Photo-oxygenation of histidine residue inhibits α-synuclein aggregation.

Aggregation of α-synuclein (α-syn) into amyloid is the pathological hallmark of several neurodegenerative disorders, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. It is widely accepted that α-syn aggregation is associated with neurodegeneration, although the mechanisms are not yet fully understood. Therefore, the inhibition of α-syn aggregation is a potential therapeutic approach against these diseases. This study used the photocatalyst for α-syn photo-oxygenation, which selectively adds oxygen atoms to fibrils. Our findings demonstrate that photo-oxygenation using this photocatalyst successfully inhibits α-syn aggregation, particularly by reducing its seeding ability. Notably, we also discovered that photo-oxygenation of the histidine at the 50th residue in α-syn aggregates is responsible for the inhibitory effect. These findings indicate that photo-oxygenation of the histidine residue in α-syn is a potential therapeutic strategy for synucleinopathies.

Quantitative Assays for Catalytic Photo-Oxygenation of Alzheimer Disease-Related Tau Proteins.

Catalytic photo-oxygenation of tau amyloid is a potential therapeutic approach to tauopathies, including Alzheimer disease (AD). However, tau is a complex target containing great molecular size and heterogeneous isoforms/proteoforms. Although catalytic photo-oxygenation has been confirmed when using catalyst 1 and recombinant tau pretreated with heparin, its effects on tau from human patients have not yet been clarified. In this study, focusing on the histidine residues being oxygenated, we have constructed two assay systems capable of quantitatively evaluating the catalytic activity when used on human patient tau: (1) fluorescence labeling at oxygenated histidine sites and (2) LC-MS/MS analysis of histidine-containing fragments. Using these assays, we identified 2 as a promising catalyst for oxygenation of human tau. In addition, our results suggest that aggregated tau induced by heparin is different from actual AD patient tau in developing effective photo-oxygenation catalysts.

Photo-oxygenation by a biocompatible catalyst reduces amyloid-ß levels in Alzheimer's disease mice.

Amyloid formation and the deposition of the amyloid-ß peptide are hallmarks of Alzheimer's disease pathogenesis. Immunotherapies using anti-amyloid-ß antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer's disease by enhancing microglial clearance of amyloid-ß peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-ß via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-ß from the brains of living Alzheimer's disease model mice, and enhances the microglial degradation of amyloid-ß peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-ß strategy in Alzheimer's disease, which is compatible with immunotherapy.

Photo-oxygenation inhibits tau amyloid formation.

Tau amyloid formation and deposition are responsible for the onset of Alzheimer's disease. In particular, the seeding activity of the tau protein plays an important role in the spreading of tau pathology via its propagation in the human brain. Here we demonstrate that catalytic photo-oxygenation markedly suppresses tau seeding activity, resulting in the inhibition of amyloid formation, both in vitro and in cultured cells.

Percutaneous radiofrequency ablation for lung tumors beneath the rib under CT fluoroscopic guidance with gantry tilt.

BACKGROUND: Radiofrequency (RF) ablation of lung tumors has become a treatment of choice, especially for unresectable cases. However, RF ablation of small lung lesions located just beneath the rib is difficult. PURPOSE: To evaluate the efficacy and safety of gantry tilting for the performance of RF ablation of peripheral lesions located beneath the rib. MATERIAL AND METHODS: Our study was based on 18 of 293 lesions in the lung for which RF ablation was performed under CT scan fluoroscopic guidance at our institution between October 2004 and March 2009. For these 18 lesions, RF ablation was performed with gantry tilting because a rib blocked visualization of the RF ablation route even after other attempts had been made to change the relationship between the target and the rib. RESULTS: All RF needles, with only one exception, were successfully advanced to hit the tumor. The commonest complication was a pneumothorax, which occurred in seven procedures. No serious complications occurred. The progression-free rates were 82.4% at 6 months, 62.5% at 12 months, and 30% at 24 months. Mean local progression-free duration was 17.6+/-11.6 months (range 4-36 months). CONCLUSION: RF ablation under CT scan fluoroscopic guidance with gantry tilt is a useful and safe technique for RF ablation of lung nodules located beneath the rib.

Survival rates of patients with choriocarcinoma treated with chemotherapy without hysterectomy: effects of anticancer agents on subsequent births.

OBJECTIVES: The outcomes of patients with choriocarcinoma treated with fertility-preserving techniques and the children born to patients subjected to combined chemotherapy were examined retrospectively. METHODS: We treated 191 patients with choriocarcinoma from 1965 through 2001. Of these, 62 were treated with fertility-preserving techniques (50 were cured and 12 died) and 129 with hysterectomy (88 were cured and 41 died). RESULTS: Between 1965 and 1972, survival in the hysterectomy group increased. Thereafter, no significant differences between the two groups were observed. Subsequently, the number of cases with uterus preservation increased and occupied about two thirds of all cases. There were no significant differences in patient survival between the two groups by FIGO stage, although the data tended to support uterus preservation. Of the 50 patients who underwent fertility-preserving treatment for choriocarcinoma, 23 conceived for a total of 43 pregnancies. Thirty-four children were born without congenital malformations. However, two babies were born with ventricular septal defect (VSD) and one with tetralogy of Fallot (TOF) (3/34; 8.8%). The three children were the second child born after combination chemotherapy. The total dose of Methotrexate (MTX) was higher in patients who delivered a child with a heart anomaly (P < 0.02). CONCLUSIONS: Patients treated with fertility-preserving modalities had comparable survival rates to those undergoing hysterectomy at more recent time points. The incidence of congenital heart abnormalities was higher for patients undergoing combined chemotherapy than in the general population. The influence of anti-cancer agents on oocytes should be incorporated into any treatment plans for patients wishing to bear children.