an earlier period. The 209 patients significantly optimized those indices, while the number of patients with chelation success, increased from 6% to 51% (P < .0001). In group A, ChS after about 8 years increased from 21 to 46% (P = .006), while in Group B, from 0% to 60% (P < .001) after about 7 years. Deaths over the 2 periods showed significant reduction. Combined clearance of cardiac and liver iron (ChS) is feasible and should become the new target for all patients. This requires, serial magnetic resonance imagings and often prolonged intensified chelation for patients.
Topics: Humans; Iron Chelating Agents; beta-Thalassemia; Deferoxamine; Deferiprone; Chelation Therapy; Pyridones; Iron; Liver
PubMed: 37832083
DOI: 10.1097/MD.0000000000035455 -
Neurotherapeutics : the Journal of the... Oct 2023
PubMed: 37817049
DOI: 10.1007/s13311-023-01448-3 -
International Wound Journal Feb 2024There is an increasing use of non-medicated wound dressing with claims of irreversible bacterial binding. Most of the data are from in vitro models which lack clinical...
There is an increasing use of non-medicated wound dressing with claims of irreversible bacterial binding. Most of the data are from in vitro models which lack clinical relevance. This study employed a range of in vitro experiments to address this gap and we complemented our experimental designs with in vivo observations using dressings obtained from patients with diabetes-related foot ulcers. A hydrophobic wound dressing was compared with a control silicone dressing in vitro. Test dressings were placed on top of a Pseudomonas aeruginosa challenge suspension with increasing concentrations of suspension inoculum in addition to supplementation with phosphate buffered saline (PBS) or increased protein content (IPC). Next, we used the challenge suspensions obtained at the end of the first experiment, where bacterial loads from the suspensions were enumerated following test dressing exposure. Further, the time-dependent bacterial attachment was investigated over 1 and 24 h. Lastly, test dressings were exposed to a challenge suspension with IPC, with or without the addition of the bacteriostatic agent Deferiprone to assess the impacts of limiting bacterial growth in the experimental design. Lastly, two different wound dressings with claims of bacterial binding were obtained from patients with chronic diabetes-related foot ulcers after 72 h of application and observed using scanning electron microscope (SEM). Bacteria were enumerated from each dressing after a 1-h exposure time. There was no statistical difference in bacterial attachment between both test dressings when using different suspension inoculum concentrations or test mediums. Bacterial attachment to the two test dressings was significantly lower (p < 0.0001) when IPC was used instead of PBS. In the challenge suspension with PBS, only the hydrophobic dressing achieved a statistically significant reduction in bacterial loads (0.5 ± 0.05 log colony forming units; p = 0.001). In the presence of IPC, there was no significant reduction in bacterial loads for either test dressing. When bacterial growth was arrested, attachment to the test dressings did not increase over time, suggesting that the number of bacteria on the test dressings increases over time due to bacterial growth. SEM identified widespread adsorption of host fouling across the test dressings which occurred prior to microbial binding. Therein, microbial attachment occurred predominantly to host fouling and not directly to the dressings. Bacterial binding is not unique to dialkylcarbamoyl chloride (DACC) dressings and under clinically relevant in vitro conditions and in vivo observations, we demonstrate (in addition to previously published work) that the bacterial binding capabilities are not effective at reducing the number of bacteria in laboratory models or human wounds.
Topics: Humans; Diabetic Foot; Anti-Infective Agents; Bandages; Foot Ulcer; Bacteria
PubMed: 37770025
DOI: 10.1111/iwj.14416 -
BioMed Research International 2023The primary aim of this study was to evaluate the prevalence of iron overload and the real-world clinical effectiveness of the iron chelation therapies (ICTs) in Syrian... (Observational Study)
Observational Study
OBJECTIVES
The primary aim of this study was to evaluate the prevalence of iron overload and the real-world clinical effectiveness of the iron chelation therapies (ICTs) in Syrian patients with transfusion-dependent beta thalassemia major (BTM) prior to and during the ongoing Syrian conflict.
METHODS
This single-center, two-stage observational study was conducted at Homs National Thalassemia Center (HNTC) prior to (2009) and during (2019) the armed conflict. The prevalence and the severity of iron overload, as well as the effectiveness of four iron chelation regimens, were assessed using serum ferritin (SF) concentrations as a means of monitoring in two cohorts of BTM patients receiving deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), or a combination of DFO and DFP therapy in both years. Statistical analyses encompassed one-way ANOVA, Kruskal-Wallis, Mann-Whitney , and chi-square (2) tests for the comparisons of the variables and the frequencies between the two cohorts and subgroups.
RESULTS
We included all eligible BTM patients at HNTC in 2009 ( = 205) and 2019 ( = 172). Only 84 patients from the 2009 cohort were accessible in 2019. Our findings revealed that 98% and 89% of the patients had iron overload ( ≥ 1500 ng/mL) and comparable elevated median SF concentrations (3868 and 3757 ng/mL) in 2009 and 2019, respectively ( = 0.275). Furthermore, patients on DFO demonstrated the poorest control of iron overload and the highest SF concentrations (4319 and 5586 ng/mL), whereas those on DFX achieved superior outcomes and the lowest SF concentrations (3355 and 2152 ng/mL) in both years. Twenty-six patients from the 2019 cohort received no ICT for six years (from 2012 to 2018) and experienced extremely severe iron overload with SF levels ranging between 4481 and 16,000 ng/mL.
CONCLUSIONS
Our findings prove a high prevalence of iron overload and suboptimal chelation outcomes in Syrian BTM patients, both prior to and during the ongoing armed conflict, despite the provision of free ICTs at HNTC. Poor adherence and older age of patients may explain the unfavorable outcomes of DFO and (DFO+DFP) regimens, whereas younger age and higher socioeconomic status may have contributed to the lowest SF and superior outcomes in patients on DFX. This study also demonstrates the crucial role of the National Thalassemia Centers, namely HNTC, in providing health services to BTM patients in times of peace and conflict.
Topics: Humans; Animals; Cricetinae; beta-Thalassemia; Prevalence; Syria; Analysis of Variance; Iron Overload; Mesocricetus
PubMed: 37743972
DOI: 10.1155/2023/8911518 -
Redox Biology Nov 2023Toxoplasmosis is a major infectious disease, affecting approximately one-third of the world's population; its main clinical manifestation, ocular toxoplasmosis (OT), is...
Toxoplasmosis is a major infectious disease, affecting approximately one-third of the world's population; its main clinical manifestation, ocular toxoplasmosis (OT), is a severe sight-threatening disease. Nevertheless, the diagnosis of OT is based on clinical findings, which needs improvement, even with biochemical tests, such as polymerase chain reaction and antibody detections. Furthermore, the efficacy of OT-targeted treatment is limited; thus, additional measures for diagnosis and treatments are needed. Here, we for the first time report a significantly reduced iron concentration in the vitreous humor (VH) of human patients infected with OT. To obtain further insights into molecular mechanisms, we established a mouse model of T. gondii infection, in which intravitreally injected tracer Fe, was accumulated in the neurosensory retina. T. gondii-infected eyes showed increased lipid peroxidation, reduction of glutathione peroxidase-4 expression and mitochondrial deformity in the photoreceptor as cristae loss. These findings strongly suggest the involvement of ferroptotic process in the photoreceptor of OT. In addition, deferiprone, an FDA-approved iron chelator, reduced the iron uptake but also ameliorated toxoplasma-induced retinochoroiditis by reducing retinal inflammation. In conclusion, the iron levels in the VH could serve as diagnostic markers and iron chelators as potential treatments for OT.
Topics: Animals; Mice; Humans; Toxoplasmosis, Ocular; Ferroptosis; Toxoplasma; Chorioretinitis; Retina; Iron
PubMed: 37738924
DOI: 10.1016/j.redox.2023.102890 -
Neural Regeneration Research Mar 2024The positive effect of levodopa in the treatment of Parkinson's disease, although it is limited in time and has severe side effects, has encouraged the scientific... (Review)
Review
The positive effect of levodopa in the treatment of Parkinson's disease, although it is limited in time and has severe side effects, has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons. Successful preclinical studies with coenzyme Q10, mitoquinone, isradipine, nilotinib, TCH346, neurturin, zonisamide, deferiprone, prasinezumab, and cinpanemab prompted clinical trials. However, these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease, despite its severe side effects after 4-6 years of chronic treatment. The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson's disease treatment is a big problem. In our opinion, the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, that induce a very fast, massive and expansive neurodegenerative process, which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons. The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's patients is due to (i) a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron, (ii) a neurotoxic event that is not expansive and (iii) the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons. The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome, since it (i) is generated within neuromelanin-containing dopaminergic neurons, (ii) does not cause an expansive neurotoxic effect and (iii) triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson's disease. In conclusion, based on the hypothesis that the neurodegenerative process of idiopathic Parkinson's disease corresponds to a single-neuron neurodegeneration model, we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2. It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.
PubMed: 37721280
DOI: 10.4103/1673-5374.380878 -
The Journal of International Medical... Sep 2023Superficial siderosis of the central nervous system (SSCNS) is a rare disease characterized by iron deposition on the tissue surface of the middle axis system. We report... (Review)
Review
Superficial siderosis of the central nervous system (SSCNS) is a rare disease characterized by iron deposition on the tissue surface of the middle axis system. We report the case of a man in his late 40 s who was admitted to the hospital with ataxia. A physical examination revealed cerebellar ataxia, sensorineural deafness, and bilateral pyramidal tract injury. Susceptibility-weighted magnetic resonance imaging showed linear hypointense signals on the surface of the cerebral hemispheres, sulcus gyrus, lateral ventricles, and cerebellum. The patient underwent treatment with deferiprone, mecobalamin, and vitamin B1, and the symptoms were not aggravated. The patient's daily living ability was near normal after 1 year of follow-up. A literature review indicated that most SSCNS patients present diverse clinical manifestations. Clinicians may consider SSCNS in patients with hearing impairment and gait ataxia, especially for those receiving anticoagulant therapy and with a history of brain injury or accident.
Topics: Male; Humans; Siderosis; Central Nervous System; Brain Injuries; Hearing Loss, Sensorineural; Cell Membrane
PubMed: 37702555
DOI: 10.1177/03000605231198389 -
PLoS Neglected Tropical Diseases Aug 2023Iron is a trace metal element that is essential for the survival of cells and parasites. The role of iron in cerebral toxoplasmosis (CT) is still unclear. Deferiprone...
Iron is a trace metal element that is essential for the survival of cells and parasites. The role of iron in cerebral toxoplasmosis (CT) is still unclear. Deferiprone (DFP) is the orally active iron chelator that binds iron in a molar ratio of 3:1 (ligand:iron) and promotes urinary iron excretion to remove excess iron from the body. The aims of this experiment were to observe the alterations in iron in brains with Toxoplasma gondii (T. gondii) acute infections and to investigate the mechanism of ferroptosis in CT using DFP. We established a cerebral toxoplasmosis model in vivo using TgCtwh3, the dominant strains of which are prevalent in China, and treated the mice with DFP at a dose of 75 mg/kg/d. Meanwhile, we treated the HT-22 cells with 100 μM DFP for half an hour and then infected cells with TgCtwh3 in vitro. A qRT-PCR assay of TgSAG1 levels showed a response to the T. gondii burden. We used inductively coupled plasma mass spectrometry, an iron ion assay kit, Western blot analysis, glutathione and glutathione disulfide assay kits, a malonaldehyde assay kit, and immunofluorescence to detect the ferroptosis-related indexes in the mouse hippocampus and HT-22 cells. The inflammatory factors interferon-γ, tumor necrosis factor-α, transforming growth factor-β, and arginase 1 in the hippocampus and cells were detected using the Western blot assay. Hematoxylin and eosin staining, electron microscopy, and the Morris water maze experiment were used to evaluate the brain injuries of the mice. The results showed that TgCtwh3 infection is followed by the activation of ferroptosis-related signaling pathways and hippocampal pathological damage in mice. The use of DFP led to ferroptosis resistance and attenuated pathological changes, inflammatory reactions and T. gondii burden of the mice, prolonging their survival time. The HT-22 cells with TgCtwh3 activated the ferroptosis pathway and was inhibit by DFP in vitro. In TgCtwh3-infected cells, inflammatory response and mitochondrial damage were severe, but these effects could be reduced by DFP. Our study elucidates the mechanism by which T. gondii interferes with the host's iron metabolism and activates ferroptosis, complementing the pathogenic mechanism of CT and further demonstrating the potential value of DFP for the treatment of CT.
Topics: Animals; Mice; Toxoplasmosis, Cerebral; Deferiprone; Ferroptosis; Iron; Brain Injuries
PubMed: 37651502
DOI: 10.1371/journal.pntd.0011607 -
Antibiotics (Basel, Switzerland) Jul 2023Metal ions, including Fe, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic...
Metal ions, including Fe, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including . To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of . While all TOB-DEF conjugates were inactive against , the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, containing a C tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe concentration.
PubMed: 37627681
DOI: 10.3390/antibiotics12081261