Safety assessment, radioiodination and preclinical evaluation of antinuclear antibody as novel medication for prostate cancer in mouse xenograft model.

This study aims to provide in vitro and in vivo data to support the utilization of antinuclear antibodies (ANAs) as novel tools for the diagnosis and treatment of prostate cancers. The hematological, biochemical, and histological toxicities of ANAs were assessed at the doses of 5 and 50 µg per mouse. Radiolabeling study was then conducted with ANA and 131I using the chloramine T method, and the biodistribution and treatment efficacy were subsequently investigated in a PC3 xenograft model. No changes in clinical behavior or signs of intoxication, necrosis, or malignancy were observed in ANA-treated mice. 131I-ANA was obtained in very high yield and radiochemical purity, at 94.97 ± 0.98% and 98.56 ± 0.29%, respectively. They achieved immunoreactivity fraction of 0.841 ± 0.17% with PC-3 cells. Levels of radiolabeled ANAs were 1.15-10.14 times higher in tumor tissues than in other examined organs at 24 h post-injection. The tumor growth inhibition rates were 28.33 ± 5.01% in PC3 xenografts mice treated with 131I-ANAs compared with controls and a nearly twofold improvement in median survival was observed. These results demonstrate that radioimmunotherapy of radiolabeled natural ANAs may be an effective treatment for prostate tumors.

Optimizing Meropenem in Highly Resistant Klebsiella pneumoniae Environments: Population Pharmacokinetics and Dosing Simulations in Critically Ill Patients.

Critically ill patients are characterized by substantial pathophysiological changes that alter the pharmacokinetics (PK) of hydrophilic antibiotics, including carbapenems. Meropenem is a key antibiotic for multidrug-resistant Gram-negative bacilli, and such pathophysiological alterations can worsen treatment outcomes. This study aimed to determine the population PK of meropenem and to propose optimized dosing regimens for the treatment of multidrug-resistant Klebsiella pneumoniae in critically ill patients. Two plasma samples were collected from eligible patients over a dosing interval. Nonparametric population PK modeling was performed using Pmetrics. Monte Carlo simulations were applied to different dosing regimens to determine the probability of target attainment and the cumulative fraction of response, taking into account the local MIC distribution for K. pneumoniae. The targets of 40% and 100% for the fraction of time that free drug concentrations remained above the MIC (ƒT>MIC) were tested, as suggested for critically ill patients. A one-compartment PK model using data from 27 patients showed high interindividual variability. Significant PK covariates were the 8-h creatinine clearance for meropenem and the presence of an indwelling catheter for pleural, abdominal, or cerebrospinal fluid drainage for the meropenem volume of distribution. The target 100% ƒT>MIC for K. pneumoniae, with a MIC of ≤2 mg/liter, could be attained by the use of a continuous infusion of 2.0 g/day. Meropenem therapy in critically ill patients could be optimized for K. pneumoniae isolates with an MIC of ≤2 mg/liter by using a continuous infusion in settings with more than 50% isolates have a MIC of ≥32mg/L.

Efficacy of nimotuzumab (hR3) conjugated with 131I or 90Y in laryngeal carcinoma xenograft mouse model.

PURPOSE: The humanized monoclonal antibody hR3, both alone and in combination with other chemotherapeutic agents and radiotherapy, can be used to treat head and neck cancers. Substantial progress has been made in the development of targeted radioimmunotherapy using iodine-131 (131I) and yttrium-90 (90Y) radioisotopes in recent years. In the present study, we examined the efficacy of hR3 conjugated with 131I or 90Y to inhibit tumor growth in a laryngeal carcinoma xenograft tumor model. METHODS: hR3 was labeled with 131I or 90Y to generate the conjugates 131I-hR3 or 90Y-hR3. The conjugates were incubated with HEp-2 laryngeal carcinoma cells to evaluate binding capacity. The efficacy of the labeled hR3 conjugates to treat laryngeal cancer was also evaluated in nude mice inoculated with HEp-2 tumors. RESULTS: The purified radioimmunoconjugates with specific activities of 187-191 MBq/mg had radiochemical purity >98% and >80% immunoreactivity with HEp-2 cells. Mice with HEp-2 xenografts treated with 131I-hR3 or 90Y-hR3 showed reduced tumor volume and improved survival rates compared to the untreated control group and the group treated with unlabeled hR3. At equivalent doses, radioimmunotherapeutic hR3 labeled with 90Y had increased tumor inhibition activity compared to hR3 labeled with 131I. CONCLUSIONS: 131I-hR3 and 90Y-hR3 are promising targeted radiopharmaceuticals for treatment of head and neck cancers, especially laryngeal cancers.

Acclimatization of Rhizophagus irregularis Enhances Zn Tolerance of the Fungus and the Mycorrhizal Plant Partner.

Arbuscular mycorrhizal (AM) fungi confer heavy metal tolerance to plants, but this characteristic differs between different AM fungal strains. We tested the hypotheses if acclimatization of an AM fungus to Zn stress is possible and if this leads also to higher Zn tolerance of mycorrhizal plants. The AM fungus Rhizophagus irregularis was acclimatized in root organ cultures (Daucus carota L.) to Zn resulting in an acclimatized (Acc+) strain. The non-acclimatized (Acc-) strain remained untreated. Fungal development and RNA accumulation of a set of stress-related genes were analyzed in root organ cultures and the capacity of conferring Zn tolerance to maize plants was investigated in pot cultures. Development of Acc+ strain was significantly higher than Acc- strain, when strains were grown in Zn-enriched root organ cultures, whereas the growth of the Acc+ strain was reduced on normal medium probably due to a higher Zn demand compared to the Acc- strain. RNA accumulation analyses revealed different expression patterns of genes encoding glutathione S-transferase (RiGST), superoxide dismutase (RiSOD) and glutaredoxin (RiGRX) between the two strains. Plants inoculated with the Acc+ strain showed higher biomass and lower Zn content than those inoculated with the Acc- strain. The results showed that R. irregularis can be acclimatized to increased amounts of Zn. This acclimatization leads not only to improved fungal development in Zn-stress conditions, but also to an increase of mycorrhiza-induced Zn tolerance of colonized plants.