The relative biological importance of cis--syn cyclobutane dimer and pyrimidine(6-4)pyrimidone photoadduct ([6-4] photoadduct) appears to be dependent on the biological species, dipyrimidine sites and local conformational variation induced at the damaged sites. The single-strained deoxynucleotide 10-mers containing the site-specific (6-4) adduct or cis--syn cyclobutane dimer of thymidylyl(3'-->5')-thymidine were generated by direct photolysis of d(CGCATTACGC) with UVC (220-260 nm) irradiation or UVB (260-320 nm) photosensitization. Three-dimensional structures of the duplex cis--syn and (6-4) decamers of d(CGCATTACGC)xd(GCGTAATGCG) were determined by NMR spectroscopy and the relaxation matrix refinement method. The NMR data and structural calculations establish that Watson-Crick base pairing is still intact at the cis--syn dimer site while the hydrogen bonding is absent at the 3'-side of the (6-4) lesion where the T-->C transition mutation is predominantly targeted. Overall conformation of the duplex cis--syn decamer was B-DNA and produced a 9 degree bending in the DNA helix, but a distinctive base orientation of the (6-4) lesion provided a structural basis leading to 44 degree helical bending. The observed local structure and conformational rigidity at the (6-4) adduct of the thymidylyl(3'-5')-thymidine (T-T [6-4]) lesion site suggest the potential absence of hydrogen bonding at the 3' sides of the (6-4) lesion with a substituted nucleotide during replication under SOS conditions. Contrasting structural distortions induced ny the T-T (6-4) adduct with respect to the T-T cis--syn cyclobutane pyrimidine photodimer may explain the large differences in mutation spectrum and repair activities between them.

The impact of protons on metallic nanoparticles (MNPs) produces the potent release of MNP-induced secondary electrons and characteristic x-rays. To determine the ability of secondary radiations to enhance proton treatment, the therapeutic irradiation of tumors was investigated in mice receiving 100-300 mg MNPs/kg intravenously prior to single dose, 10-41 Gy, proton irradiation. A proton beam was utilized to irradiate nanoparticles with a single Bragg peak set to occur inside a tumor volume (fully absorbed) or to occur after the beam had traversed the entire body. The dose-dependent increase in complete tumor regression (CTR) was 37-62% in the fully-absorbed irradiation group or 50-100% in the traversing irradiation group, respectively, compared with the proton-alone control mice (p < 0.01). One year survival was 58-100% versus 11-13% proton alone. The dose-dependent increase of intracellular reactive oxygen species level was 12-36% at 10 Gy compared with the proton-alone control cell. Therapeutic effective drug concentration that led to 100% CTR with a proton dose of 31 Gy was measured either 41 µg Au/g tissue or 59 µg Fe/g tissue. MNP-based proton treatment increased not only percent CTR and survival in vivo but also ROS generation in vitro, suggesting tumor dose enhancement from secondary radiation as one potent pathway of therapeutic enhancement.

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Metallic nanoparticles (MNP) are able to release localized x-rays when activated with a high energy proton beam by the particle-induced x-ray emission (PIXE) effect. The exploitation of this phenomenon in the therapeutic irradiation of tumors has been investigated. PIXE-based x-ray emission directed at CT26 tumor cells in vitro, when administered with either gold (average diameter 2 and 13 nm) or iron (average diameter 14 nm) nanoparticles (GNP or SNP), increased with MNP solution concentration over the range of 0.1-2 mg ml(-1). With irradiation by a 45 MeV proton therapy (PT) beam, higher concentrations had a decreased cell survival fraction. An in vivo study in CT26 mouse tumor models with tumor regression assay demonstrated significant tumor dose enhancement, thought to be a result of the PIXE effect when compared to conventional PT without MNP (radiation-only group) using a 45 MeV proton beam (p < 0.02). Those receiving GNP or SNP injection doses of 300 mg kg(-1) body weight before proton beam therapy demonstrated 90% or 75% tumor volume reduction (TVR) in 20 days post-PT while the radiation-only group showed only 18% TVR and re-growth of tumor volume after 20 days. Higher complete tumor regression (CTR) was observed in 14-24 days after a single treatment of PT with an average rate of 33-65% for those receiving MNP compared with 25% for the radiation-only group. A lower bound of therapeutic effective MNP concentration range, in vivo, was estimated as 30-79 µg g(-1) tissue for both gold and iron nanoparticles. The tumor dose enhancement may compensate for an increase in entrance dose associated with conventional PT when treating large, solid tumors with a spread-out Bragg peak (SOBP) technique. The use of a combined high energy Bragg peak PT with PIXE generated by MNP, or PIXE alone, may result in new treatment options for infiltrative metastatic tumors and other diffuse inflammatory diseases.

The DNA duplex‐decamer containing a site‐specific (6‐4) photoadduct of thymidylyl(3′→5′)thymidine was generated by direct photolytic ultraviolet C irradiation of d(CGCATTACGC). The three‐dimensional structure of the duplex (6‐4) decamer, d(CGCAT[6‐4]TACGC) · d(GCGTAATGCG), has been determined by two‐dimensional NMR spectroscopy and a relaxation matrix refinement method. NMR data and structural calculations established that the formation of the (6‐4) adduct in the B‐DNA duplex retains Watson‐Crick‐type hydrogen bonding throughout the duplex except at the 3′‐side of the (6‐4) lesion where the T→C transition mutation is predominantly targeted [LeClerc, J. E., Borden, A. & Lawrence, C. W. (1991) Proc. Natl Acad. Sci. USA 88, 9685–9689], but leads to a 44° bending in the overall DNA helix. Perpendicular base orientation of the (6‐4) lesion provides a structural basis where potential hydrogen bonding at the 3′ sides of the (6‐4) adduct with substituted nucleotide is improbable during replication under stringent conditions.

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A Bessel-like beam was generated in a novel all-fiber integrated structure. A concentric ring intensity pattern was achieved by the multimode interference along the coreless silica fiber, which was then focused by the integrated micro-lens to result in a Bessel-like beam. The average beam diameter of 7.5 μm maintained over 500 μm axial length for a continuous wave Yb-doped fiber laser input oscillating at the wavelength of 1.08 μm. The generated beam was successfully applied to two-dimension optical trapping and longitudinal transport of multiple dielectric particles confirming its unique non-diffracting and self-reconstructing nature. Physical principle of operation, fabrication, and experimental results are discussed.