Commissioning of high current H+/D+ ion beams for the prototype accelerator of the International Fusion Materials Irradiation Facility.

The Linear IFMIF (International Fusion Materials Irradiation Facility) Prototype Accelerator (LIPAc) is aiming at demonstrating the low energy section of a 40 MeV/125 mA IFMIF deuteron accelerator up to 9 MeV with a full beam current in cw operation. For such a high-power beam, the LIPAc injector is required to produce a 100 keV D+ beam with 140 mA and match it for injection into the Radio Frequency Quadrupole (RFQ) accelerator. The injector is designed by CEA-Saclay based on the high intensity light ion source (SILHI). In 2019, the commissioning of the RFQ to demonstrate the D+ beam acceleration at a low duty cycle (0.1%) was conducted. A nominal beam current of 125 mA D+ beam was accelerated up to 5 MeV through the RFQ successfully. The LIPAc injector fully satisfied the requirements for RFQ beam commissioning at the pulse mode.

High flux circularly polarized gamma beam factory: coupling a Fabry-Perot optical cavity with an electron storage ring.

We report and discuss high-flux generation of circularly polarized γ-rays by means of Compton scattering. The γ-ray beam results from the collision of an external-cavity-enhanced infrared laser beam and a low emittance relativistic electron beam. By operating a non-planar bow-tie high-finesse optical Fabry-Perot cavity coupled to a storage ring, we have recorded a flux of up to (3.5 ± 0.3) × 108 photons per second with a mean measured energy of 24 MeV. The γ-ray flux has been sustained for several hours. In particular, we were able to measure a record value of up to 400 γ-rays per collision in a full bandwidth. Moreover, the impact of Compton scattering on the electron beam dynamics could be observed resulting in a reduction of the electron beam lifetime correlated to the laser power stored in the Fabry-Perot cavity. We demonstrate that the electron beam lifetime provides an independent and consistent determination of the γ-ray flux. Furthermore, a reduction of the γ-ray flux due to intrabeam scattering has clearly been identified. These results, obtained on an accelerator test facility, warrant potential scaling and revealed both expected and yet unobserved effects. They set the baseline for further scaling of the future Compton sources under development around the world.

Demonstration of the stabilization technique for nonplanar optical resonant cavities utilizing polarization.

Based on our previously developed scheme to stabilize nonplanar optical resonant cavities utilizing polarization caused by a geometric phase in electromagnetic waves traveling along a twisted path, we report an application of the technique for a cavity installed in the Accelerator Test Facility, a 1.3-GeV electron beam accelerator at KEK, in which photons are generated by laser-Compton scattering. We successfully achieved a power enhancement of 1200 with 1.4% fluctuation, which means that the optical path length of the cavity has been controlled with a precision of 14 pm under an accelerator environment. In addition, polarization switching utilizing a geometric phase of the nonplanar cavity was demonstrated.

The stem cell transcription factor ZFP57 induces IGF2 expression to promote anchorage-independent growth in cancer cells.

Several common biological properties between cancer cells and embryonic stem (ES) cells suggest the possibility that some genes expressed in ES cells might have important roles in cancer cell growth. The transcription factor ZFP57 is expressed in self-renewing ES cells and its expression level decreases during ES cell differentiation. This study showed that ZFP57 is involved in the anchorage-independent growth of human fibrosarcoma HT1080 cells in soft agar. ZFP57 overexpression enhanced, whereas knockdown suppressed, HT1080 tumor formation in nude mice. Furthermore, ZFP57 regulates the expression of insulin-like growth factor 2 (IGF2), which has a critical role in ZFP57-induced anchorage-independent growth. ZFP57 also promotes anchorage-independent growth in ES cells and immortal fibroblasts. Finally, immunohistochemical analysis revealed that ZFP57 is overexpressed in human cancer clinical specimens. Taken together, these results suggest that the ES-specific transcription factor ZFP57 is a novel oncogene.

Experimental validation of a novel compact focusing scheme for future energy-frontier linear lepton colliders.

A novel scheme for the focusing of high-energy leptons in future linear colliders was proposed in 2001 [P. Raimondi and A. Seryi, Phys. Rev. Lett. 86, 3779 (2001)]. This scheme has many advantageous properties over previously studied focusing schemes, including being significantly shorter for a given energy and having a significantly better energy bandwidth. Experimental results from the ATF2 accelerator at KEK are presented that validate the operating principle of such a scheme by demonstrating the demagnification of a 1.3 GeV electron beam down to below 65 nm in height using an energy-scaled version of the compact focusing optics designed for the ILC collider.

Particle therapy for mucosal melanoma of the head and neck. A single-institution retrospective comparison of proton and carbon ion therapy.

PURPOSE: To retrospectively analyze treatment outcomes after particle therapy using protons or carbon ions for mucosal melanoma of the head and neck (HNMM) at the Hyogo Ion Beam Medical Center, as well as to compare proton therapy (PT) and carbon ion therapy (CIT). PATIENTS AND METHODS: Data from 62 HNMM patients without metastasis, treated with PT or CIT between October 2003 and April 2011 were analyzed. Median patient age was 70.5 years (range 33-89 years). Of the total patients, 33 (53 %) had received PT and 29 (47 %) had undergone CIT. Protocols for 65 or 70.2 GyE in 26 fractions were used for both ion types. RESULTS: Median follow-up was 18.0 months (range 5.2-82.7 months). The 1-/2-year overall survival (OS) and local control (LC) rates were 93 %/61 % and 93 %/78 % for all patients, 91 %/44 % and 92 %/71 % for the PT patients and 96 %/62 % and 95 %/59 % for the CIT patients, respectively. No significant differences were observed between PT and CIT. Local recurrence was observed in 8 patients (PT: 5, CIT: 3) and 29 (PT: 18, CIT: 11) experienced distant metastases. Acute reactions were acceptable and all patients completed the planned radiotherapy. Regarding late toxicity, grade 3 or greater events were observed in 5 patients (PT: 3, CIT: 2), but no significant difference was observed between PT and CIT. CONCLUSION: Our single-institution retrospective analysis demonstrated that particle therapy for HNMM achieved good LC, but OS was unsatisfactory. There were no significant differences between PT and CIT in terms of either efficacy or toxicity.

Particle therapy using carbon ions or protons as a definitive therapy for patients with primary sacral chordoma.

OBJECTIVE: This study retrospectively evaluated the efficacy and toxicity of particle therapy using carbon ions or protons for primary sacral chordomas. METHODS: We evaluated 23 patients with primary sacral chordoma treated with carbon ion therapy (CIT) or proton therapy (PT) between July 2005 and June 2011 at the Hyogo Ion Beam Medical Center, Hyogo, Japan. The median patient age was 72 years. 14 patients were treated with 70.4 Gy equivalents (GyE) in 16 fractions and 9 were treated with 70.4 GyE in 32 fractions. CIT was used for 16 patients, and PT was used for 7 patients. RESULTS: The median follow-up period was 38 months. At 3 years, local control (LC), overall survival (OS) and progression-free survival (PFS) for all patients were 94%, 83% and 68%, respectively. The log-rank test revealed that male sex was significantly related to better PFS (p=0.029). No other factors, including dose fractionation and ion type, were significant for LC, OS or PFS. In nine patients, ≥ Grade 3 acute dermatitis was observed, and ≥ Grade 3 late toxicities were observed in nine patients. The 32-fraction protocol reduced severe toxicities in both the acute and late phases compared with the 16-fraction protocol. CONCLUSION: Particle therapy for patients with sacral chordoma showed favourable LC and OS. Severe toxicities were successfully reduced by modifying the dose fractionation and treatment planning in the later treatment era. Thus, this therapeutic modality should be considered useful and safe. ADVANCES IN KNOWLEDGE: This is the first study including both CIT and PT for sacral chordomas.

Effect of inhomogeneity in a patient's body on the accuracy of the pencil beam algorithm in comparison to Monte Carlo.

The pencil beam algorithm (PBA) is reasonably accurate and fast. It is, therefore, the primary method used in routine clinical treatment planning for proton radiotherapy; still, it needs to be validated for use in highly inhomogeneous regions. In our investigation of the effect of patient inhomogeneity, PBA was compared with Monte Carlo (MC). A software framework was developed for the MC simulation of radiotherapy based on Geant4. Anatomical sites selected for the comparison were the head/neck, liver, lung and pelvis region. The dose distributions calculated by the two methods in selected examples were compared, as well as a dose volume histogram (DVH) derived from the dose distributions. The comparison of the off-center ratio (OCR) at the iso-center showed good agreement between the PBA and MC, while discrepancies were seen around the distal fall-off regions. While MC showed a fine structure on the OCR in the distal fall-off region, the PBA showed smoother distribution. The fine structures in MC calculation appeared downstream of very low-density regions. Comparison of DVHs showed that most of the target volumes were similarly covered, while some OARs located around the distal region received a higher dose when calculated by MC than the PBA.

The maneuver to release an incarcerated obturator hernia.

An obturator hernia occurs through the pelvic obturator canal, a rigid ring made up of the underside of the superior pubic ramus and the obturator fascia. Obturator hernias have been associated with a high mortality due to the difficulty in diagnosis and the population in which it occurs. We examined four patients diagnosed with incarcerated obturator hernia, and showed that the strangulated intestine was not necrotic. We flexed the diseased leg calmly and repeatedly with slight rotation toward the outside and slight adduction toward the inside at supine position. The pain vanished suddenly during this maneuver. After this maneuver, the patients were able to undergo elective surgery after a certain interval. We discuss the possible use of this maneuver to release an incarcerated obturator hernia.

Induction of sodium iodide symporter gene and molecular characterisation of HNF3 beta/FoxA2, TTF-1 and C/EBP beta in thyroid carcinoma cells.

Thyroid carcinoma cells often do not express thyroid-specific genes including sodium iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (TG), and thyrotropin-stimulating hormone receptor (TSHR). Treatment of thyroid carcinoma cells (four papillary and two anaplastic cell lines) with histone deacetylase inhibitors (SAHA or VPA) modestly induced the expression of the NIS gene. The promoter regions of the thyroid-specific genes contained binding sites for hepatocyte nuclear factor 3 beta (HNF3 beta)/forkhead box A2 (FoxA2), thyroid transcription factor 1 (TTF-1), and CCAAT/enhancer binding protein (C/EBP beta). Quantitative reverse transcription-polymerase chain reaction (RT-PCR) showed decreased expression of HNF3 beta/FoxA2 and TTF-1 mRNA in papillary thyroid carcinoma cell lines, when compared with normal thyroid cells. Forced expression of these genes in papillary thyroid carcinoma cells inhibited their growth. Furthermore, the CpG island in the promoter region of HNF3 beta/FoxA2 was aberrantly methylated; and treatment with 5-aza-2-deoxycytidine (5-Az) induced its expression. Immunohistochemical staining showed that C/EBP beta was localised in the nucleus in normal thyroid cells but was detected in the cytoplasm in papillary thyroid carcinoma cells. Subcellular fractionation of papillary thyroid carcinoma cell lines also demonstrated high levels of expression of C/EBP beta in the cytoplasm, suggesting that a large proportion of C/EBP beta protein is inappropriately localised in the cytoplasm. In summary, these findings reveal novel abnormalities in thyroid carcinoma cells.

Preservation of ultrastructure and immunoreactivity in cryosections of brain tissue stored in a sucrose-gelatin solution at freezing temperatures.

We evaluated the preservation of ultra-structure and immunoreactivity in cryosections of central nervous system tissue mounted with and stored in a sucrose-gelatin solution for one month at -20 degrees C or -80 degrees C. The ultra-structure of synaptic structure in these sections was well preserved and comparable to that of freshly cut cryosections. Quantitative analysis of mitochondrial ultra-structure demonstrated gradually lower degrees of preservation in sections stored at -20 degrees C and -80 degrees C compared with that in freshly cut sections. We observed distinct metabotropic glutamate receptor 1 (mGluR1)-immunogold labelling at peri-synaptic sites in freshly cut sections and also in those stored at -20 degrees C and -80 degrees C. Quantitative analysis of mGluR1 immunoreactivity revealed that the total number of immunogold particles per synapse and the number of non-specifically bound particles were similar under all three conditions. However, the percentage of gold particles bound to a specific synaptic region was greatest in freshly cut sections (79.0%) and progressively lower in sections stored at -20 degrees C (76.1%), in which sections were not frozen, and in sections stored at -80 degrees C (68.0%). These data indicate that ultra-thin cryosections may be conveniently stored in a sucrose-gelatin solution at -20 degrees C for cryoultramicrotomy-immunolabelling.

The Ras-MAPK pathway downregulates Caveolin-1 in rodent fibroblast but not in human fibroblasts: implications in the resistance to oncogene-mediated transformation.

Normal human diploid fibroblasts (HDFs) are refractory to oncogene-mediated transformations in vitro, compared with rodent fibroblasts. As successful oncogene-mediated transformations of normal HDFs have been reported using the human telomerase catalytic subunit, it has been considered that telomerase activity contributes to the species-specific transformability. However, these transformed HDFs are much less malignant compared with those of rodent cells, suggesting the existence of undefined mechanisms that render HDFs resistant to malignant transformation. Here, cDNA microarray analysis identified caveolin-1 as one of the possible cellular factors involved in such mechanisms. The mitogen-activated protein kinases (MAPK) pathway downregulates Caveolin-1 in rodent fibroblasts, transformed by coexpression of the SV40 early region and activated H-Ras. In contrast, the coexpression of these two oncogenes in HDFs failed to reduce the expression level of Caveolin-1. These results strongly suggest the presence of critical differences in events following the phosphorylation of ERK during the activation process of the MAPK signaling pathway between human and rodent cells, as the ERK protein was similarly phosphorylated in both systems. Furthermore, the small interfering RNA-mediated suppression of Caveolin-1 facilitated the oncogene-mediated transformation of normal HDFs, clearly indicating that the differences in the transformability between human and rodent cells are due, at least in part, to the mechanism responsible for the resistance to Ras-induced Caveolin-1 downregulation in HDFs.

Scatter factors in proton therapy with a broad beam.

In the absence of a predictor of beam output in proton therapy using a broad beam, the beam output is obtained for individual treatments by calibrating the beam monitors. The calibration is carried out under conditions similar to the treatment conditions but with a phantom instead of the patient. However, the dose in the phantom a priori differs from that in the patient. In order to deliver the accurate dose, a correction factor has been introduced to correct the difference. This correction factor is referred to as a scatter factor in an analogy with photon therapy, and is defined as the ratio of the dose at the prescription point in the patient to the dose at the calibration point in the phantom. Under the calibration conditions at Hyogo Ion Beam Medical Center (HIBMC), the range compensator and the collimator, which are usually required in proton therapy with a broad beam, are not used. Therefore the scatter factor includes the effects of the devices as well as the difference between the dose in the patient and that in the phantom. We have developed an estimator using a dose calculation based on the pencil beam algorithm and implemented it in a treatment planning system (TPS) for clinical use. This estimator estimates the scatter factor by calculating the ratio of the doses under the same conditions in the TPS. In order to evaluate the performance of the estimator, demonstrations were carried out for cases with measurable outcomes using a gantry nozzle at HIBMC. We observed 2-3% differences between the measurements and the estimations. These differences were considered to result from the limitations of the dose calculation algorithm in modelling the beam and the patient.

Interventions in Kawasaki disease.

During the past 10 years, the clinical experience of catheter interventional treatment in Kawasaki disease has gradually increased. These treatments include balloon angioplasty, stent implantation, rotational ablation, and transluminal coronary revascularization. Because coronary artery stenosis in Kawasaki disease commonly involves severe calcification, in contrast with adult atherosclerotic coronary artery lesions, the indication or technique of catheter intervention for adult patients cannot be directly determined. Satisfactory acute results for coronary balloon angioplasty were obtained in patients in a relatively short interval from the onset of disease, especially within 6 years. However, the incidence of restenosis after angioplasty was still high. Rotational ablation may be the most appropriate catheter intervention for Kawasaki disease. The advantage of rotational ablation is the high success rate, even in patients with calcified coronary artery stenosis. Stent implantation requires larger arterial access and is not possible in younger children. Care should be paid to the detection of new aneurysm formation because this was associated with the use of additional balloon angioplasty using high-pressure balloon inflation. Anticoagulation or antiplatelet regimens are essential for long-term management.

A new cytochemical method for ultrastructural localization of Co2+ in rat hippocampal CA1 pyramidal neurons in vitro.

This paper describes new cytochemical method for the ultrastructural localization of Co(2+) following blockade of synaptic transmission. In the CA1 region of rat hippocampal slices, electrical stimulation of the Schaffer collaterals elicited field excitatory postsynaptic potentials (fEPSPs). The fEPSPs were completely blocked within 2 min after the addition of Co(2+) (2 mM). The slice was then fixed and precipitated Co(2+) was examined by means of a solution containing 2.5% glutaraldehyde and 10 mM K(3)[Fe(3+)(CN)(6)] in 90 mM NaCl. Electron spectroscopic imaging confirmed Co in the precipitate. The precipitates were found as clusters on the membranes of the fine apical dendrites and their spine heads of CA1 pyramidal neurons. No clustered precipitate was found when slices were treated: (1) without Co(2+); (2) after recovery from the Co(2+)-induced blockade of fEPSPs; (3) without electrical stimulation of the Schaffer collaterals; and (4) with dl-2-amino-5-phosphonopentanoate and 6-cyano-7-nitroquinoxaline-2,3-dione. After administrating glutamate (5 mM) in the presence of tetrodotoxin (1 microM) and Co(2+), precipitates were found on dendritic membranes and spine heads. These results indicate that the Schaffer collaterals stimulation induces the binding of Co(2+) on CA1 pyramidal neuron membrane.

Mitochondrial protease Omi/HtrA2 enhances caspase activation through multiple pathways.

Omi/HtrA2 is a mitochondrial serine protease that is released into the cytosol during apoptosis and promotes cytochrome c (Cyt c)dependent caspase activation by neutralizing inhibitor of apoptosis proteins (IAPs) via its IAP-binding motif. The protease activity of Omi/HtrA2 also contributes to the progression of both apoptosis and caspase-independent cell death. In this study, we found that wild-type Omi/HtrA2 is more effective at caspase activation than a catalytically inactive mutant of Omi/HtrA2 in response to apoptotic stimuli, such as UV irradiation or tumor necrosis factor. Although similar levels of Omi/HtrA2 expression, XIAP-binding activity, and Omi/HtrA2 mitochondrial release were observed among cells transfected with catalytically inactive and wild-type Omi/HtrA2 protein, XIAP protein expression after UV irradiation was significantly reduced in cells transfected with wild-type Omi/HtrA2. Recombinant Omi/HtrA2 was observed to catalytically cleave IAPs and to inactivate XIAP in vitro, suggesting that the protease activity of Omi/HtrA2 might be responsible for its IAP-inhibiting activity. Extramitochondrial expression of Omi/HtrA2 indirectly induced permeabilization of the outer mitochondrial membrane and subsequent Cyt c-dependent caspase activation in HeLa cells. These results indicate that protease activity of Omi/HtrA2 promotes caspase activation through multiple pathways.

Therapeutic trials for a rabbit model of EBV-associated Hemophagocytic Syndrome (HPS): effects of vidarabine or CHOP, and development of Herpesvirus papio (HVP)-negative lymphomas surrounded by HVP-infected lymphoproliferative disease.

Epstein-Barr virus-associated hemophagocytic syndrome (EBV-AHS), which is often associated with fatal infectious mononucleosis or T-cell lymphoproliferative diseases (LPD), is a distinct disease characterized by high mortality. Treatment of patients with EBV-AHS has proved challenging. To develop some therapeutic interventions for EBV-AHS, we examined the effectiveness of an antiviral agent (vidarabine) or chemotherapy (CHOP), using a rabbit model for EBV-AHS. Fourteen untreated rabbits were inoculated intravenously with cell-free virions of the EBV-like virus Herpesvirus papio (HVP). All of the rabbits died of HVP-associated (LPD) and hemophagocytic syndrome (HPS) between 21 and 31 days after inoculation. Furthermore, three HVP-infected rabbits treated with vidarabine died between days 23 and 28 after inoculation, and their clinicopathological features were no different from those of untreated rabbits, indicating that this drug is not effective at all to treat HVP-induced rabbit LPD and HPS. Three of the infected rabbits that were treated with one course, with an incomplete set of three courses, or with three full courses of CHOP treatment died of HVP-induced LPD and HPS with a bleeding tendency and/or with opportunistic infections. They died on the 26th, 62nd and 105th day after virus inoculation, respectively. CHOP treatment transiently suppressed the HVP-induced LPD and contributed to the prolonged survival time of two infected rabbits. However, it did not remove all of the HVP-infected cells from the infected rabbits, and residual HVP-infected lymphocytes caused recurrences of rabbit LPD and HPS. The most interesting finding of this experiment was observed in the infected rabbit with the longest survival time of 105 days: HVP-negative lymphomas surrounded by HVP-induced LPD developed in the larynx and ileum of this rabbit, causing an obstruction of the lumen. We concluded that these were not secondary lymphomas caused by CHOP treatment, because no suspicious lesions were detected in three uninfected rabbits that were treated with three courses of CHOP for 120 days. It is therefore necessary to clarify the mechanism by which HVP-negative lymphomas associated with HVP-induced LPD can develop. Our data from therapeutic trials using EBV-AHS animal models indicate that vidarabine is not effective as an agent to treat HVP-infected rabbits, and even the cytotoxic chemotherapy of CHOP is not sufficient to cure the HVP-infected rabbits or to prolong the survival time of infected rabbits. Further studies will therefore be required to develop better therapies to treat EBV-AHS.

Increased angiogenic growth factor in cyanotic congenital heart disease.

To examine the relationship between the plasma levels of angiogenic growth factors and the severity of cyanosis, 80 patients with cyanotic heart disease (CHD) and 81 healthy controls were studied. Median age and mean arterial blood oxygen saturation respectively were 4.2 years and 81% in CHD subjects and 4.8 years and 98% in controls. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) were measured in plasma using enzyme-linked immunoassay. Plasma VEGF levels in controls depended negatively on age (p < 0.0001) until 3 months, when VEGF was no longer elevated. No such age dependence was found for HGF. Although VEGF levels did not differ between CHD and control subjects up to the age of 3 months, VEGF was significantly elevated in CHD patients older than 3 months compared to controls of similar age (149 +/- 106 vs 65 +/- 23 pg/ml, p < 0.0001). Moreover, the VEGF levels were negatively correlated with oxygen saturation (p = 0.03) and positively correlated with hemoglobin (p = 0.004) in CHD patients aged between 3 months and 10 years. Although the physiologic elevation of VEGF in the neonatal period decreases rapidly if oxygen saturation is normal, VEGF elevations persist if systemic hypoxia is present.