Evaluating the effect of high-density measurement mode on patient-specific quality assurance for head and neck cancer with ArcCHECK.

The high-density measurement (HDm) mode of the ArcCHECK device can achieve a twofold resolution enhancement compared to the standard measurement (Sm) mode. The aim of this study was to evaluate the effect of HDm on the gamma passing rate (GPR) for the patient-specific quality assurance (PSQA) in head and neck cancer. We retrospectively evaluated 30 patients who underwent volumetric modulated arc therapy (VMAT) for head and neck cancer. Absolute gamma analysis was performed on Sm and HDm data. We also investigated correlations between the modulation complexity score for VMAT (MCSv) and differences in the GPR between the two measurement modes. The global GPR of Sm and HDm was 81.0% ± 8.4% and 82.6% ± 7.6% for the 2%/2 mm criterion, 94.0% ± 4.1% and 94.9% ± 3.6% for the 3%/2 mm criterion, and 96.6% ± 2.4% and 97.0% ± 2.4% for the 3%/3 mm criterion, respectively. HDm slightly improved GPR (p < 0.01) for the 2%/2 mm criterion. Differences in GPR between Sm and HDm for the 2%/2 mm, 3%/2 mm, and 3%/3 mm criteria were 1.6% ± 3.0%, 0.8% ± 2.0%, and 0.4% ± 1.2%, respectively. No correlation was identified between the MCSv and the difference in GPR between Sm and HDm. Despite an improvement in GPR with HDm, the difference in GPR between Sm and HDm was approximately 2% even when the tighter criteria were used. Moreover, the change in the GPR between Sm and HDm did not depend on plan complexity. Thus, the effect of HDm on GPR is limited for the PSQA in VMAT for head and neck cancer.

[Creation of a Stereo-paired Bone Anatomical Chart Using Human Bone Specimens for X-ray Anatomical Education Part III: Addition of Anaglyph Three-dimensional Images for Those Who Hardly See Stereo-paired Photographs with the Naked Eye].

We published a report entitled "Creation of a stereo-paired bone anatomical chart using human bone specimen for radiation education" in this journal in order to accurately understand the surface structure and three-dimensional structure of bones, and assist in bone image interpretation. However, some people cannot see stereoscopically with the naked eye. Therefore, we created anaglyph three-dimensional (3D) images from stereo-paired images of the stereo X-ray anatomical chart of the bone specimen. The anaglyph of the bone surface and X-ray images facilitates stereoscopic viewing with red-blue 3D glasses. The stereo X-ray anatomical chart of the bone specimen with anaglyph 3D images was converted into an electronic data file in the same manner as the stereo X-ray anatomical chart of the bone specimen, which can be easily used in any radiological examination rooms or at home through an electronic medium. We made it possible to perform correlative stereoscopic observations of the bone surface and X-ray images using red-blue 3D glasses.

A variant of death-receptor 3 associated with rheumatoid arthritis interferes with apoptosis-induction of T cell.

Rheumatoid arthritis (RA) is a chronic polyarthritis of unknown etiology. To unravel the molecular mechanisms in RA, we performed targeted DNA sequencing analysis of patients with RA. This analysis identified a variant of the death receptor 3 (DR3) gene, a member of the family of apoptosis-inducing Fas genes, which contains four single-nucleotide polymorphisms (SNPs) and a 14-nucleotide deletion within exon 5 and intron 5. We found that the deletion causes the binding of splicing regulatory proteins to DR3 pre-mRNA intron 5, resulting in a portion of intron 5 becoming part of the coding sequence, thereby generating a premature stop codon. We also found that this truncated DR3 protein product lacks the death domain and forms a heterotrimer complex with wildtype DR3 that dominant-negatively inhibits ligand-induced apoptosis in lymphocytes. Myelocytes from transgenic mice expressing the human DR3 variant produced soluble truncated DR3, forming a complex with TNF-like ligand 1A (TL1A), which inhibited apoptosis induction. In summary, our results reveal that a DR3 splice variant that interferes with ligand-induced T cell responses and apoptosis may contribute to RA pathogenesis.

Bioconjugation of Serum Albumin to a Maleimide-appended Porphyrin/Cyclodextrin Supramolecular Complex as an Artificial Oxygen Carrier in the Bloodstream.

HemoCD is an inclusion complex of per-O-methylated ß-cyclodextrin dimer and an iron(II) porphyrin, which forms a stable O2 complex in water. Therefore, hemoCD has the potential for use as a synthetic O2 carrier in mammalian blood. In this study, a hemoCD derivative having a maleimide group (Mal-hemoCD) was conjugated to a Cys residue of serum albumin via a Michael addition reaction in order to increase the circulation time of the O2 carrier. The O2 -binding affinities (P1/2 [Torr]) and half-lives (t1/2 [h]) of the O2 adducts at pH 7.4 and 25 °C were determined to be 9 Torr and 23 h for Mal-hemoCD, and 10 Torr and 14 h for albumin-conjugated hemoCD (Alb-hemoCD). Our pharmacokinetic study revealed that renal excretion of Alb-hemoCD was effectively suppressed and that half of injected Alb-hemoCD remained in blood at 3 h after injection. It is noteworthy that Mal-hemoCD also had a long circulation time because of the bioconjugation reaction that occurred during circulation in the bloodstream.

Enantioselective alkylation of aldehydes using functionalized alkylboron reagents catalyzed by a chiral titanium complex.

A practical method is developed for the synthesis of enantioenriched functionalized secondary alcohols through catalytic enantioselective alkylation of aldehydes. Functionalized alkylboron reagents, [FG-(CH2)n]3B (FG = Br, TIPSO, PhtN, CO2(i)Pr, and CN) prepared from terminal olefin precursors by hydroboration, undergo enantioselective addition to aldehydes in the presence of a catalytic amount (5 mol %) of 3-(3,5-diphenylphenyl)-H8-BINOL and excess titanium tetraisopropoxide to afford the corresponding functionalized alcohols in high enantioselectivities up to 99% ee.

Inhibition by menthol and its related chemicals of compound action potentials in frog sciatic nerves.

AIMS: Transient receptor potential (TRP) vanilloid-1 (TRPV1) and melastatin-8 (TRPM8) channels play a role in transmitting sensory information in primary-afferent neurons. TRPV1 agonists at high concentrations inhibit action potential conduction in the neurons and thus have a local anesthetic effect. The purpose of the present study was to know whether TRPM8 agonist menthol at high concentrations has a similar action and if so whether there is a structure-activity relationship among menthol-related chemicals. MAIN METHODS: Compound action potentials (CAPs) were recorded from the frog sciatic nerve by using the air-gap method. KEY FINDINGS: (-)-Menthol and (+)-menthol concentration-dependently reduced CAP peak amplitude with the IC(50) values of 1.1 and 0.93 mM, respectively. This (-)-menthol activity was resistant to non-selective TRP antagonist ruthenium red; TRPM8 agonist icilin did not affect CAPs, indicating no involvements of TRPM8 channels. p-Menthane, (+)-limonene and menthyl chloride at 7-10 mM minimally affected CAPs. On the other hand, (-)-menthone, (+)-menthone, (-)-carvone, (+)-carvone and (-)-carveol (in each of which chemicals OH or O group was added to p-menthane and limonene) and (+)-pulegone inhibited CAPs with extents similar to that of menthol. 1,8-Cineole and 1,4-cineole were less effective while thymol and carvacrol were more effective than menthol in inhibiting CAPs. SIGNIFICANCE: Menthol-related chemicals inhibited CAPs and were thus suggested to exhibit local anesthetic effects comparable to those of lidocaine and cocaine as reported previously for frog CAPs. This result may provide information to develop local anesthetics on the basis of the chemical structure of menthol.

Heat shock protein 90 is required for increased DNA binding activity of activator protein-1, a heterodimer of Fos/JunD, in rheumatoid synovial cells under inflammatory stimuli.

We have studied the DNA binding profiles of activator protein-1 (AP-1) involved in synovial overgrowth and osteoporosis in rheumatoid arthritis (RA) in relation to the molecular chaperon heat shock protein 90 (HSP90). The AP-1 binding activity of the nuclear extracts of rheumatoid synovial cells was basically increased as compared with osteoarthritic synovial cells. Upon stimulation with inflammatory cytokines IL-1beta or TNFalpha, the AP-1 binding activity was further increased in rheumatoid synovial cells, and increased AP-1 protein was composed as heterodimers of Fos and JunD which was not known before as a major component of AP-1 in rheumatoid synovial cells. The increase of AP-1 binding activity as induced by inflammatory cytokines was specifically inhibited by geldanamycin, radicicol or herbimycin A, specific inhibitors of HSP90, while AP-1 protein was not decreased by geldanamycin. Further, HSP90 protein was not decreased by the inhibitors. The findings indicate that HSP90 is required for increased AP-1 binding activity of rheumatoid synovial cells under inflammatory stimuli and that AP-1 binding activity is inhibited by functionally inactivating HSP90 with the inhibitors.

Human wee1 kinase is directly transactivated by and increased in association with c-Fos/AP-1: rheumatoid synovial cells overexpressing these genes go into aberrant mitosis.

Wee1 kinase downregulates the M-phase promoting factor, a complex of cdc2 and cyclin B kinase, that controls mitotic cell division. We isolated human wee1 kinase gene promoter and found that it contained one AP-1-binding motif in its promoter region (5'-CGAGTCA-3'; -823/-817), through which wee1 kinase gene was directly transactivated by c-Fos/AP-1. In rheumatoid synovial cells, wee1 kinase was increased in conjunction with the increase of c-Fos/AP-1 and the substrate of wee1, cdc2, was phosphorylated. The amount of wee1 and c-Fos and the phosphorylation of cdc2 were decreased after treatment of the cells with an inhibitor of AP-1, curcumin. A significant proportion of cultured synovial cells of the patients with rheumatoid arthritis, but not those of osteoarthritis, shifted to a tetraploid (4C) state upon long-term culture. Thus, human wee1 kinase gene is directly transactivated by and increased in association with c-Fos/AP-1, and rheumatoid synovial cells overexpressing these genes go into aberrant mitosis.

p21waf1/cip1 is down-regulated in conjunction with up-regulation of c-Fos in the lymphocytes of rheumatoid arthritis patients.

Features characteristic to rheumatoid arthritis (RA) including synovial overgrowth and joint destruction are experimentally produced by augmenting c-fos gene expression. We show that cyclin dependent kinase inhibitor p21waf1/cip1, that inhibits cell proliferation, is down-regulated in conjunction with up-regulation of c-fos in the lymphocytes of patients with RA. As to the mechanism of down-regulation of p21waf1/cip1 gene expression, transfection studies in U937 cells showed that c-fos down-regulated phosphorylation and dimerization of signal transducers and activators of transcription (STAT) 1, thereby inhibiting interferon -induced transactivation of p21waf1/cip1. Phosphorylation of STAT1 was indeed decreased in the lymphocytes of patients with RA. Thus, under overexpression of c-fos gene, c-Fos inactivates STAT1 to down-regulate p21waf1/cip1 gene expression in the lymphocytes of patients with RA, and in this way may enhance proliferation of lymphocytes.

[The molecular genetics of rheumatoid arthritis disease gene].

Rheumatoid arthritis(RA) is a chronic polyarthritis of unknown etiology affecting approximately 1% of the population worldwide. Previous studies have shown that the ratio of the risk for siblings of patients with the disease versus the prevalence of that disease in the general population (lambda s) is much greater in RA, suggesting that genetic factors may be involved in familial clustering. Using microsatellite marker analysis and sib-pair linkage study, we have identified three chromosome regions D1S214/253, D8S556 and DXS1232/984 as candidate loci for RA disease genes. In this article, we review the molecular genetic findings on the RA disease genes located respectively at each of the above chromosome regions. We show that the death receptor 3(DR3) gene, a Fas family member, containing nucleotide polymorphism is the candidate disease gene located at D1S214/253. We also identify the mutant forms of angiopoietin-1(Ang-1) and Dbl proto-oncogenes respectively as the candidate genes located at D8S556 and DXS1232/984. We surmise that these mutations are responsible for the impairment of apoptosis induction, angiogenesis and leukocyte function in the patients, which may predispose to autoimmunity.