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This study tested the applicability of airborne scanning laser altimetry (LiDAR) for characterizing surface connectivity of floodplain water bodies by comparing it with in situ measurements of water levels, and examined whether LiDAR derived data accurately predicted the occurrence of globally imperilled unionid mussels. We intensively examined 10 isolated and 3 connected floodplain water bodies (IWBs and CWBs, respectively) located within a 15-km lowland segment of the Kiso River in Japan. Using a digital elevation model (DEM) of floodplain ground surface, which is derived from LiDAR, and water surface DEM, which is obtained from records of water level fluctuations, the frequency of surface connectivity between IWBs and the main channel (inundation frequency) was calculated. Inundation frequency of IWBs was also measured in situ using water level and temperature probes. Also, the occurrence of mussels in CWBs and IWBs were examined. LiDAR derived data well predicted in situ derived one with a high level of accuracy (r 2 > 0.77), validating the LiDAR-based approach. Some errors existed in the predictive model, indicating that the applicability of LiDAR data is limited by its spatial resolution and snapshot nature. The occurrence of mussels was positively explained by an increasing level of inundation frequency, and the high accuracies of empirical models were validated using data for other 67 water bodies within the study segment. This study overall demonstrated a high potential of LiDAR data for efficiently monitoring hydrological and biological conditions of floodplain water bodies in the Kiso River and beyond. Copyright # 2010 John Wiley & Sons, Ltd.

When two closely related species migrate to divergent spawning sites, divergent use of spawning habitats can directly reduce heterospecific mating. Furthermore, adaptations to divergent spawning habitats can promote speciation as a by-product of ecological divergence. Here, we investigated habitat isolation and ecological divergence between two anadromous forms of threespine stickleback (Gasterosteus aculeatus), the Japan Sea and Pacific Ocean forms. In several coastal regions of eastern Hokkaido, Japan, these forms migrate to the same watershed to spawn. Our field surveys in a single watershed revealed that segregation of distinct spawning sites between the two forms was maintained within the watershed across multiple years. These spawning sites diverged in salinity and predator composition. Morphological and physiological divergence between the forms also occurs in the direction predicted by ecological differences between the spawning sites. Our data indicate that migration into divergent spawning habitats can be an important mechanism contributing to speciation and phenotypic divergence in anadromous fishes.

Signal transducer and activator of transcription (STAT)3 is a reported mediator of molecular-targeted drug-induced keratinocyte toxicity. Our purpose was to assess the association of single nucleotide polymorphisms (SNPs) in STAT3 with hand-foot skin reactions (HFSR) in patients with metastatic renal cell carcinoma (mRCC) treated with multiple tyrosine kinase inhibitors (mTKIs). Sixty-five Japanese patients with clear cell renal cell carcinoma who were treated with any mTKI at Kobe University Hospital were retrospectively genotyped to elucidate a potential association between STAT3 polymorphisms and HFSR development. The final analysis included 60 patients. HFSR was observed in 46 patients. The GG, GC, and CC genotypes at rs4796793 were found in 9, 27, and 24 patients, respectively. Three other STAT3 polymorphisms exhibited tight linkage disequilibrium with rs4796793. A significant association was found between the rs4796793 allele and HFSR [G vs. C; odds ratio [OR], 4.33; 95 % confidence interval [CI], 1.80–10.45; P = 0.001]. The GG genotype had the highest OR compared with GC + CC genotypes (OR, 10.75; 95 % CI, 2.38–48.07; P = 0.001). In a time-to-event Kaplan–Meier analysis, a statistically significant difference was observed between the GC + CC and the GG genotypes (P = 0.009). The rs4796793 genotype appears to be a novel factor for mTKI-induced HFSR in patients with mRCC. Prospective translational trials with larger numbers of patients are required to confirm our results. This research suggests a potential benefit of STAT3 polymorphism screening in patients treated with mTKIs.

Juvenile three-spined stickleback Gasterosteus aculeatus in their nursery pond had a bimodal length distribution after October in their first year of life. A sea-run migration of all individuals belonging to the lower modal group was observed, with a peak in early November. These data suggest that partial migration based on the early status of individual juveniles occurs in the Pacific Ocean form of three-spined stickleback.

The Japan sea form of the threespine stickleback, Gasterosteus aculeatus, was found to spawn in the seawater tidal pool of the Cape Benkei, western Hokkaido Island, Japan, in 2001 and 2003. Nest-guarding males, adult females and juveniles of this form were also observed in four tidal pools of the Capes Benkei, Kabuto and Kamui, in 2001–2003. Otolith Sr:Ca ratios in sticklebacks collected from these tidal pools were relative high from the core to the edge, suggesting they lived in seawater environments throughout its life cycle. These findings suggest that a part of the Japan Sea formȁ9s individuals in western Hokkaido Island have the potential to breed in the coastal sea and the life history style has evolved in dependence on the seawater environment.

Cordyceps militaris (CM) is gaining attention as a traditional medicinal food, but its molecular biological mechanisms for anti-cancer activity are not identified or clarified. We aimed to elucidate the synthesizing apoptotic effects of CM extracts and to determine the biological effects of CM extract against cordycepin alone in a renal cell carcinoma (RCC) cell line. CM extract showed higher effects of growth inhibition, apoptotic effect, and cell cycle arrest than cordycepin alone. Moreover, CM extract activated extracellular signal-regulated kinase (Erk) highly more than cordycepin alone. We suggest that cordycepin and CM extract induced apoptosis via the activation of Erk dominantly and AMP-activated protein kinase slightly; CM extract has more potent effects on apoptotic effects associated with Erk activation than cordycepin alone.

Spawning migration patterns were compared between sympatric populations of the anadromous Japan Sea (JS) form and Pacific Ocean (PO) form of the threespine stickleback Gasterosteus aculeatus in the Lake Akkeshi–Bekanbeushi River system, eastern Hokkaido, Japan. In Akkeshi Bay and Lake Akkeshi, the JS form had longer collecting peak periods and more collection peaks than the PO form. Furthermore, although the PO form migrated upstream in freshwater habitats, the greater part of the JS form stayed in brackish waters before breeding. These findings suggest that the 2 forms have distinctly different spawning migration patterns and breeding grounds.

Background: Mammalian target of rapamycin (mTOR) inhibitors are associated with dermatological adverse events. The chief aim of this study was to examine the relation between the signal transducer and activator of transcription 3 (STAT3) protein and the dermatological adverse events associated with the mTOR inhibitor everolimus. Methods: We evaluated the effects of STAT3 activity and related signal transduction activities on everolimusinduced cell growth inhibition in the human keratinocyte HaCaT cell line via a WST-8 assay, and on signal transduction mechanisms involved in everolimus treatments via a western blot analysis. Apoptosis was evaluated using an imaging cytometric assay. Results: The cell growth inhibitory effects of everolimus were enhanced by stattic or STA-21, which are selective inhibitors of STAT3, treatment in HaCaT cells, although such effects were not observed in Caki-1 and HepG2 cells. Phosphorylation at tyrosine 705 of STAT3 was decreased by treatment with everolimus in a dose-dependent manner in HaCaT cells; in contrast, phosphorylation at serine 727 was not decreased by everolimus, but slightly increased. Furthermore, we found that pretreatment of p38 MAPK inhibitor and transfection with constitutively active form of STAT3 in HaCaT cells resisted the cytostatic activity of everolimus. Conclusions: These findings suggest that STAT3 activity may be a biomarker of everolimus-induced dermatological toxicity.

The aim of the present study was to investigate dexamethasone (DEX)-induced secretion of cystatin C (Cys C) and the effect of cisplatin (CDDP) and 5-fluorouracil (5-FU) on Cys C secretion in human cancer cell lines. KYSE150, A549 and Caki-2 human cancer cell lines were cultured on plastic dishes and treated with DEX (100 nM) for 24, 48 and 72 h. KYSE150 cells were co-treated with DEX, CDDP (10 μM), and 5-FU (2 μM). The effects of DEX, CDDP and 5-FU on cell viability were evaluated. Results showed Cys C secretion levels in the culture medium of DEX-treated KYSE150 cells to be 1.8- to 2.3-fold higher compared to those in the culture medium of control cells. A similar tendency was observed in A549 cells at all the time points, whereas a significant increase in the Cys C secretion by Caki-2 cells was observed only 24 h after DEX treatment. Regarding KYSE150 cells, the secretion of Cys C was also enhanced by co-treatment of CDDP or 5-FU with DEX, although it was not affected by the co-administration of DEX and mifepristone, a glucocorticoid receptor antagonist. At concentrations that are typically used in esophageal cancer chemotherapy, CDDP and 5-FU demonstrated a moderate level of cytotoxicity in KYSE150 cells in contrast to DEX. These findings suggested that DEX has the potential to enhance the extracellular secretion of Cys C in esophageal cancer cells, possibly due to the transcriptional regulation mediated by glucocorticoid receptor activity.

While aprepitant is actually recommended for the prevention of nausea and vomiting induced by a single cisplatin administration, it is still unclear whether it has a clinical benefit when administered along with daily administrations of low- dose cisplatin(20mg/m2 days 1-5). This study was conducted to evaluate the efficacy of aprepitant in patients receiving daily administration of low-dose cisplatin.Our study focused on 25 patients who received cancer therapy including cisplatin, with or without aprepitant (days 1-5). We performed a retrospective study to identify any significant positive effect of aprepitant in the prevention of nausea and vomiting for 10 days(days 1-10). Because cisplatin has a long half-life, we assessed the delayed phase nausea and vomiting(days 6-10).Multiple-day dosing of aprepitant was effective for prevention of nausea(Odds ratio: 0. 30, p= 0. 0012)and vomiting(Odds ratio: 0. 04, p=0. 0001)throughout the observation. Furthermore, we observed a significant positive effect of aprepitant in the prevention of delayed nausea(Odds ratio: 0. 19, p=0. 0083)and vomiting(Odds ratio: 0. 07, p=0. 0040). These findings suggest that multiple-day dosing of aprepitant is useful for the inhibition of acute delayed nausea and vomiting caused by chemotherapy including daily administration of low-dose cisplatin.

In the present study, the time–concentration profile of platinum (Pt) in plasma was compared to that of serum cystatin C (Cys C) in Japanese esophageal cancer patients receiving perioperative cisplatin-based chemotherapy. Five male and one female patients receiving 2 successive cycles of cisplatin-based chemotherapy combined with 5-fluorouracil, the treatment for esophageal squamous cell carcinoma, participated in this study. The pharmacokinetic parameters in each patient were calculated from the individual plasma Pt concentration–time curve after intravenous infusion of cisplatin using the one-compartment model. Within a week of starting the first cycle of chemotherapy, serum Cys C concentrations increased in all patients from 122.6 to 143.0 %, subsequently returning to baseline levels in approximately 10 days. A similar increase in serum Cys C levels also occurred during the second treatment cycle. However, no increase in serum creatinine levels was observed during either treatment cycle. In addition, the concentration of plasma Pt 2 days after treatment in the first and second cycles did not correlate with those of either serum Cys C or creatinine. Finally, the half-life of Pt in plasma during the first treatment cycle was not significantly different from that in the second cycle. These findings suggest that concentration fluctuations in serum Cys C are unlikely to correlate with Pt elimination from the plasma and that renal function estimates based on serum Cys C concentration might be underestimated during perioperative cisplatin-based chemotherapy for esophageal cancer.

The Mekong giant catfish Pangasianodon gigas is endemic to the Mekong River basin, and is recognized as endangered species, largely due to overfishing and development of the river basin. We monitored food intake of P. gigas in a stable environment in an aquarium over a 6-year period and analyzed their feeding rhythm and fasting periods. The daily food intake for each fish was recorded from 18 June 2004 to 17 June 2010. The feeding rhythm or pattern was determined by the fast Fourier transform (FFT) analysis. The FFT analysis revealed that different cycles of feeding rhythm (168.8, 313.1, and 365.3 days) in three catfishes and no observable cycles in two catfishes. However, three catfishes showed subordinate peaks with approximately 365 days (365.3 days for all). These suggest that, at least, four of five catfish had have approximately 365-days feeding cycle. We also showed that all catfish undergo long-term fasting periods (> 20 days). Of note, the feeding/fasting pattern coincides with the wet/dry seasons in Thailand, which also corresponds to the abundance of the catfish food resource (Cladophora spp.). We found that P. gigas exhibit a seasonal feeding rhythm that is synchronized by food availability. Furthermore, we found that the seasonal feeding rhythm was gradually dampened over time, suggesting that the observed seasonal feeding rhythm with long-term fasting of the catfish is likely controlled by an endogenous clock system. To our knowledge, this is the first case of quantification of the seasonal feeding rhythm with fasting periods in teleost fish.

Sexual antagonism, or conflict between the sexes, has been proposed as a driving force in both sex chromosome turnover and speciation. Although closely related species often have different sex chromosome systems, it is unknown whether sex chromosome turnover contributes to the evolution of reproductive isolation between species. In this study, we show that a newly evolved sex chromosome harbours genes that contribute to speciation in threespine stickleback fish (Gasterosteus aculeatus). We first identified a neo-sex chromosome system found only in one member of a sympatric species pair in Japan. We then performed genetic linkage mapping of male-specific traits important for reproductive isolation between the Japanese species pair. The neo-X chromosome harbours loci for male courtship display traits that contribute to behavioural isolation, while the ancestral X chromosome contains loci for both behavioural isolation and hybrid male sterility. Our work not only provides strong evidence for a large-X effect on reproductive isolation in a vertebrate system, but also provides direct evidence that a young neo-X chromosome contributes to reproductive isolation between closely related species. Our data suggest that sex chromosome turnover might play a greater role in speciation than previously appreciated.

e15622 Background: Signal transducer and activator of transcription (STAT) 3 has been reported to be a mediator for keratinocyte toxicity induced by molecular-targeted drugs. Our purpose was to assess the association between single nucleotide polymorphisms (SNPs) in the STAT3 gene and hand-foot skin reaction (HFSR) in metastatic renal cell carcinoma (mRCC) patients treated with multi-kinase inhibitors (MKIs). Methods: Sixty-five mRCC patients treated with MKIs (sunitinib, sorafenib, or axitinib) were genotyped for rs4796793 in the 5′ region of the STAT3 gene. We retrospectively analyzed 60 patients whose first MKI therapy lasted for more than 4 months, regardless of the presence or absence of HFSR, and who developed HFSR within 4 months before treatment failure. Results: MKIs sunitinib, sorafenib, and axitinib were given to 35, 16, and 9 patients, respectively. HFSR was observed in 46 patients. Genotypes GG, GC, and CC at rs4796793 were found in 9, 27, and 24 patients, respectively. A significant associat...

The 19F NMR spectrum of triflupromazine hydrochloride (TFZ) in a buffer solution (pH 6.8) showed a single sharp signal of the TFZ CF3 group at 13.5 ppm from the external trifluoroacetic acid. The addition of 1 mM HSA or BSA to the sample solution caused a split of the CF3 signal into two broadened signals shifted to slightly lower (0.2 ppm) and higher (0.7 ppm) fields, respectively, from the original position. Denaturation of the albumins by guanidine hydrochloride (3M) restored the two broadened signals to a slightly broadened single signal, indicating that TFZ has at least two binding sites on HSA and BSA, respectively. From the competitive binding 19F NMR experiments using Warfarin (Site-I ligand), l-tryptophan (Site-II ligand), NaCl, and oleate, the signal at high field was assigned to the TFZ bound to Site II. Comparison of the signal intensity revealed that the affinity of TFZ for Site II on HSA was considerably higher than that on BSA. The low-field signal could be identified as a weight-averaged signal between nonspecifically bound TFZ to HSA (BSA) and free TFZ in the water phase. In the presence of physiological concentrations of NaCl, major binding of TFZ to HSA and BSA was considered to be nonspecific. The present work indicates that 19F NMR is very useful for obtaining important detailed information regarding the binding of fluorinated drugs to serum albumins.

A simple 19F NMR spectrometric method was proposed for the determination of the partition coefficients of fluorinated psychotropic drugs, trifluoperazine (TFPZ), flunitrazepam (FNZ) and flurazepam (FZ) between phosphatidylcholine (PC) bilayer of small unilamellar vesicles (SUVs) and water (buffer). Each 19F NMR spectrum of these drugs in the presence of PC SUV showed a single signal accompanying a PC concentration-depending shift change and broadening, which indicated a fast exchange of these drugs between the water phase and the PC bilayer of SUV. From the relationship between the 19F chemical shift change (Deltadelta) of each drug and the PC concentration, the molar partition coefficients (K(p)'s) were calculated and obtained with a good precision of RSD below 6%. The fractions of the partitioned drugs calculated by using the obtained K(p)-values were in a good agreement with the experimental values. The results demonstrate that the 19F NMR method can be usefully applied to the determination of partition coefficients of many drugs having fluorine atom(s) without any separation procedure, especially for drugs which do not have absorption in the ultraviolet or visible region, or those having absorption but show insignificant spectral changes according to their incorporation to PC bilayers (e.g. FNZ).

Hand–foot skin reaction is a most common multi-kinase inhibitor-related adverse event. This study aimed to examine whether the toxicity of sorafenib and sunitinib for human keratinocytes was associated with inhibiting signal transduction and activator of transcription 3 (STAT3). We studied whether STAT3 activity affects sorafenib- and sunitinib-induced cell growth inhibition in HaCaT cells by WST-8 assay. Stattic enhanced the cell-growth inhibitory and apoptotic effects of sorafenib and sunitinib. HaCaT cells transfected with constitutively-active STAT3 (STAT3C) were resistant to the sorafenib- and sunitinib-induced cell growth inhibition. STAT3 activity decreased after short-term treatment with sorafenib and sunitinib in a dose-dependent manner and recovered after long-term treatment with sorafenib and sunitinib at low doses. Moreover, the expression of survivin and bcl-2 decreased after treatment with sorafenib and sunitinib was concomitant with variations in STAT3 activity. Sorafenib-induced STAT3 inhibition was mediated by regulation via MAPK pathways in HaCaT cells, while sunitinib-induced STAT3 inhibition was not. Thus, STAT3 activation mediating apoptosis suppressors may be a key factor in sorafenib and sunitinib-induced keratinocyte cytotoxicity.

Sex chromosomes turn over rapidly in some taxonomic groups, where closely related species have different sex chromosomes. Although there are many examples of sex chromosome turnover, we know little about the functional roles of sex chromosome turnover in phenotypic diversification and genomic evolution. The sympatric pair of Japanese threespine stickleback (Gasterosteus aculeatus) provides an excellent system to address these questions: the Japan Sea species has a neo-sex chromosome system resulting from a fusion between an ancestral Y chromosome and an autosome, while the sympatric Pacific Ocean species has a simple XY sex chromosome system. Furthermore, previous quantitative trait locus (QTL) mapping demonstrated that the Japan Sea neo-X chromosome contributes to phenotypic divergence and reproductive isolation between these sympatric species. To investigate the genomic basis for the accumulation of genes important for speciation on the neo-X chromosome, we conducted whole genome sequencing of males and females of both the Japan Sea and the Pacific Ocean species. No substantial degeneration has yet occurred on the neo-Y chromosome, but the nucleotide sequence of the neo-X and the neo-Y has started to diverge, particularly at regions near the fusion. The neo-sex chromosomes also harbor an excess of genes with sex-biased expression. Furthermore, genes on the neo-X chromosome showed higher non-synonymous substitution rates than autosomal genes in the Japan Sea lineage. Genomic regions of higher sequence divergence between species, genes with divergent expression between species, and QTL for inter-species phenotypic differences were found not only at the regions near the fusion site, but also at other regions along the neo-X chromosome. Neo-sex chromosomes can therefore accumulate substitutions causing species differences even in the absence of substantial neo-Y degeneration., Author Summary Sex is ubiquitous, but sex-determining mechanisms are evolutionarily labile. Even in taxa with genetic sex determination mechanisms, closely related species often have different sex chromosomes. Although there are many examples of such sex chromosome turnover, we know little about the functional roles of sex chromosome turnover in phenotypic diversification and genomic evolution. Using the Japan Sea species of threespine stickleback (Gasterosteus aculeatus), which has a neo-sex chromosome derived from a Y-autosome fusion, we found that incipient neo-X and neo-Y chromosomes have started to diverge in both coding and non-coding regions and to accumulate genes with sex-biased expression. We further found that non-synonymous mutation rates are elevated on the neo-X chromosome in the Japan Sea lineage. Finally, the neo-X chromosome contributes to phenotypic divergence between the Japan Sea species and the ancestral Pacific Ocean species, but the causative genes were distributed broadly on the neo-X chromosome. These results suggest that neo-sex chromosome formation may create a genomic location where mutations causing inter-species differences can accumulate, thereby promoting phenotypic divergence between incipient species.

e19517 Background: Quality of life (QOL) has not been evaluated in Japanese patients with advanced cancer by EORTC QLQ C-15 PAL, which was developed to measure QOL in palliative care. The patient c...

Closely related species of fish often exhibit different migration patterns. Even within species, anadromous and resident populations can be found in a diverse number of taxa. Although several environmental factors that regulate behavioral and physiological changes associated with fish migration have been identified, the genetic mechanisms underlying the variation in the ability to respond to these environmental cues in fishes that show different migratory behaviors are not well known. The three-spined stickleback Gasterosteus aculeatus (Linnaeus 1758) is a good model system for elucidation of the genetic basis for variation in migratory behaviors and other physiological changes associated with migration. First, the three-spined stickleback exhibits great inter-population variation in migration patterns. Second, genetic and genomic tools are now available for studying this species. In the present study, variation in the migration patterns among G. aculeatus populations and the recent progress in our understanding of the genetic and physiological basis for variation in traits important for G. aculeatus migration are reviewed.

2013年度