Discovery of New Isotope

The new isotope ^{241}U was synthesized and systematic atomic mass measurements of nineteen neutron-rich Pa-Pu isotopes were performed in the multinucleon transfer reactions of the ^{238}U+^{198}Pt system at the KISS facility. The present experimental results demonstrate the crucial role of the multinucleon transfer reactions for accessing unexplored neutron-rich actinide isotopes toward the N=152 shell gap in this region of nuclides.

Study of the N=32 and N=34 Shell Gap for Ti and V by the First High-Precision Multireflection Time-of-Flight Mass Measurements at BigRIPS-SLOWRI.

The atomic masses of ^{55}Sc, ^{56,58}Ti, and ^{56-59}V have been determined using the high-precision multireflection time-of-flight technique. The radioisotopes have been produced at RIKEN's Radioactive Isotope Beam Factory (RIBF) and delivered to the novel designed gas cell and multireflection system, which has been recently commissioned downstream of the ZeroDegree spectrometer following the BigRIPS separator. For ^{56,58}Ti and ^{56-59}V, the mass uncertainties have been reduced down to the order of 10 keV, shedding new light on the N=34 shell effect in Ti and V isotopes by the first high-precision mass measurements of the critical species ^{58}Ti and ^{59}V. With the new precision achieved, we reveal the nonexistence of the N=34 empirical two-neutron shell gaps for Ti and V, and the enhanced energy gap above the occupied νp_{3/2} orbit is identified as a feature unique to Ca. We perform new Monte Carlo shell model calculations including the νd_{5/2} and νg_{9/2} orbits and compare the results with conventional shell model calculations, which exclude the νg_{9/2} and the νd_{5/2} orbits. The comparison indicates that the shell gap reduction in Ti is related to a partial occupation of the higher orbitals for the outer two valence neutrons at N=34.

A phase II trial of stereotactic body radiotherapy in 4 fractions for patients with localized prostate cancer.

PURPOSE/OBJECTIVE(S): To report results from our phase II study of stereotactic body radiotherapy (SBRT) delivering 36 Gy in 4 fractions for patients with localized prostate cancer. MATERIALS/METHODS: We enrolled 55 patients treated with SBRT delivering 36 Gy in 4 fractions between 2015 to 2018. All patients were categorized as low-risk (n = 4), intermediate-risk (n = 31) or high-risk (n = 20) according to National Comprehensive Cancer Network criteria. Median age was 73 years (range 54-86 years). Two-thirds of patients (n = 37) had received androgen-deprivation therapy for 3-46 months (median, 31 months). Median duration of follow-up was 36 months (range 1-54 months). We used Radiation Therapy Oncology Group and National Cancer Institute-Common Toxicity Criteria version 4 for toxicity assessments. Quality of life (QOL) outcomes were also evaluated using the Expanded Prostate Cancer Index Composite (EPIC). RESULTS: Protocol treatments were completed for all patients. Six patients experienced biochemical failures. Among these six patients, three patients experienced clinical failure. One patient showed bone metastasis before biochemical failure. One patient died of gastric cancer. The 3-year biochemical control rate was 89.8%. Acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were observed in 5 patients (9%) and 6 patients (11%), respectively. No grade 3 or higher acute toxicities were observed. Late grade 2 GU and GI toxicities were observed in 7 patients (13%) and 4 patients (7%), respectively. Late grade 3 GU and GI toxicities were observed in 1 patient (1.8%) each. EPIC scores decreased slightly during the acute phase and recovered within 3 months after treatment. CONCLUSION: Our phase II study showed that SBRT delivering 36 Gy in 4 fractions was safe and effective with favorable QOL outcomes, although this regimen showed slightly more severe toxicities compared to current standards.

Pathway for the Production of Neutron-Rich Isotopes around the N=126 Shell Closure.

Absolute cross sections for isotopically identified products formed in multinucleon transfer in the (136)Xe+(198)Pt system at ∼8 MeV/nucleon are reported. The isotopic distributions obtained using a large acceptance spectrometer demonstrated the production of the "hard-to-reach" neutron-rich isotopes for Z<78 around the N=126 shell closure far from stability. The main contribution to the formation of these exotic nuclei is shown to arise in collisions with a small kinetic energy dissipation. The present experimental finding corroborates for the first time recent predictions that multinucleon transfer reactions would be the optimum method to populate and characterize neutron-rich isotopes around N=126 which are crucial for understanding both astrophysically relevant processes and the evolution of "magic" numbers far from stability.

In-gas-cell laser ion source for KEK isotope separation system.

The KEK isotope separation system (KISS) is an element-selective isotope separator under development at RIKEN. The in-gas-cell laser ion source is a critical component of the KISS, a gas cell filled with argon gas of 50 kPa enclosed in a vacuum chamber. In the gas cell, nuclear reaction products are stopped (i.e., thermalized and neutralized) and transported by a laminar flow of argon to the ionization region just upstream of the gas outlet, and thereby an element of interest among those reaction products is selectively ionized by two-color resonant laser irradiation. Recently, we succeeded to extract laser-ionized Fe ions by injecting an energetic Fe beam into the gas cell. Recent off- and on-line test results were presented and discussed.

Wall-loss distribution of charge breeding ions in an electron cyclotron resonance ion source.

We investigated the ion-loss distribution on the sidewall of an electron cyclotron resonance (ECR) plasma chamber using the 18-GHz ECR charge breeder at the Tokai Radioactive Ion Accelerator Complex (TRIAC). Similarities and differences between the ion-loss distributions (longitudinal and azimuthal) of different ion species (i.e., radioactive (111)In(1+) and (140)Xe(1+) ions that are typical volatile and nonvolatile elements) was qualitatively discussed to understand the element dependence of the charge breeding efficiency. Especially, the similarities represent universal ion loss characteristics in an ECR charge breeder, which are different from the loss patterns of electrons on the ECRIS wall.

Wall-loss distribution of charge breeding ions in an electron cyclotron resonance ion source.

The ion loss distribution in an electron cyclotron resonance ion source (ECRIS) was investigated to understand the element dependence of the charge breeding efficiency in an electron cyclotron resonance (ECR) charge breeder. The radioactive (111)In(1+) and (140)Xe(1+) ions (typical nonvolatile and volatile elements, respectively) were injected into the ECR charge breeder at the Tokai Radioactive Ion Accelerator Complex to breed their charge states. Their respective residual activities on the sidewall of the cylindrical plasma chamber of the source were measured after charge breeding as functions of the azimuthal angle and longitudinal position and two-dimensional distributions of ions lost during charge breeding in the ECRIS were obtained. These distributions had different azimuthal symmetries. The origins of these different azimuthal symmetries are qualitatively discussed by analyzing the differences and similarities in the observed wall-loss patterns. The implications for improving the charge breeding efficiencies of nonvolatile elements in ECR charge breeders are described. The similarities represent universal ion loss characteristics in an ECR charge breeder, which are different from the loss patterns of electrons on the ECRIS wall.

KEKCB electron cyclotron resonance charge breeder at TRIAC.

The KEKCB is an electron cyclotron resonance (ECR) ion source for converting singly charged ions to multicharged ones at Tokai Radioactive Ion Accelerator Complex. By using the KEKCB, singly charged gaseous and nongaseous ions were converted to multicharged ones of A/q approximately 7 with efficiencies of 7% and 2%, respectively. The conversion efficiency was found to be independent of the lifetime of the radioactive nuclei having lifetimes of the order of one second. Three collimators located at the entrance and the exit of the KEKCB defined the beam axis and facilitated beam injection. Grinding and washing the surfaces of aluminum electrode and plasma chamber dramatically reduced impurities originating from the ECR plasma of the KEKCB.

Determination of trace amounts of total arsenic in environmental samples by hydride generation flow injection-AAS using a mixed acid as a pretreatment agent.

A method is described for the determination of total arsenic by hydride generation-atomic absorption spectrophotometry using a mixed acid as a pretreatment. Hydride generation is done by the flow-injection method. The authors investigated in detail the temperature and time of decomposition using inorganic, organic arsenic and environmental standard samples, pretreated with nitric-perchloric-sulfuric mixed acid. By using a mixed acid as a pretreatment agent at 220 degrees C, the decomposition time could be shortened and the blank value of arsenic from the reagents used was reduced. The mixed acid of nitric-perchloric-sulfuric was also found to be effective as a pretreatment agent for organic arsenic compounds in which a dimethylated compound, sodium cacodylate or biological samples, is known to be one of the indecomposables. The present approach was proved to be satisfactory as a pretreatment for the quantitative analysis of trace amounts of total arsenic in liquid or solid environmental samples, such as geothermal water, sediments and biological samples.

Nodulisporic acid A synthetic studies. 1. Overall strategy and construction of a western hemisphere subtarget.

In this, the first of two Letters, we outline our overall strategy for the construction of (+)-nodulisporic acid A (1), a representative member of a new class of indole diterpenes. In addition, we describe the efficient assembly of (-)-6, an advanced western hemisphere subtarget, comprising the ABC rings of (+)-nodulisporic acid A (1). The synthesis proceeded in 9% overall yield (longest linear sequence, 11 steps), exploiting a Shibasaki-Mori tandem transmetalation-cyclization to construct ring B. [reaction: see text]

Nodulisporic acid A synthetic studies. 2. Construction of an eastern hemisphere subtarget.

In this, the second of two Letters, we describe an effective assembly of (+)-4, an eastern hemisphere subtarget comprising the FGH rings of (+)-nodulisporic acid A (1) (17 steps, 9% overall yield). Central to the synthesis is a Koga three-component conjugate addition-alkylation sequence which secures the trans orientation of the vicinal quaternary methyl groups. [reaction: see text]

Development and characterization of a hybrid bioartificial liver using primary hepatocytes entrapped in a basement membrane matrix.

For the development of a bioartificial liver (BAL) support device, it is most important to establish highly differentiated liver cells cultured at high density. When rat hepatocytes were cultured on a basement membrane matrix, Engelbreth-Holm-Swarm (EHS) gel, their rates of albumin secretion were very high, as measured by ELISA, and these high rates were maintained for more than three weeks of culturing. This level of activity greatly exceeded that of hepatocytes cultured on a plastic substratum, poly-N-p-vinylbenzyl-D-lactonamide (PVLA), on a single layer of collagen, or in a collagen sandwich culture. In an in vitro perfusion experiment, rat hepatocytes rapidly and completely removed ammonia from Eagle's MEM supplemented with 0.2 mM NH4Cl, although ammonia levels of the medium serially increased in modules containing HepG2 cells. A hybrid liver support system was developed and consisted of plasma perfusion through porous hollow fiber modules inoculated with 10 billion porcine hepatocytes entrapped in EHS gel. This system was applied to pigs with ischemic liver failure 8 hr after creation of a portocaval shunt and hepatic devascularization. In animals treated with the BAL support system, blood bicarbonate levels were increased immediately after treatment, and hemodynamic stability was improved. In control pigs, on the other hand, blood bicarbonate levels and blood pressure remained low. Plasma levels of ammonia and lactate decreased in pigs treated with the BAL device, but not in control animals. These results indicate that primary hepatocytes outperform HepG2 cells as a source of biotransformation functions in a BAL system and that the use of a BAL support device in combination with a hollow fiber module and hepatocytes entrapped in EHS gel has potential advantages for clinical use in patients with fulminant hepatic failure.

Rebamipide suppresses formyl-methionyl-leucyl-phenylalanine (fMLP)-induced superoxide production by inhibiting fMLP-receptor binding in human neutrophils.

The purpose of the present work was to investigate the mechanism underlying the inhibitory action of rebamipide on superoxide anion (O2) production induced by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP) in human neutrophils. Phosphatidylinositol 3,4,5-trisphosphate (PIP(3)), a product of phosphoinositide 3-OH-kinase (PI 3-kinase) accumulated in response to fMLP and this accumulation was well correlated with O2 production in human neutrophils. Rebamipide inhibited PIP(3) production in parallel with the inhibition of fMLP-induced O2 production. PI 3-kinase activity in anti-PI 3-kinase p85 immunoprecipitates was not affected by the presence of rebamipide, therefore rebamipide did not have a direct inhibitory action on PI 3-kinase activity. Since rebamipide had no inhibitory effect on O2 production induced by NaF, a direct activator of G protein, the target of the inhibitory action of rebamipide appears to be a component of the signal transduction pathway upstream of G protein. Scatchard analysis of [3H]fMLP binding to human neutrophil membrane revealed that rebamipide increased the K(D) value of [3H]fMLP without altering the number of [3H]fMLP binding sites, suggesting that rebamipide has a competitive antagonistic action against the fMLP-receptor. The competitive antagonistic action was further confirmed by the finding that rebamipide caused a parallel shift to the right in the dose-response curve of O2 production induced by fMLP. These results provide evidence that the competitive inhibitory action of rebamipide on the fMLP-receptor plays a main role in its inhibitory action on fMLP-induced O2 production.

Diethyldithiocarbamate enhances production of nitric oxide and TNF-alpha by lipopolysaccharide-stimulated rat Kupffer cells.

Previous studies have shown that large doses of diethyldithiocarbamate (DDC) cause liver injury in rats and the pathogenesis of this injury involves, in part, release of superoxide anion by Kupffer cells. The purpose of this study was to evaluate if DDC was able to stimulate other potentially toxic mediators such as nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) using isolated rat Kupffer cells. DDC alone did not stimulate the release of NO and TNF-alpha by Kupffer cells. Interestingly, when Kupffer cells were stimulated by lipopolysaccharide (LPS), DDC (0-30 microM) enhanced the production of both NO and TNF-alpha in a concentration-dependent manner. Therefore, we further studied how DDC modulated the response of Kupffer cells to LPS. Immunocytochemical studies revealed that DDC increased the amount of inducible NO synthase and TNF-alpha protein in Kupffer cells after their exposure to LPS. The enhanced effects of DDC on the release of NO and TNF-alpha from Kupffer cells was inhibited by N-acetyl-L-cysteine (an inhibitor of transcription factor NF-kappaB activation). By using a specific antibody for NF-kappaBp65, it was found that DDC enhanced the LPS-activated nuclear translocation of NF-kappaB. There was no evidence of intracellular oxidative stress following either LPS alone or DDC + LPS exposure. The stimulatory effect of DDC on both NO and TNF-alpha release was inhibited by H-7 (an inhibitor of protein kinase C) but not H-8 (an inhibitor of cAMP-dependent protein kinase). These findings demonstrate that DDC enhances the production of NO and TNF-alpha by LPS-stimulated Kupffer cells and suggest that protein kinase C plays a critical role in mediating these effects of DDC.

Histopathological changes induced by zinc hydroxide in rat lungs.

Rat lungs were histologically examined at 1, 7, 14 and 28 days following a single intratracheal instillation of zinc hydroxide (1 mM). After one day of treatment, no confirmatory findings were noted. The zinc hydroxide injections were followed by an increase in proliferating cell nuclear antigen labeling indices in both alveolar macrophages and terminal bronchioles. After 7 days, the zinc hydroxide-treated lungs showed thickening of the interstitium with infiltration by alveolar macrophages, and an increase in the grade of Masson's trichrome staining (collagen fiber) in the alveolar interstitium. Thereafter, these morphological changes disappeared. The vehicle- and zinc sulfate (1 mM)-exposed lungs had no abnormalities at any time point. Formazan deposits in alveolar macrophages, formed as a result of nitro blue tetrazolium reduction, were increased in zinc hydroxide-treated lung slices, suggesting that zinc hydroxide stimulated super oxide anion generation from alveolar macrophages. These results show that zinc hydroxide can induce morphological alterations of rat lungs.

Proliferation of hepatocytes and attenuation from carbon tetrachloride hepatotoxicity by gadolinium chloride in rats.

Intravenous injection of gadolinium chloride (GdCl3) at a dose of 10 mg/kg caused an increase in proliferating cell nuclear antigen labeling index and the grade of pyronin positivity (RNA level) in rat liver. In CCl4-exposed rats, pretreatment with GdCl3 also showed a preventive effect of the liver injury both biochemically and histologically. Moreover, the proliferative action preceded the attenuative effect of the liver injury. Results suggest that GdCl3 induces hepatocyte proliferation, and this action of GdCl3 may modify the development of CCl4-induced liver injury.

Structure-activity relationship of bromoeudistomin D, a powerful Ca2+ releaser in skeletal muscle sarcoplasmic reticulum.

Bromoeudistomin D and 9-methyl-7-bromoeudistomin D which have a beta-carboline skeleton are powerful Ca2+ releasers from skeletal muscle sarcoplasmic reticulum exhibiting caffeine-like properties. We examined the effects of bromoeudistomin D analogues on Ca(2+)-induced Ca2+ release from skeletal muscle sarcoplasmic reticulum. Among bromoeudistomin D analogues, the Ca(2+)-releasing activities of carboline derivatives were higher than those of carbazole derivatives, suggesting that a carboline skeleton is significantly important for the manifestation of Ca(2+)-releasing activity and Ca2+ sensitivity of Ca(2+)-induced Ca2+ release. On the contrary, the analogues which have a carbazole skeleton and bromine at C-6 inhibit both Ca(2+)- and caffeine-induced Ca2+ release. 9-Methyl-substitution of the analogue elevated its Ca(2+)-releasing activity. Moreover, there is a close correlation between the enhancement of [3H]ryanodine binding to sarcoplasmic reticulum by the analogues and the activation of Ca2+ release by them. Bromoudistomin D analogues may provide valuable information about the structure-function relationship of the ryanodine receptor/Ca2+ release channels in skeletal muscle sarcoplasmic reticulum.

Role of Kupffer cells in rat liver injury induced by diethyldithiocarbamate.

The hepatotoxicity of diethyldithiocarbamate was examined using an in vitro rat liver slice system. Concentration- and time-dependent losses of intracellular K+ and adenosine triphosphate (ATP) levels were observed in rat liver slices incubated with diethyldithiocarbamate at concentrations between 1 and 10 mM over a 4-h period. Histological study revealed perivenous hepatocyte damage. To examine the involvement of Kupffer cells in diethyldithiocarbamate-induced cytotoxicity, rats were injected intravenously with 10 mg/kg of gadolinium chloride (GdCl3) which diminishes Kupffer cell function. Incubation of liver slice preparations from the GdCl3-treated rats with diethyldithiocarbamate showed marked inhibition of the cytotoxicity induced by diethyldithiocarbamate. Moreover, in vitro addition of manganese-superoxide dismutase, a superoxide anion scavenger, or dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, also showed potent inhibition. However, dexamethasone, an inhibitor of tumor necrosis factor, and N,N'-diphenyl-p-phenylenediamine (DPPD), an antioxidant, showed partial prevention of cytotoxicity. Formazan deposits formed as a result of nitro blue tetrazolium reduction were found in Kupffer cells at an early stage after diethyldithiocarbamate treatment, while lipid peroxidation occurred after 3 h. Both pretreatment with GdCl3 in vivo and addition of DMSO in vitro prevented the increase in lipid peroxidation within the liver slice preparations induced by diethyldithiocarbamate. These findings suggest that Kupffer cell function may be involved in the pathogenesis of diethyldithiocarbamate hepatotoxicity.

Zinc hydroxide induced respiratory burst in rat neutrophils.

The effects of zinc hydroxide on the respiratory burst and phagocytosis by rat neutrophils were examined. Zinc hydroxide induced an increase in oxygen consumption and O2- production. Electronmicroscopy showed that neutrophils engulfed zinc hydroxide particles by phagocytosis. Pertussis toxin (0.25, 0.5, 1.0 micrograms/ml) and EGTA (1, 2, 5 mM) inhibited zinc hydroxide-induced O2- production in a dose-dependent manner. The inhibitors of protein kinase C, 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine and N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide inhibited zinc hydroxide-induced O2- production with IC50 values ranging between 10 microM and 25 microM. The inhibitory study using an inhibitor of myosin light chain kinase, 1-(5-iodo-naphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine, showed IC50 values ranging from 5 microM to 10 microM. These findings indicate that zinc hydroxide induces respiratory burst and phagocytosis by rat neutrophils.