Evaluation of 11 C-choline positron emission tomography/computed tomography for determining treatment response in castration-resistant prostate cancer patients.

OBJECTIVE: The utility of 11 C-choline positron emission tomography/computed tomography for determining treatment response as compared with prostate-specific antigen response and prognosis prediction in castration-resistant prostate cancer patients was investigated. METHODS: Eighty-four 11 C-choline-positron emission tomography/computed tomography scans before/after treatments with abiraterone (n = 12 patients), enzalutamide (n = 3), docetaxel (n = 9), cabazitaxel (n = 5), radiation therapy alone (n = 3), radiation therapy, enzalutamide, and/or abiraterone (n = 5), radium-223 (n = 4), and radiofrequency ablation (n = 1) in 42 castration-resistant prostate cancer patients were retrospectively examined. Prostate-specific antigen values were determined before and after treatment. Using the Kaplan-Meier method, the correlation of Positron Emission Tomography Response Criteria In Solid Tumors with prostate-specific antigen response and prognostic impact was evaluated. RESULTS: Pretreatment 11 C-choline-positron emission tomography/computed tomography findings identified local, lymph node, bone, and visceral metastasis in 12, 12, 29, and five patients, respectively. Following treatments, complete metabolic response was noted in one, partial metabolic response in eight, stable metabolic disease in 13, and progressive metabolic disease in 20. Mean prostate-specific antigen change for complete metabolic response, partial metabolic response, stable metabolic disease and progressive metabolic disease was -48.9%, -55.0% (range -92.4% to -19.1%), -4.2% (-33.2% to 35.1%), and 142.7% (30.7% to 373.8%), respectively, significantly greater in the progressive metabolic disease cases (P < 0.01). Positron Emission Tomography Response Criteria In Solid Tumors was well correlated with prostate-specific antigen change. Patients with no progression (complete metabolic response/partial metabolic response/stable metabolic disease) showed significantly longer cancer-specific survival than progressive metabolic disease (P < 0.005). Using pretreatment 11 C-choline-positron emission tomography/computed tomography results to divide into three groups; (a) local and/or lymph node metastasis without bone metastasis (n = 10), (b) <6 bone metastasis sites (n = 16), (c) ≥6 bone metastasis sites and/or visceral metastasis (n = 16), cancer-specific survival showed significant stratification (P < 0.001). CONCLUSIONS: 11 C-choline-positron emission tomography/computed tomography may reflect castration-resistant prostate cancer metastatic lesion activity for treatment response and prognosis evaluations.

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.

BACKGROUND: Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease. METHODS: CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed. RESULTS: CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum. CONCLUSION: Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.

Copper-trafficking efficacy of copper-pyruvaldehyde bis(N4- methylthiosemicarbazone) on the macular mouse, an animal model of Menkes disease.

BACKGROUND: Menkes disease (MD) is a disorder of copper transport caused by ATP7A mutations. Although parenteral copper supplements are partly effective in treating MD, the copper level in the brain remains insufficient, whereas copper accumulates in the kidney. We investigated the copper-trafficking efficacy of copper-pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-PTSM), a lipophilic copper complex, in macular mice, an animal model of MD. METHODS: Macular mice were treated with cupric chloride (CuCl2) or Cu-PTSM on postnatal days 4, 10, and 17. At 4 wk of age, the copper levels in major organs and cytochrome oxidase (CO) activity in brain tissue were measured. Hematology, blood biochemistry, and urinary ß2-microglobulin (ß2-M) secretion were also assessed. RESULTS: The copper levels in the brains of the Cu-PTSM-treated group remained low, but CO activity in the cerebral and cerebellar cortices in the Cu-PTSM-treated group were higher than those in the CuCl2-treated group. There were no significant differences in hematological or biochemical findings or in urinary ß2-M secretion among the groups. CONCLUSION: Although the copper-trafficking efficacy of Cu-PTSM was limited, the improved CO activity in the brain suggests that Cu-PTSM delivered copper more effectively to neuronal CO than did CuCl2. Reduced renal copper accumulation may be beneficial in prolonged copper supplementation.

Quantitative trait loci controlling resistance to cadmium rhizotoxicity in two recombinant inbred populations of Arabidopsis thaliana are partially shared by those for hydrogen peroxide resistance.

To understand mechanisms of cadmium (Cd) tolerance variation associated with root elongation in Arabidopsis thaliana, quantitative trait loci (QTLs) and epistasis were analyzed using relative root length (RRL: % of the root length in +Cd to -Cd) as a tolerant index. Using the composite interval mapping method, three major QTLs (P < 0.05) were detected on chromosomes 2, 4 and 5 in the recombinant inbred population derived from a cross between Landsberg erecta (Ler-0) and Columbia (Col-4). The highest logarithm of odds (LOD) of 5.6 was detected with the QTL on chromosome 5 (QTL5), which is linked to the genetic marker CDPK9 and explained about 26% of the Cd tolerance variation. There was no significant difference in Cd-translocation ratio from roots to shoots between tolerant and sensitive recombinant inbreed lines (RILs), while greater accumulations of reactive oxygen species were observed in the roots of sensitive RILs. This suggested that accumulation of ROS would explain Cd tolerance variation of the Ler/Col RILs, which is mainly controlled by the QTL on chromosome 5. The QTL5 in Ler/Col population was also detected as one of the major QTLs controlling tolerances to hydrogen peroxide and to copper, which is another ROS generating rhizotoxic metal. The same chromosomal position was detected as a common major QTL for Cd and hydrogen peroxide tolerances in a different recombinant inbreed (RI) population derived from a cross of Col-gl1 and Kashmir (Kas-1). These data, along with a multitraits QTL analysis in both sets of RILs, suggest that peroxide damage depends on the genotype at a major Cd-tolerant locus on the upper part of chromosome 5.

Association mapping of cadmium, copper and hydrogen peroxide tolerance of roots and translocation capacities of cadmium and copper in Arabidopsis thaliana.

Association mapping analysis of Cd, Cu and H (2)O (2) tolerance, judged by relative root length (RRL: % of root length in stress condition relative to that in control condition), and Cd and Cu translocation ratios (amount of metal in the shoot to the total) were performed using 90 accessions of Arabidopsis thaliana. Using 140 SNPs that were distributed across the genome, association mapping analysis was performed with a haploid setting by the Q + K method, which minimizes detection of false associations by combining the Q-matrix of the structured association (Q) with kinship (K) to control for the population structure. Six, five and five significant (-log (10)P-value is 1.3 > or =) linkages were detected between the SNPs and Cd, Cu and H(2)O(2) resistant RRLs, respectively. In addition, six significant linkages were identified with translocation capacities of Cd and Cu. Among those detected loci, two each of Cu and Cd tolerance RRLs were collocated with those of H(2)O(2) tolerance RRL, while one locus each was detected by Cu and Cd tolerance RRLs that collocated with their translocation ratios. These results suggested that these factors might partly explain the phenotypic variation of tolerance RRLs to Cd and Cu of Arabidopsis thaliana. Finally, using a different approach to analyze interactions between individual phenotypes, namely clustering analysis, we found an expected segregation of resistant SNPs (single-nucleotide polymorphisms) of the multiple RRLs in the typical accession groups carrying multiple traits. Almost none of the loci detected by association mapping analysis were linked to the loci of previously identified critical genes regulating the traits, suggesting that this could be useful to identify complex architecture of genetic factors determining variation among multiple accessions.

Identification of Characteristic Components and Foodstuffs in Healthy Japanese Diet and the Health Effects of a Diet with Increased Use Frequency of these Foodstuffs.

SCOPE: Our recent study showed that the 1975 Japanese diet exhibited strong health benefits. In the current study, we aimed to develop a diet with even higher health benefits. METHODS: First, to determine the characteristic components in the 1975 diet, we used mass spectrometry for analysis of Japanese diets from several years and performed principal component analysis. Next, a diet with an increased use frequency of foodstuffs contained characteristic components (the modified diet) was prepared and fed to mice. RESULTS: Performed principal component analysis revealed that the 1975 diet contained 14 characteristic components that were found in fish, fruits, vegetables, seaweed, soybean foods, soup stock "dashi", and fermented seasoning. Based on these, the modified diet was prepared and fed to mice. The liver total cholesterol and serum LDL cholesterol decreased significantly in mice fed the modified diet and serum total cholesterol showed a downward trend, compared to mice fed the 1975 diet. There was no difference between the modified diet and the control groups. In addition, serum adiponectin level increased in mice fed the modified diet and serum TBARS and IL-6 levels decreased. CONCLUSION: By modifying the 1975 diet, it was possible to make a diet with more benefit.

Imaging of gefitinib-related interstitial lung disease: multi-institutional analysis by the West Japan Thoracic Oncology Group.

Gefitinib (Iressatrade mark) is an epidermal growth factor receptor tyrosine kinase inhibitor that has been approved for the treatment of lung cancer in Japan, however, after marketing several cases of severe pulmonary toxicity were reported. The West Japan Thoracic Oncology Group conducted an independent survey of acute pulmonary toxicity and interstitial lung disease (ILD) caused by gefitinib in its member's institutions. The purpose of this study was to clarify the image characteristics of ILD caused by the molecular-targeting drug gefitinib. A total of 1976 patients had been treated with gefitinib between August and December 2002, and 102 of them were suspected of having acute pulmonary toxicity and ILD. A final definite diagnosis of gefitinib-induced ILD was made by at least three radiologists based on a review and analysis of the chest radiography and CT findings plus the clinical data in the medical records. The imaging findings were classified into four patterns: (A) a nonspecific area with ground-glass attenuation, (B) a multifocal area of airspace consolidations, (C) patchy distribution of ground-glass attenuation accompanied by interlobar septal thickening, and (D) extensive bilateral ground-glass attenuation or airspace consolidations with traction bronchiectasis. CT as well as chest radiography had been performed in 65 of the 102 patients at the onset of ILD, and chest radiography alone had been performed in 26. After excluding 11 cases with insufficient data and 21 cases concluded to be other pulmonary diseases, 70 patients were diagnosed with gefitinib-induced ILD. Finally, the diagnostic image findings were classified as pattern A in 29 cases, pattern B in 7 cases, pattern C in 3 cases, pattern D in 20 cases and others in 11 cases. The CT images were classified as pattern A, B, C, and D in 24, 7, 1, and 12 cases, respectively. The mortality rate was significantly higher in the patients with pattern D than the other patterns. Pattern D were thought to represent the features of diffuse alveolar damage. In conclusion, the molecular-targeting drug gefitinib induces pulmonary toxicity at a certain rate and the imaging findings of ILD induced by gefitinib are similar to those of pulmonary toxicity induced by conventional antineoplastic agents.

Comparison and characterization of biosorption by Weissella viridescens MYU 205 of periodic group 12 metal ions.

Because heavy metals cause various health hazards, we studied biosorption by Weissella viridescens MYU 205. MYU 205 showed high biosorption for Cd (II) and Hg (II) and was low for Zn (II). The Hg (II) biosorption rate was high at about 80%. Different biosorptions were shown for each metal after successive incubation. About 20% of the Zn (II) biosorption was observed after 3 h. Cd (II) biosorption increased in a time-dependent manner until 3 h, then gradually decreased. Hg (II) was immediately sorbed at 79.6 ± 4.7% and decreased at 3 h to 52.9 ± 2.6%, and then gradually increased to 77.8 ± 3.6%. Using heat-killed cells, the rate of biosorption of Zn (II) and Cd (II) decreased whereas Hg (II) tended to increase. The metal resistance was high, that is Zn (II) > Cd (II) > Hg (II); while the affinity was opposite where MYU 205 showed high affinity to Hg (II) and low affinity to Zn (II). Our data shows lactic acid bacteria may be powerful heavy metal sorbents for detoxification.

Biosorption of heavy metals by lactic acid bacteria and identification of mercury binding protein.

Heavy metals cause various health hazards. Using lactic acid bacteria (LAB), we tested the biosorption of heavy metals e.g. cadmium (Cd) (II), lead (Pb) (II), arsenic (As) (III), and mercury (Hg) (II). Cd (II) sorption was tested in 103 strains using atomic absorption spectrophotometery (AAS). Weissella viridescens MYU 205 (1 × 10(8) cells/ml) decreased Cd (II) levels in citrate buffer (pH 6.0) from one ppm to 0.459 ± 0.016 ppm, corresponding to 10.46 µg of Cd (II). After screening, 11 LAB strains were tested using various pH (pH 4.0, 5.0, 6.0, 7.0) showing the sorption was acid sensitive; and was cell concentration dependent, where the Cd (II) concentration decreased from one ppm to 0.042 (max)/0.255 (min) ppm at 1 × 10(10) cells/ml. Additionally, the biosorption of Pb (II), As (III), and Hg (II) were tested using an inductively coupled plasma mass spectrometer (ICP-MS). The Hg (II) concentration was reduced the most followed by Pb (II) and As (III). Many of the bacterial cell surface proteins of W. viridescens MYU 205 showed binding to Hg (II) using the Hg (II) column assay. Having a CXXC motif, a ∼14 kDa protein may be one of the Hg (II) binding proteins. LAB biosorption may aid the detoxification of people exposed to heavy metals.

Amino acid polymorphisms in strictly conserved domains of a P-type ATPase HMA5 are involved in the mechanism of copper tolerance variation in Arabidopsis.

Copper (Cu) is an essential element in plant nutrition, but it inhibits the growth of roots at low concentrations. Accessions of Arabidopsis (Arabidopsis thaliana) vary in their tolerance to Cu. To understand the molecular mechanism of Cu tolerance in Arabidopsis, we performed quantitative trait locus (QTL) analysis and accession studies. One major QTL on chromosome 1 (QTL1) explained 52% of the phenotypic variation in Cu tolerance in roots in a Landsberg erecta/Cape Verde Islands (Ler/Cvi) recombinant inbred population. This QTL regulates Cu translocation capacity and involves a Cu-transporting P(1B-1)-type ATPase, HMA5. The Cvi allele carries two amino acid substitutions in comparison with the Ler allele and is less functional than the Ler allele in Cu tolerance when judged by complementation assays using a T-DNA insertion mutant. Complementation assays of the ccc2 mutant of yeast using chimeric HMA5 proteins revealed that N923T of the Cvi allele, which was identified in the tightly conserved domain N(x)(6)YN(x)(4)P (where the former asparagine was substituted by threonine), is a cause of dysfunction of the Cvi HMA5 allele. Another dysfunctional HMA5 allele was identified in Chisdra-2, which showed Cu sensitivity and low capacity of Cu translocation from roots to shoots. A unique amino acid substitution of Chisdra-2 was identified in another strictly conserved domain, CPC(x)(6)P, where the latter proline was replaced with leucine. These results indicate that a portion of the variation in Cu tolerance of Arabidopsis is regulated by the functional integrity of the Cu-translocating ATPase, HMA5, and in particular the amino acid sequence in several strictly conserved motifs.

Characterisation of lanthanum toxicity for root growth of Arabidopsis thaliana from the aspect of natural genetic variation.

The mechanism of lanthanum (La3+) toxicity on root growth of Arabidopsis was studied by physiological and genetic approaches using Landsberg erecta (Ler) × Columbia (Col) recombinant inbred lines (RILs) and other natural accessions. Quantitative trait locus (QTL) analyses revealed regulation of La3+ tolerance of the Ler × Col RILs by multiple genetic factors consisted of three significant QTLs and seven epistatic interacting loci pairs. The La content in the root tip was not correlated with La3+ tolerance in the RILs, indicating that the observed La3+ rhizotoxicity was not related to direct toxicity of La3+ in the symplast. The La3+ tolerance of root growth in the RILs was not correlated with Al3+ and Cu2+ tolerances, but was correlated with tolerances for other rare earth elements, including Gd3+, a known Ca2+ channel antagonist, and verapamil, a Ca2+ channel blocker. The genetic architecture of verapamil tolerance in root growth, which was identified by QTL analysis, was closely related to that of La3+ tolerance. La3+ tolerance and verapamil tolerance or Gd3+ tolerance in natural accessions of Arabidopsis also showed a positive correlation. These results indicate that the major La3+ toxicity on the root growth of Arabidopsis may involve its action as a Ca2+ channel antagonist.

Improvement of the optical signal-to-noise ratio in common-path holographic storage by use of a polarization-controlling media structure.

A holographic storage arrangement with common-path optics is likely to suffer from degradation of the optical signal-to-noise ratio (SNR) owing to scattering of the reference beam. Instead of the conventional method of spatial separation between the reference beam and a reconstruction beam, adoption of a combined spatial and polarization separation is proposed. To achieve polarization separation by using a photopolymer as the recording material, a media structure including retardation films and a reflection layer is proposed such that the polarization states of the two beams are the same inside the material but orthogonal outside. Preliminary experiments to show the feasibility of this idea for improving optical SNR are also demonstrated.

Regulation of the intracellular free iron pool by Dpr provides oxygen tolerance to Streptococcus mutans.

Dpr is an iron-binding protein required for oxygen tolerance in Streptococcus mutans. We previously proposed that Dpr could confer oxygen tolerance to the bacterium by sequestering intracellular free iron ions that catalyze generation of highly toxic radicals (Y. Yamamoto, M. Higuchi, L. B. Poole, and Y. Kamio, J. Bacteriol. 182:3740-3747, 2000; Y. Yamamoto, L. B. Poole, R. R. Hantgan, and Y. Kamio, J. Bacteriol. 184:2931-2939, 2002). Here, we examined the intracellular free iron status of wild-type (WT) and dpr mutant strains of S. mutans, before and after exposure to air, by using electron spin resonance spectrometry. Under anaerobic conditions, free iron ion concentrations of WT and dpr strains were 225.9 +/- 2.6 and 333.0 +/- 61.3 microM, respectively. Exposure of WT cells to air for 1 h induced Dpr expression and reduced intracellular free iron ion concentrations to 22.5 +/- 5.3 microM; under these conditions, dpr mutant cells maintained intracellular iron concentration at 230.3 +/- 28.8 microM. A decrease in cell viability and genomic DNA degradation was observed in the dpr mutant exposed to air. These data indicate that regulation of the intracellular free iron pool by Dpr is required for oxygen tolerance in S. mutans.

A case of TSH receptor antibody-positive hyperthyroidism with functioning metastases of thyroid carcinoma.

The presence of TSH receptor antibody (TRAb) is rarely responsible for hyperthyroidism due to metastatic lesions of thyroid carcinoma. A 70-year-old woman was incidentally found to be thyrotoxic around the time that external irradiation was performed for multiple bone metastases 9 years after subtotal thyroidectomy for follicular carcinoma. Hyperthyroidism persisted after oral administration of thiamazole. Relevant laboratory data were as follows: FT4 9.6 ng/L, FT3 7.3 ng/L, TSH <0.19 mU/L, TBII 70, TSAb 735, and Tg 32,000 microg/L. 131I-total body scan showed 131I accumulation in the occipital bone, cervical vertebra, thoracic vertebra, ilium, and residual thyroid gland. Since the ilium uptake (11.6) was markedly higher compared to the residual thyroid gland uptake (0.14), four subsequent 131I therapies were performed. The patient became hypothyroid, and TBII became negative. TSAb became negative after the first 131I-therapy but has increased again to 204 at present. Tg was 1,962 microg/L despite high TSH levels. 131I accumulation in the residual thyroid, cervical vertebra, and thoracic vertebra disappeared. Also 131I accumulation in the ilium has gradually decreased, but the image in the occipital bone has become markedly distinctive. This is a rare case characterized by TRAb-positive hyperthyroidism, by T3-predominant thyrotoxicosis, and by stronger accumulation of 131I in the metastatic tumor than in the residual thyroid gland. Thus, the response to TRAb and 131I-therapy is different among metastatic thyroid tissues.