Low-dose energetic protons induce adaptive and bystander effects that protect human cells against DNA damage caused by a subsequent exposure to energetic iron ions

During interplanetary missions, astronauts are exposed to mixed types of ionizing radiation. The low ‘flux’ of the high atomic number and high energy (HZE) radiations relative to the higher ‘flux’ of low linear energy transfer (LET) protons makes it highly probable that for any given cell in the body, proton events will precede any HZE event. Whereas progress has been made in our understanding of the biological effects of low-LET protons and high-LET HZE particles, the interplay between the biochemical processes modulated by these radiations is unclear. Here we show that exposure of normal human fibroblasts to a low mean absorbed dose of 20 cGy of 0.05 or 1-GeV protons (LET ∼ 1.25 or 0.2 keV/μm, respectively) protects the irradiated cells (P < 0.0001) against chromosomal damage induced by a subsequent exposure to a mean absorbed dose of 50 cGy from 1 GeV/u iron ions (LET ∼ 151 keV/μm). Surprisingly, unirradiated (i.e. bystander) cells with which the proton-irradiated cells were co-cultured were also significantly protected from the DNA-damaging effects of the challenge dose. The mitigating effect persisted for at least 24 h. These results highlight the interactions of biological effects due to direct cellular traversal by radiation with those due to bystander effects in cell populations exposed to mixed radiation fields. They show that protective adaptive responses can spread from cells targeted by low-LET space radiation to bystander cells in their vicinity. The findings are relevant to understanding the health hazards of space travel.     

A lanthanide complex with dual biosensing properties: CEST (chemical exchange saturation transfer) and BIRDS (biosensor imaging of redundant deviation in shifts) with europium DOTA-tetraglycinate

Responsive contrast agents (RCAs) composed of lanthanide(III) ion (Ln3R) complexes with a variety of1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (DOTA4S) derivatives have shown great potential as molecular imaging agents for MR. A variety of LnDOTA–tetraamide complexes have been demonstrated as RCAs for molecular imaging using chemical exchange saturation transfer (CEST). The CEST method detects proton exchange between bulk water and any exchangeable sites on the ligand itself or an inner sphere of bound water that is shifted by a paramagnetic Ln3R ion bound in the core of the macrocycle. It has also been shown that molecular imaging is possible when the RCA itself is observed (i.e. not its effect on bulk water) using a method called biosensor imaging of redundant deviation in shifts (BIRDS). The BIRDS method utilizes redundant information stored in the nonexchangeable proton resonances emanating from the paramagnetic RCA for ambient factors such as temperature and/or pH.Thus, CEST and BIRDS rely on exchangeable and nonexchangeable protons, respectively, for biosensing. We posited that it would be feasible to combine these two biosensing features into the same RCA (i.e. dual CEST and BIRDS properties). A complex between europium(III) ion (Eu3R) and DOTA–tetraglycinate [DOTA–(gly)S4] was used to demonstrate that its CEST characteristics are preserved, while its BIRDS properties are also detectable. The in vitro temperature sensitivity of EuDOTA–(gly)S4 was used to show that qualitative MR contrast with CEST can be calibrated using quantitative MR mapping with BIRDS, thereby enabling quantitative molecular imaging at high spatial resolution.     

Backscatter Radiation at Tissue-Titanium Interfaces Analyses of Biological Effects from 60Co and Protons

It has been claimed that implanted metals can cause backscatter radiation in radiation therapy with a dose enhancement at the bone-metal and tissue-metal interfaces on the beam entrance side. Theoretical calculations and experimental measurements with ionization chambers have indicated that such effects might be significant. Titanium implants are increasingly used in oral and maxillo-facial surgery for reconstruction purposes. A more detailed knowledge of backscatter-induced effects is therefore desired when head and neck cancers in patients with implants are treated with radiotherapy. We have made comparisons of cell survival after irradiation of two types of cultured cells grown directly on titanium metal and on plastic control supports. The cell cultures were irradiated with either ⁶⁰Co photons or range modulated protons. No significant differences in the colony-forming capacity were found between the irradiated cells grown on titanium and those grown on plastic control supports. This was the case for both radiation types and the results were also observed to be dose-independent. The only observed phenomena were that the two cell-lines differed in radiosensitivity and that protons gave higher biological effects than gamma radiation. The results show that there were no significant changes in cell survival at the interface between the tissue equivalent medium and titanium support indicating that a dose increase induced by backscatter radiation, which possibly could demolish the osseointegration or induce osteoradionecrosis, are minimal when high energy photons or range modulated protons are applied.     

Effects of peptide-binding on the proton n.m.r. spectrum of bovine neurophysin-I

The effects of binding L-phenylalanyl-L-phenylalanine amide and related peptides on the 220 MHz and 300 MHz proton n.m.r. spectra of bovine neurophysin-I were studied. Throughout both the aliphatic and aromatic proton regions, marked binding-induced changes in the protein spectrum occur which are best explained by invoking conformational change within the neurophysin dimer, in addition to direct perturbation of individual protein protons by bound peptide. In the region downfield from 6 p.p.m., a new resonance, centered at 6.45 p.p.m. was resolved in 300 MHz spectra. This resonance is tentatively assigned to a non-exchangeable -NH and undergoes a reversible binding-induced broadening. Also in this region, the binding-induced chemical shift change in the ortho ring protons of Tyr-49 was used to explore additional aspects of the kinetics of peptide-binding. The results indicate that peptides with affinities ≥ 10⁴M^-1 exhibit slow to intermediate exchange rates on the time scale of the Tyr-49 chemical shift change, but that fast exchange can be achieved with peptides having affinities ? 10²M^-1.     

Particle beam radiotherapy for head and neck tumors: radiobiological basis and clinical experience

BACKGROUND: Head and neck tumors are often located near critical organs, making it impossible to deliver a dose of conventional radiotherapy high enough to eradicate the disease. Our aim was to review the potential benefits and available clinical experience of particle beam therapy (hadrontherapy) in the treatment of these tumors. METHODS: A review of the literature was carried out through a MEDLINE search (publications between 1980 and 2005). RESULTS: A review of the available clinical data shows that particle beam therapy can offer several radiobiological and physical advantages over conventional photon radiotherapy: improved dose distribution permits dose escalation within the target and optimal sparing of normal tissue. Preclinical and clinical studies suggest that there may be benefits to using hadrontherapy for tumors characterized by poor radiosensitivity and critical location. At present, the most used hadrons are protons and, as yet on an experimental basis, carbon ions. It is now well accepted that there are certain indications for using proton therapy for skull base tumors (chordoma and chondrosarcoma), paranasal sinus carcinomas, selected nasopharyngeal tumors, and neutron/ion therapy for salivary gland carcinomas (in particular, adenoid cystic tumors). Its viability in other cases, such as locally advanced squamous cell carcinoma, melanoma, soft tissue sarcoma, and bone sarcoma, is still under investigation. CONCLUSIONS: Hadrontherapy can be beneficial in the treatment of tumors characterized by poor radiosensitivity and critical location. Further clinical and radiobiological studies are warranted for improved selection of patient population.     

Dose response and kinetics of foci disappearance following exposure to high- and low-LET ionizing radiation

Purpose: The effect of different radiation qualities on (i) 53BP1 (p53 Binding Protein 1) and p-ATM (phosphorylated ataxia telangiectasia mutated) foci induction, and (ii) on the kinetics of foci disappearance was analysed.

Material and methods: Normal human skin fibroblasts were exposed to 240 kV broad-field X-rays or targeted with individually counted helium (³He) particles or protons (¹H) from a Charged Particle Microbeam. Anti-p-ATM and anti-53BP1 antibodies were used for foci visualisation via immunocytochemistry.

Results: 1 Gy of X-rays yielded ≈ 33 53BP1-positive foci/cell. The ratio between the number of delivered particles and yielded tracks was found to be 1:1 and 3:1 after targeted ³He and ¹H irradiation, respectively. It was determined that ≈ 50% of radiation-induced damage was repaired as measured by loss of foci during the first 2, 6, and 10 hours following X-ray, protons, and ³He irradiation, respectively.

Conclusions: There was significant radiation quality dependence for 53BP1- and p-ATM-positive foci induction observed. Foci disappearance was radiation dose-independent in the samples irradiated with X-rays. Our results confirm that kinetics of foci disappearance depends on radiation quality, even when individual ions are targeted to cells.