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The goal of this study is to clarify the underlying mechanisms of metastasis suppression by carbon-ion radiotherapy combined with immature dendritic cell immunotherapy (CiDC), which was shown previously to suppress pulmonary metastasis in an NR-S1-bearing C3H/He mouse model.

Magnetic moments arranged at the corners of a honeycomb lattice are predicted to form a novel state of matter, Kitaev quantum spin liquid, under the influence of frustration effects between bond-dependent Ising interactions. Some layered honeycomb iridates and related materials, such as Na$_{2}$IrO$_{3}$ and $\alpha$-RuCl$_{3}$, are proximate to Kitaev quantum spin liquid, but bosonic spin-wave excitations associated with undesirable antiferromagnetic long-range order mask the inherent properties of Kitaev Hamiltonian. Here, we use $^{63}$Cu nuclear quadrupole resonance to uncover the low energy spin excitations in the nearly ideal honeycomb lattice of effective spin $S = 1/2$ at the Ir$^{4+}$ sites in Cu$_{2}$IrO$_{3}$. We demonstrate that, unlike Na$_{2}$IrO$_{3}$, Ir spin fluctuations exhibit no evidence for critical slowing down toward magnetic long range order in zero external magnetic field. Moreover, the low energy spin excitation spectrum is dominated by a mode that has a large excitation gap comparable to the Ising interactions, a signature expected for Majorana fermions of Kitaev quantum spin liquid., Comment: 18 figs

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.

BiNi_1-x_Fe_x_O_3_の結晶構造、電荷分布、負熱膨張特性の研究を実施した。低温では極性を持ち、Bi3+_0.5(1+x)_Bi5+_0.5(1-x)_Ni2+_1-x_Fe3+_x_O_3_の電荷分布とBi3+/Bi5+の短距離秩序を示す。昇温過程における電荷移動による体積減少量は、Bi5+-Ni2+間の電荷移動に影響するFe3+への置換量xが増加すると減少する。しかし0.25

We use $^{79}$Br nuclear quadrupole resonance (NQR) to demonstrate that ultra slow lattice dynamics set in below the temperature scale set by the Cu-Cu super-exchange interaction $J$~($\simeq160$~K) in the kagome lattice Heisenberg antiferromagnet Zn-barlowite. The lattice completely freezes below 50~K, and $^{79}$Br NQR lineshapes become twice broader due to increased lattice distortions. Moreover, the frozen lattice exhibits an oscillatory component in the transverse spin echo decay, a typical signature of pairing of nuclear spins by indirect nuclear spin-spin interaction. This indicates that some Br sites form structural dimers via a pair of kagome Cu sites prior to the gradual emergence of spin singlets below $\sim30$~K. Our findings underscore the significant roles played by subtle structural distortions in determining the nature of the disordered magnetic ground state of the kagome lattice., Phys. Rev. Lett. (in press)

ペロブスカイト酸化物Bi1-xPbxNiO3 (0.6

Biallelic germline mutations in the DNA mismatch repair gene MLH1 lead to constitutional mismatch repair–deficiency syndrome and an increased risk for childhood hematopoietic malignancies, including lymphoma and leukemia. To examine how Mlh1 dysfunction promotes lymphoma as well as the influence of ionizing radiation (IR) exposure, we used a Mlh1–/– mouse model and whole-exome sequencing to assess genomic alterations in 23 T-cell lymphomas, including 8 spontaneous and 15 IR-associated lymphomas. Exposure to IR accelerated T-cell lymphoma induction in the Mlh1–/– mice, and whole-exome sequencing revealed that IR exposure neither increased the number of mutations nor altered the mutation spectrum of the lymphomas. Frequent mutations were evident in genes encoding transcription factors (e.g. Ikzf1, Trp53, Bcl11b), epigenetic regulators (e.g. Suv420h1, Ep300, Kmt2d), transporters (e.g. Rangap1, Kcnj16), extracellular matrix (e.g. Megf6, Lrig1), cell motility (e.g. Argef19, Dnah17), protein kinase cascade (e.g. Ptpro, Marcks) and in genes involved in NOTCH (e.g. Notch1), and PI3K/AKT (e.g. Pten, Akt2) signaling pathways in both spontaneous and IR-associated lymphomas. Frameshift mutations in mononucleotide repeat sequences within the genes Trp53, Ep300, Kmt2d, Notch1, Pten and Marcks were newly identified in the lymphomas. The lymphomas also exhibited a few chromosomal abnormalities. The results establish a landscape of genomic alterations in spontaneous and IR-associated lymphomas that occur in the context of mismatch repair dysfunction and suggest potential targets for cancer treatment.

We investigate the structural and magnetic properties of a Kitaev spin liquid candidate material Ag$_3$LiIr$_2$O$_6$ based on $^7$Li nuclear magnetic resonance line shape, Knight shift and spin-lattice relaxation rate $1/T_1$. The first sample A shows signatures of magnetically ordered spins, and exhibits one sharp $^7$Li peak with FWHM increasing significantly below 14~K. $1/T_1^{stretch}$ of this sample displays a broad local maximum at 40~K, followed by a very sharp peak at $T_N = 9\pm1$~K due to critical slowing down of Ir spin fluctuations, a typical signature of magnetic long range order. In order to shed light on the position-by-position variation of $1/T_1$ throughout the sample, we use Inverse Laplace Transform $T_1$ analysis based on Tikhonov regularization to deduce the density distribution function $P(1/T_1)$. We demonstrate that $\sim 60\%$ of Ir spins are statically ordered at the NMR measurement timescale but the rest of the sample volume remains paramagnetic even at 4.2~K, presumably because of structural disorder induced primarily by stacking faults. In order to further investigate the influence of structural disorder, we compare these NMR results with those of a second sample B, which has been shown by transmission electron microscope to have domains with unwanted Ag inclusion at Li and Ir sites within the Ir honeycomb planes. The sample B displays an additional NMR peak with relative intensity of $\sim 17\%$. The small Knight shift and $1/T_1$ of these defect-induced $^7$Li sites and the enhancement of bulk susceptibility at low temperatures suggest that these defects generate domains of only weakly magnetic Ir spins accompanied by free spins, leading to a lack of clear signatures of long-range order. The apparent lack of long-range order could be easily misinterpreted as evidence for the realization of a spin liquid ground state in highly disordered Kitaev lattice., 10 figures

Background A total of 10%–20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. Methods We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10−8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. Results Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10−10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10−10), and rs11122573 with hematuria (Pmeta = 1.8 × 10−8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10−6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. Conclusions This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

Fos‑related antigen 1 (Fra‑1) has roles in a variety of cell functions, including cell proliferation, differentiation, transformation, and invasiveness, and it is upregulated in various cancers. We investigated the role of Fra‑1 in cellular radioresistance using cells of two human colorectal cancer cell lines, SW620 and SW480. We found that SW620 cells are more sensitive than SW480 cells at doses greater than 6 Gy for X‑ray or 3 Gy for carbon‑ion (C‑ion) radiation. Fra‑1 expression tended to be decreased by the radiation in a dose‑dependent manner in both cell lines; of note, a greater reduction of Fra‑1 expression was observed in SW620 cells, especially at 6 Gy of X‑ray or 3 Gy of C‑ion irradiation, than in SW480 cells, indicating a possible association between Fra‑1 downregulation and cellular radiosensitivity. Knockdown of Fra‑1 in SW480 cells significantly increased the radiosensitivity to X‑ray or C‑ion radiation. On the other hand, overexpression of Fra‑1 in SW620 cells significantly enhanced the radioresistance to C‑ion radiation, suggesting a role of Fra‑1 in radioresistance. Furthermore, we found that downregulation of Fra‑1 protein in irradiated SW620 cells was regulated via protein degradation through a proteasome‑dependent pathway. Overall, our results indicate a role of Fra‑1 in radioresistance to both X‑ray and C‑ion radiation for colorectal cancer cell lines.

NPAT plays a role in S phase entry as a substrate of cyclin E-CDK2 and activation of histone gene transcription. Although analysis of its sequence indicates that NPAT contains typical nuclear localization signals (NLS) comprising segments of positively charged amino acids, there are currently no experimental data to show that these predictive NLS are functional. To investigate whether these sequences are effective for nuclear transport of NPAT, an NPAT-green fluorescent protein fusion (NP-GFP) was constructed. After transfection of the fusion gene containing the full coding region of NPAT into cultured cells, the NP-GFP product was found exclusively in the nucleus. As expected, some deletion mutants which retain the basic amino acid clusters at the carboxyl terminus also localize the fusion protein in the nucleus. However other fusions, which lacked one of the three basic amino acid-clusters were distributed throughout the nucleus and cytoplasm. Therefore all three clusters of basic residues are necessary for localization of NPAT to the nucleus. However, another sequence outside the carboxyl terminal region functions similar to NLS. Construction of GFP fusions with a series of truncated forms of NPAT indicated that a short peptide sequence consisting of mainly hydrophobic amino acids near the central domain of NPAT also contribute to localizing the protein in the nucleus.

This paper presents a phase description of chaotic dynamics for the study of chaotic phase synchronization. A prominent feature of the proposed description is that it systematically incorporates the dynamics of the non-phase variables inherent in the system. Taking these non-phase dynamics into account is essential for capturing the complicated nature of chaotic phase synchronization, even in a qualitative manner. We numerically verified the validity of the proposed description in application to the R\"{o}ssler and Lorenz oscillators, and we found that our method provides an accurate description of the characteristic distorted shapes of the synchronization regions for these chaotic oscillators. Furthermore, the proposed description allows us to systematically identify and describe the origin of this distortion.

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p, Chromosome 8q24 is known to be a major susceptibility region for prostate cancer risk. Here the authors analyze genetic data across the 8q24 region from 71,535 prostate cancer patients identifying 12 risk loci, three previously unreported, highlighting the contribution of germline variation at this locus.

Purpose: Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage-repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker. Methods and Materials: The present study was conducted in a cohort of patients with breast cancer to evaluate the possible associations between genetic variants in radioresponsive genes described previously and the risk of developing RT-induced acute skin adverse reactions. We tested 22 genetic variants reported in 18 genes (ie, NFE2L2, OGG1, NEIL3, RAD17, PTTG1, REV3L, ALAD, CD44, RAD9A, TGFbR3, MAD2L2, MAP3K7, MAT1A, RPS6KB2, ZNF830, SH3GL1, BAX, and XRCC1) using TaqMan assay-based real-time polymerase chain reaction. At the end of RT, the severity of skin damage was scored, and the subjects were dichotomized as nonoverresponders (Radiation Therapy Oncology Group grade 2) for analysis. Results: Of the 22 single nucleotide polymorphisms studied, the rs8193 polymorphism lying in the micro-RNA binding site of 30-UTR of CD44 was significantly (PZ.0270) associated with RT-induced adverse skin reactions. Generalized multifactor dimensionality reduction analysis showed significant (PZ.0107) gene-gene interactions between MAT1A and CD44. Furthermore, an increase in the total number of risk alleles was associated with increasing occurrence of overresponses (PZ.0302). Conclusions: The genetic polymorphisms in radioresponsive genes act as genetic modifiers of acute normal tissue toxicity outcomes after RT by acting individually (rs8193), by gene-gene interactions (MAT1A and CD44), and/or by the additive effects of risk alleles.

We will propose that Merge is not freely applicable. Its application is strictly restricted regarding selectional restriction, i.e. feature matching. In this article, it will be shown that a category, C strictly fi nds a suitable partner in the process of operation: Merge. In its application, Tensed nominals can be considered which are observed across language families in the world. That implies that the phenomenon seems to stem from a mechanism universally. We will fi nd some characteristics of Tensed nominals. Then, we will argue that a parallelism between nominal structures and clauses is attested.

In recent years, advanced radiation therapy techniques, including stereotactic body radiotherapy and carbon‑ion radiotherapy, have progressed to such an extent that certain types of cancer can be treated with radiotherapy alone. The therapeutic outcomes are particularly promising for early-stage lung cancer, with results that match those of surgical resection. Nevertheless, patients may still experience local tumor recurrence, which might be exacerbated by the acquisition of radioresistance after primary radiotherapy. Notwithstanding the risk of tumors acquiring radioresistance, secondary radiotherapy is used increasingly to treat recurrent tumors. In this context, it appears essential to comprehend the radiobiological effects of repeated photon and particle irradiation and their underlying cellular and molecular mechanisms to achieve the most favorable therapeutic outcome. However, to date, the mechanisms of acquisition of radioresistance in cancer cells have mainly been studied after repeated in vitro X-ray irradiation. In contrast, other critical aspects of radioresistance remain mostly unexplored, including the response to carbon‑ion irradiation of X-ray radioresistant cancer cells, the mechanisms of acquisition of carbon‑ion resistance, and the consequences of repeated in vivo X-ray or carbon‑ion irradiation. In this review, we discuss the underlying mechanisms of acquisition of X-ray and carbon‑ion resistance in cancer cells, as well as the phenotypic differences between X-ray and carbon‑ion resistant cancer cells, the biological implications of repeated in vivo X-ray or carbon‑ion irradiation, and the main open questions in the field.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Additional file 7. Generation and genotyping a P. falciparum mutant line lacking expression of CSP (PfΔcsp). A. The PfΔcsp line was generated using CRISPR/Cas9 methodology. The pfcsp gene was replaced by insertion of a mCherry expression cassette (mCherry under control of the of the constitutive gapdh promoter) using donor-DNA plasmids pLf0086. A schematic representation of the pfcsp locus before and after insertion of the construct showing the location of the restriction sites (A: AvaII), sizes (in bp) of restriction fragments (red for Southern blot analysis), location of primers (p), PCR amplicons and sizes of the fragments (in black) used to analyse correct disruption of the pfcsp and insertion of the mCherry cassette (B, C). HR1, HR2: pfcsp homology (targeting) regions. The figure is not shown to scale. Primer sequences can be found in Additional file 8. B. Diagnostic PCR confirming correct integration of the mCherry cassette into the PfCSP locus. 5′ integration PCR (lane 2; primers p15/p19); pfcsp open reading frame (lane 3; primers p17/p18); P. falciparum sequestrin as a control gene (lane 1; primers p22/p23); mCherry gene (lane 4; primers P20/P21) of cloned parasites of PfΔcsp (cl3) and WT. C. Southern blot analysis of AvaII/XhoI restricted DNA of WT and PfΔcsp parasites confirms the specific integration of the mCherry cassette into the pfcsp gene locus. DNA was hybridized with a probe targeting the homology region 2 (upper panels; HR2; primers p3/p4; see (A) of pfcsp. The hybridization pattern observed with the HR2 probe identified the expected different-sized DNA fragments in WT and pf-pvcsp parasites (2057 bp and 4105 bp). In addition to show absence of donor-DNA plasmid and presence of single cross-over events DNA was hybridized with a probe for the ampicillin gene (lower panels; intermediate donor-DNA plasmid pLf0040 digested with AatII and PvuI).

Additional file 2. List of primers used in this study.

Cancer patients without metastasis are generally considered as candidates for curative localized radiation therapy. However, while the benefits of localized radiation have been demonstrated by many clinical studies, recurrences or distant metastases that develop after local treatment remain a major therapeutic challenge. Several in vitro and in vivo studies have reported that irradiation may subsequently alter tumor aggression by reducing or promoting the invasiveness of the remaining cancer cells after radiation, which appears to differ depending on the form of radiation, as well as the investigated cell lines. Cell lines recapitulate cancer heterogeneity based on the characteristics reflected in their genetic abnormalities, and thus can be used as a tool to investigate the genetic basis of cancer aggression. Importantly, molecular insights into this process would allow us to tailor drug treatments for use in combination with local radiation treatment. This review summarizes the diverse responses of cancer cell invasiveness induced by radiation, and discusses the possible molecular pathways and the genetic variations that may affect radiation-altered invasion.

Although various mechanisms have been inferred for combinatorial actions of multiple carcinogens, these mechanisms have not been well demonstrated in experimental carcinogenesis models. We evaluated mammary carcinogenesis initiated by combined exposure to various doses of radiation and chemical carcinogens. Female rats at 7 weeks of age were gamma-irradiated (0.2–2 Gy) and/or exposed to 1-methyl-1-nitrosourea (20 or 40 mg/kg, single intraperitoneal injection) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (40 mg/kg/day by gavage for 10 days) and were observed until 50 weeks of age. The incidence of mammary carcinoma increased steadily as a function of radiation dose in the absence of chemicals; mathematical analysis supported an additive increase when radiation was combined with a chemical carcinogen, irrespective of the chemical species and its dose. Hras mutations were characteristic of carcinomas that developed after chemical carcinogen treatments and were overrepresented in carcinomas induced by the combination of radiation and MNU (but not PhIP), indicating an interaction of radiation and MNU at the level of initiation. The expression profiles of seven classifier genes, previously shown to distinguish two classes of rat mammary carcinomas, categorized almost all examined carcinomas that developed after individual or combined treatments with radiation (1 Gy) and chemicals as belonging to a single class; more comprehensive screening using microarrays and a separate test sample set failed to identify differences in gene expression profiles among these carcinomas. These results suggest that a complex, multilevel interaction underlies the combinatorial action of radiation and chemical carcinogens in the experimental model.

Background: A total of 10%–20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. Methods: We conducted an individual patient data meta-analysis of six genome-wide association studies (n=3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 X E-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n=962). All statistical tests were two-sided. Results: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 X E-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 X E-10), and rs11122573 with hematuria (Pmeta = 1.8 X E-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 X E-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent.

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We report $^{133}$Cs NMR and $^{75}$As Nuclear Quadrupole Resonance (NQR) measurements on the normal metallic state above $T_c$ of a quasi-one-dimensional superconductor Cs$_2$Cr$_3$As$_3$ ($T_c < 1.6$~K). From the $^{133}$Cs NMR Knight shift $^{133}K$ measured at the Cs1 site, we show that the uniform spin susceptibility $\chi_{spin}$ increases from 295~K to $\sim$ 60~K, followed by a mild suppression; $\chi_{spin}$ then levels off below $\sim$10~K. In contrast, a vanishingly small magnitude of $^{133}K$ indicates that Cs2 sites contribute very little to electrical conduction and the exchange interactions between 3d electrons at Cr sites. Low frequency Cr spin dynamics, reflected on $^{75}$As $1/T_1T$ (the nuclear spin-lattice relaxation rate $1/T_1$ divided by temperature $T$), shows an analogous trend as $\chi_{spin}$. Comparison with the results of $1/T_1T$ near $T_c$ with Rb$_2$Cr$_3$As$_3$ ($T_c=6.1$~K) and Rb$_2$Cr$_3$As$_3$ ($T_c=4.8$~K) establishes a systematic trend that substitution of K$^{+}$ ions with larger alkali ions progressively suppresses Cr spin fluctuations together with $T_c$., Comment: Final accepted version with 11 Figures

Local spectral functions and Nuclear Magnetic Relaxation (NMR) rates, 1/T1, for the spin-half Heisenberg antiferromagnet on the Kagome Lattice are calculated using Moriyas Gaussian approximation, as well as through an extrapolation of multiple frequency moments. The temperature dependence of the calculated rates is compared with the oxygen 1/T1 NMR data in Herbertsmithite. We find that the Gaussian approximation for 1/T1 shows behavior qualitatively similar to experiments with a sharp drop in rates at low temperatures, consistent with a spin-gapped behavior. However, this approximation significantly underestimates the magnitude of 1/T1 even at room temperature. Rates obtained from extrapolation of multiple frequency moments give very good agreement with the room temperature NMR data with J = 195 +/- 20 K and hyperfine couplings determined independently from other measurements. The use of multiple frequency moments also leads to additional low frequency weight in the local structure factors. The convergence of our calculations with higher frequency moments breaks down at low temperatures suggesting the existence of longer range dynamic correlations in the system despite the very short-range static correlations., Comment: 5 pages 4 figures

Gastrointestinal symptoms, such as abdominal pain and diarrhea, are frequently observed in patients with Plasmodium falciparum malaria. However, the correlation between malaria intestinal pathology and intestinal microbiota has not been investigated. In the present study, infection of C57BL/6 mice with P. berghei ANKA (PbA) caused intestinal pathological changes, such as detachment of epithelia in the small intestines and increased intestinal permeability, which correlated with development with experimental cerebral malaria (ECM). Notably, an apparent dysbiosis occurred, characterized by a reduction of Firmicutes and an increase in Proteobacteria. Furthermore, some genera of microbiota correlated with parasite growth and/or ECM development. By contrast, BALB/c mice are resistant to ECM and exhibit milder intestinal pathology and dysbiosis. These results indicate that the severity of cerebral and intestinal pathology coincides with the degree of alteration in microbiota. This is the first report demonstrating that malaria affects intestinal microbiota and causes dysbiosis.

Purpose: Our previous report indicated that carbon ion beam irradiation upregulated immunogenic, underlining the potential clinical application of radioimmunotherapy. The antimetastatic efficacy of a local combination therapy of carbon-ion radiotherapy and immunotherapy was examined using in vivo murine model. Methods and Materials: Tumors of the mouse squamous cell carcinoma (NR-S1) cells inoculated in the leg of C3H/HeMsNrs mice were locally irradiated with a single 6 Gy dosage of carbon ions (290 MeV/nucleon, 6 cm spread-out Bragg peak). Thirty-six hours after irradiation, alpha-galactosylceramide (alpha-GalCer)-pulsed dendritic cells (DCs) were injected into the leg tumor. The effects on distant lung metastases were investigated using pathological observations and immunohistochemistry. Results: The mice in the control group, which were not irradiated and not injected with alpha-GalCerpulsed DCs, had 168 +/- 53.8 metastatic nodules in their lungs at 2 weeks. The lung metastases were significantly decreased in the mouse which received the combination therapy, and the mean number of lung metastatic nodules was 2.6 +/- 1.9 (P = 0.009). In addition, the size of each lung metastasis was significantly decreased in compared to the control group (P = 0.009). Immunohistochemistry showed that ICAM-1, which activates DCs, was highly expressed on the local tumors of the carbon ionirradiated group. The expression of S100A8 in lung tissue, a marker of the lung pre-metastatic phase, was decreased in the combination therapy group. Conclusion: The combination of carbon ion radiotherapy with the injection of alpha-GalCer-pulsed DCs into the primary tumors significantly decreased the number of lung metastases.

BACKGROUND: The authors previously demonstrated that fibroblast growth factor 2 (FGF2) expression levels in tumor cells (FGF2-T) may be an indicator of the efficacy of radiotherapy in patients with cervical cancer (CC). In the current study, this finding was extended in newly enrolled patients and was investigated further in stromal FGF2 (FGF2-S) expression. METHODS: Sixty-nine patients with CC were recruited as a validation set for the immunohistochemical detection of FGF2-T from biopsy samples that were taken before (pretreatment) or 1 week after the initiation of radiotherapy (midtreatment). The authors also investigated the expression of FGF2 in tumor FGF2-S and investigated vascular endothelial growth factor (VEGF), and cluster of differentiation 31 (CD31) (also called platelet endothelial cell adhesion molecule) in these patients and in an additional 35 patients from a previous study. RESULTS: FGF2 expression was detected in tumor cells from all patients and in stromal cells from 87% of patients. FGF2-T was significantly higher in midtreatment samples (P = .0002), and a high ratio of midtreatment/pretreatment FGF2-T was related significantly to a better prognosis (P = .025). Increased VEGF expression after the initiation of radiotherapy was related significantly to positive FGF2-S in pretreatment samples (P = .035); however, it was not related to prognosis or microvessel density detected by CD31 expression. CONCLUSIONS: Radiation causes a response in tumor cells and adjacent normal cells and changes the extracellular matrix environment. In this study, the authors confirmed their previous findings and demonstrated that changes in FGF2-T expression may be used as a marker to monitor the effectiveness of radiotherapy in patients with CC. These findings should improve patient selection for molecular targeted therapies, such as cytokine inhibitors, after standard-of-care treatment. Cancer 2010. © 2010 American Cancer Society.

Purpose: To elucidate the mechanism underlying the in vivo radioprotection activity by Zn-containing, heat-treated Saccharomyces cerevisiae yeast (Zn-yeast). Materials and Methods: Zn-yeast suspension was administered into C3H/He mice immediately after WBI at 7.5 Gy. Bone marrow was extracted from the mice 6 hours after irradiation and analyzed on a microarray. Expression changes in the candidate responsive genes differentially expressed in treated mice were re-examined by qRT-PCR. The bone marrow was also examined pathologically at 6 h, 3, 7, and 14 days postirradiation. Results: Thirty-six genes, including Edn1 and Agpt2, were identified as candidate responsive genes in irradiated mouse bone marrow treated with Zn-yeast by showing a greater than three-fold change compared with control (no irradiation and no Zn-yeast) mice. The expressions of Cdkn1a, Bax, and Ccng, which are well known as radioresponsive genes, were upregulated in WBI mice and Zn-yeast treated WBI mice. Pathological examination showed the newly formed microvessels lined with endothelial cells, and small round hematopoietic cells around vessels in bone marrow matrix of mice administered with Zn-yeast after WBI, while whole-body irradiated mice developed fatty bone marrow within 2 weeks after irradiation. Conclusion: This study identified a possible mechanism for the postirradiation protection conferred by Zn-yeast. The protective effect of Zn-yeast against WBI is related to maintaining the bone marrow microenvironment, including targeting endothelial cells and cytokine release.

Purpose Ionizing irradiation might induce delayed genotoxic effects in a p53-dependent manner. However, a few reports have shown a p53 mutation as a delayed effect of radiation. In this study, we investigated the p53 gene mutation by the translocation frequency in chromosome 11, loss of p53 alleles, p53 gene methylation, p53 nucleotide sequence, and p53 protein expression/phosphorylation in p53+/+ and p53+/- mice after irradiation at a young age. \nMethods and Materials p53+/+ and p53+/- mice were exposed to 3 Gy of whole-body irradiation at 8 weeks of age. Chromosome instability was evaluated by fluorescence in situ hybridization analysis. p53 allele loss was evaluated by polymerase chain reaction, and p53 methylation was evaluated by methylation-specific polymerase chain reaction. p53 sequence analysis was performed. p53 protein expression was evaluated by Western blotting. \nResults The translocation frequency in chromosome 11 showed a delayed increase after irradiation. In old irradiated mice, the number of mice that showed p53 allele loss and p53 methylation increased compared to these numbers in old non-irradiated mice. In two old irradiated p53+/- mice, the p53 sequence showed heteromutation. In old irradiated mice, the p53 and phospho-p53 protein expressions decreased compared to old non-irradiated mice. \nConclusion We concluded that irradiation at a young age induced delayed p53 mutations and p53 protein suppression.

We successfully isolated the $^{17}$O NMR signals at the planar sites in La$_{1.885}$Sr$_{0.115}$CuO$_4$ ($T_{c}=30$ K) by applying an external magnetic field along the Cu-O-Cu bond direction of a single crystal. We demonstrate that charge order enhances incommensurate Cu spin fluctuations below $T_{charge} \simeq 80$ K., Short Note published in J. Phys. Soc. Jpn

The isolation and multiple genotyping of long individual DNA fragments are needed to obtain haplotype information for diploid organisms. Limiting dilution of sample DNA followed by multiple displacement amplification is a useful technique but is restricted to short (

Evidence has accumulated that ionizing radiation induces biological effects in non-irradiated bystander cells having received signals from directly irradiated cells; however, energetic heavy ion-induced bystander response is incompletely characterized. Here we performed microarray analysis of irradiated and bystander fibroblasts in confluent cultures. To see the effects in bystander cells, each of 1, 5 and 25 sites was targeted with 10 particles of carbon ions (18.3MeV/u, 103keV/mum) using microbeams, where particles traversed 0.00026, 0.0013 and 0.0066% of cells, respectively. diated cells, cultures were exposed to 10% survival dose (D), 0.1D and 0.01D of corresponding broadbeams (108keV/mum). Irrespective of the target numbers (1, 5 or 25 sites) and the time (2 or 6h postirradiation), similar expression changes were observed in bystander cells. Among 874 probes that showed more than 1.5-fold changes in bystander cells, 25% were upregulated and the remainder downregulated. These included genes related to cell communication (PIK3C2A, GNA13, FN1, ANXA1 and IL1RAP), stress response (RAD23B, ATF4 and EIF2AK4) and cell cycle (MYCN, RBBP4 and NEUROG1). Pathway analysis revealed serial bystander activation of G protein/PI-3 kinase pathways. Instead, genes related to cell cycle or death (CDKN1A, GADD45A, NOTCH1 and BCL2L1), and cell communication (IL1B, TCF7 and ID1) were upregulated in irradiated cells, but not in bystander cells. Our results indicate different expression profiles in irradiated and bystander cells, and imply that intercellular signaling between irradiated and bystander cells activate intracellular signaling, leading to the transcriptional stress response in bystander cells.

Purpose: To investigate the genetic risk of late urinary morbidity after carbon ion radiotherapy in prostate cancer patients. Methods and Materials: A total of 197 prostate cancer patients who had undergone carbon ion radiotherapy were evaluated for urinary morbidity. The distribution of patients with dysuria was as follows: Grade 0, 165; Grade 1, 28; and Grade 2, 4 patients. The patients were divided (2:1) consecutively into the training and test sets and then categorized into control (Grade 0) and case (Grade 1 or greater) groups. First, 450 single nucleotide polymorphisms (SNPs) in 118 candidate genes were genotyped in the training set. The associations between the SNP genotypes and urinary morbidity were assessed using Fisher's exact test. Then, various combinations of the markers were tested for their ability to maximize the area under the receiver operating characteristics (AUC-ROC) curve analysis results. Finally, the test set was validated for the selected markers. Results: When the SNP markers in the SART1, ID3, EPDR1, PAH, and XRCC6 genes in the training set were subjected to AUC-ROC curve analysis, the AUC-ROC curve reached a maximum of 0.86. The AUC-ROC curve of these markers in the test set was 0.77. The SNPs in these five genes were defined as "risk genotypes." Approximately 90% of patients in the case group (Grade 1 or greater) had three or more risk genotypes. Conclusions: Our results have shown that patients with late urinary morbidity after carbon ion radiotherapy can be stratified according to the total number of risk genotypes they harbor.

Haplotypes of multiple genes have been reported their association with risk of adverse skin reactions after radiotherapy in breast cancer patients (Int. J. Radiat. Oncol. Biol. 2007, 69, 685-693). In this study, a visible genotyping array device for a total of eight haplotypetagSNPs in two genes (PTTG1 and CD44) among above has been developed using previously established methodology (Anal. Sci. 2006, 22, 1537-1545). The device uses allele-specific extension reaction of covalently immobilized oligonucleotide primer to discriminate nucleotide at SNP site. Each primer oligonucleotide has 3'-end locked acid nucleotide modification to enhance its allelic specificity. Biotin-dUTPs provided in the reaction mixture are selectively incorporated only to the extenting oligonucleotides, enabling their use as tags for following streptavidin-conjugated alkaline phosphatase-mediated colored precipitation of substrates onto the surface of the array. Resulting colored spots on the device can be observed by naked eye and conveniently recorded by a digital camera that is commercially available at reasonable cost. Allelic discrimination of all immobilized oligonucleotides was validated using 45 reference individuals previously genotyped by MassARRAY system. Reliability of genotyping by this device was quantitatively assessed by calculating Silhouette score and resulting scores of all SNPs were proven to be beyond the cut off value of 0.65. The eight haplotype-tagSNPs can be simultaneously analyzed in a single reaction mixture within a couple of hours and multiple samples up to four can be analyzed simultaneously on a single device whose surface area is divided by a water-proof multiwell seal. This visible haplotype-tagSNP typing array device has intended benefits in convenient usage at reasonable cost and thus it would provide easy access for bedside clinical diagnosis of radiation sensitivity.

Background and purpose The management of lymphatic metastasis of early-stage oral tongue carcinoma patients is crucial for its prognosis. The purpose of this study was to evaluate the predictive ability of lymphatic metastasis after brachytherapy (BRT) for early-stage tongue carcinoma based on gene expression profiling. \nPatients and methods Pre-therapeutic biopsies from 39 patients with T1 or T2 tongue cancer were analyzed for gene expression signatures using Codelink Uniset Human 20K Bioarray. All patients were treated with low dose-rate BRT for their primary lesions and underwent strict follow-up under a wait-and-see policy for cervical lymphatic metastasis. Candidate genes were selected for predicting lymph-node status in the reference group by the permutation test. Predictive accuracy was further evaluated by the prediction strength (PS) scoring system using an independent validation group. \nResults We selected a set of 19 genes whose expression differed significantly between classes with or without lymphatic metastasis in the reference group. The lymph-node status in the validation group was predicted by the PS scoring system with an accuracy of 76%. \nConclusions Gene expression profiling using 19 genes in primary tumor tissues may allow prediction of lymphatic metastasis after BRT for early-stage oral tongue carcinoma.

菜種原油からラジカル捕捉活性物質であるCanololを効率的に回収し，精製油に添加することで機能性の優れた新規菜種油を製造することを試みた．Canololの回収法については，回収率が高くリン脂質などの不純物の混入が少ない水蒸気蒸留が適していることがわかった．Canololを高濃度に含む焙煎菜種原油から水蒸気蒸留により回収したものを菜種精製油に添加し評価した結果，酸化安定性および熱安定性は優れていたが，光安定性に若干の問題点があることがわかった．味や香りに関しては，独特の焙煎臭が感じられるが，特に悪いと感じるものではなかった．上述したように揚げ物用油としての可能性のほかに，風味を生かしたテーブルオイルとしての利用にも期待がもたれた．

Since adverse reactions in normal tissues after radiotherapy is a major dose-limiting factor, elucidation of the underlying molecular mechanisms is essential for improvement of radiotherapy. Radiation induced pneumonitis and consequential pulmonary fibrosis are well known as serious and frequent side effects after thoracic radiation therapy. Pneumonitis and consequential pulmonary fibrosis develop dose-dependently several months after irradiation, and their lethal potential impact affect the quality of life of the patients. Even though past clinical reports have indicated lower risk of advanced radiation therapies, especially carbon-ion radiotherapy, it is still an important issue for individual patients. Radiosensitivity varies depending on the genetic-background of individuals, and it is also associated with the severity of radiation-related adverse reactions. We aimed to identify molecular mechanisms, which can become novel targets for prevention or treatment of radiation induced pneumonitis and pulmonary fibrosis. To find biomarkers for prediction of prognosis or molecular targets for treatment of radiation pneumonitis/fibrosis, we performed histological analyses of the lung at different time points in fibrosis-prone (C57BL/6J) and fibrosis-resistant (C3H/He) mice strains and its F1 strain C3B6F1 mice after thoracic irradiation by carbon ion beam. In the mouse model, infiltration of inflammatory cells and mild fibrotic loci were observed in both mouse strains 24 weeks after 10Gy carbon ion irradiation. Interestingly, fibrotic loci developed and expanded, changing the shape of the lung in C57BL/6J mice, but not in C3H/He mice. Our recent analysis clearly highlighted that the type of infiltrated inflammatory cells including neutrophil and macrophage, and the difference in expression of lung remodeling proteins at these fibrotic loci, are critical factors in developing severe fibrosis after irradiation in a strain dependent manner., 15th International Congress of Radiation Research (ICRR 2015)

Carbon-ion (C-ion) radiotherapy (RT) is an advanced effective RT in tumors that are difficult to be cured by conventional RT due to its biological properties and excellent dose distribution. Although C-ion radiotherapy has shown good outcomes, metastasis control is an important matter as with any type of cancer treatment. There are some reports that C-ion irradiation tends to suppress metastasis or relevant abilities at in vitro and in vivo models. However, the underlying mechanisms are still not clearly understood. To improve C-ion RT, we aimed to find an optimal combination therapy for C-ion radiotherapy to prevent distant metastasis. In this study, we evaluated dendritic cells (DCs) immunotherapy, as a partner for C-ion radiotherapy. We used mouse allograft models using four mouse cancer cell lines (NR-S1, LM8, LLC and Colon26) and three mouse strains (C3H/He, C57BL/6J and BALB/c) under conditions that there were no significant effects on growth of transplanted tumor by the C-ion treatments. In NR-S1 or LM8 grafted C3H/He and LLC grafted C57BL/6J models, the number of lung metastasis was significantly decreased by the combined therapy. However, Colon26 grafted BALB/c model did not show the enhancement of metastasis inhibition by the combination treatment. To clarify the mechanisms behind the model difference, we investigated further by comparing LLC grafted C57BL/6J and Colon26 grafted BALB/c models. Dual legs grafted-one leg C-ion irradiation assay clearly demonstrated that local C-ion treatment was able to repress lung metastasis from distal non-irradiated tumor in both models. In contrast, in vitro co-culture assay indicated that C-ion irradiated Colon26 cells were not able to activate iDCs into the mature DCs, whereas LLC cells could. These results indicate that C-ion local irradiation by itself has strong ability to activate metastasis inhibition in the whole body, and genetic background or/and cancer cell type may have potent impact on the efficiency of the combination therapy., 15th International Congress of Radiation Research (ICRR 2015)

Hair cycle resting phase (telogen) hair follicles are known to be more radioresistant than growth phase (anagen) hair follicles. Recently, FGF18 signaling has been reported to maintain the telogen phase of the hair cycle, and also the quiescence of hair follicle stem cells. In contrast, several FGFs can exert radioprotective effects to reduce and improve radiation-induced tissue damage. This study focuses on clarifying the contribution of FGF18 to radioresistance of telogen hair follicles. Irradiation of anagen hair follicles of BALB/c mice with gamma-rays at 6 Gy caused hair follicle dystrophy, resulting in the prominent delay of hair regeneration, whereas irradiation of telogen hair follicles at 6 Gy did not induce the dystrophy even after the post-irradiation plucking. In addition, K15+ stem cells did not decrease in the telogen hair follicles after irradiation, although they prominently decreased in the anagen hair follicles after irradiation. In contrast, FGF receptor inhibitor treatment induced radiation-induced hair follicle dystrophy in the telogen phase, suggesting that FGF signaling plays an important role in the radioresistance of telogen hair follicles. Actually, administration of recombinant FGF18 inhibited the proliferation of hair follicle cells and radiation-induced apoptosis in the hair bulbs, and maintained the number of K15+ stem cells in the bulge after irradiation, so that hair was successfully regenerated after irradiation at 6 Gy in the anagen phase. Moreover, FGF18 treatment drastically reduced DNA double strand breaks in the anagen hair follicle cells 4 h after irradiation, and also decreased the transcript levels of CDK1 and Cyclin B, which play a critical role in the G2/M transition of cell cycle. These findings suggest that FGF18 signaling for hair cycle resting phase causes radioresistance in the telogen hair follicles through the enhancement of DNA repair by the cell-cycle arrest., 15th International Congress of Radiation Research (ICRR 2015)