Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Background

Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity.

Methods

The efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy).

Results

TTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the “skin sparing effect”. Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions.

Conclusions

Administration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.

     

Surgical treatment of chronic purulent diseases of extremities' bones and great joints

Results of treatment of chronic purulent diseases of extremities' bones (n=414) and great joints (n=136) were analyzed. Combined treatment included surgical sanation of the inflammatory focus, autospongioplasty of residual cavities and defects after sequesterectomy (87 cases), extrafocal osteosynthesis, aspiration- flushing drainage. In 46 cases of severe suppuration in the zone of hip joint's endoprosthesis the resection arthroplasty was performed, in 43 cases of severe consequences of ankle-joint's fracture-dislocations -- compression talo-tibial and calcaneo-tibial arthrodesis. The follow-up was 15 years. Positive results were seen in 93.6% patients.     

Excitation and inhibition processes in the neurons of the thalamic motor nuclei of normal cats and following an N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced lesion of the nigrostriatal dopaminergic system

Peculiarities of excitation and inhibition evoked in motor thalamic nuclei (VA-VL) neurons by electrical stimulation of red nucleus were studied on intact cats and after injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 5 mg/kg i.m., p.d. during five days). Two days after the last injection as much as 48% of nigral neurons were destroyed and the content of dopamine in the caudate nucleus fell to 30% as compared to intact animals. Before acute experiments all cats were anaesthetized with ketalar and immobilized with myorelaxine. It was found that MPTP injections caused a decrease of the inhibition duration and effectiveness in relay and nonrelay VA-VL neurons. The inhibition deficiency was accompanied by shortening of latencies of orthodromic responses evoked by red nucleus stimulation and facilitation of antidromic spikes invasion into somata of relay neurons after motor cortex stimulation. It was suggested that the reduction of GABAergic nigro-thalamic influences modulated by dopamine underlay the developing deficiency of inhibition.     

Effect of acceleration on pilot-sportsmen during aerial performances

Cardiovascular responses of sports-pilots to aerobatic maneuvers have been inadequately studied. However many Soviet and foreign authors believe that acceleration effects may seriously deteriorate pilot performance. Our study has shown that cardiovascular changes are to maintain the necessary level of blood pressure in brain and eye arteries. During exposure to +Gz heart rate may be as high as 160 beats/min while during exposure to -Gz it may be as low as 60 beats/min. Pulse photoplethysmography recorded inflight has shown that during exposure to +Gz its amplitude decreases until pulse oscillations disappear, suggesting the development of visual disorders. Pulse photoplethysmography has revealed cardiac arrhythmias in the form of extrasystoles in some pilots. It has also been demonstrated that during flight cardiac arrhythmias can be best detected with the aid of correlation rhythmography.     

Status of the glutathione system in gastroduodenal ulcers

Clinical and experimental studies demonstrated lowering of reduced glutathione, activation of glutathione reductase and peroxidase in peptic ulcer more pronounced in associated chronic hepatitis or non-ulcerative colitis. Clinical manifestations of the disease and biochemical shifts in glutathione system go in parallel. Disturbances of glutathione system seem to be involved in the origin and recurrences of gastroduodenal ulcer. New approaches are needed in therapeutic decisions and means in peptic ulcer especially in its combination with chronic hepatitis and non-ulcerative colitis.     

The epithelial tubules of the thymus are thymosin-dependent structures

Department of Human Anatomy, Zaporozhe Medical Institute. All-Union Research Center for Radiation Medicine, Academy of Medical Sciences of the USSR, Kiev. (Presented by Academician of the Academy of Medical Sciences of the USSR A. S. Efimov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 111, No. 3, pp. 327–330, March, 1991.