Systematic evaluation of magnetic sensitivities of anisotropic magnetoresistive sensors at liquid helium temperature for superconducting cavities.

Trapped magnetic flux in bulk superconductors reduces the quality factor Q in superconducting radio-frequency (SRF) cavities. However, the mechanisms underlying flux trapping and radio-frequency loss are not well understood. Detailed observation of the magnetic distributions is important for understanding such phenomena. Magnetic field mapping is useful for observing the magnetic field distribution around SRF cavities. Measuring the change in the magnetic field around the cavity elucidates the flux trapping behavior. Anisotropic magnetoresistive (AMR) sensors are inexpensive and small devices that can detect magnetic flux density. The magnetic sensitivities of AMR sensors need to be evaluated at liquid helium temperature for the magnetic field mapping of SRF cavities. In this study, a test stand was constructed to calibrate the magnetic sensitivities of AMR sensors in liquid helium, and 110 AMR sensors were tested using this stand. The magnetic sensitivities were evaluated systematically. A solenoid coil was used to control the uniform external magnetic field and to measure the magnetic sensitivity at low temperatures. All AMR sensors exhibited suitable sensitivities to the magnetic field around the SRF cavity. The variation in these sensitivities in all AMR sensors was ∼1%. The AMR sensors were found to have sufficient sensitivity for mapping the magnetic field around the exterior surface of the SRF cavity.

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway.

BACKGROUND: Angiosarcoma is a rare malignant neoplasm derived from endothelial cells, and because advanced angiosarcoma is resistant to standard chemotherapy its prognosis is poor. Therefore, new therapies are urgently needed. Heat shock protein (HSP)90 has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are currently testing the effectiveness of HSP90 inhibitors in various types of malignancies. OBJECTIVES: To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether the inhibition of HSP90 may have antitumour activity. METHODS: The expression of HSP90 protein in angiosarcoma was examined using immunohistochemistry and immunoblotting. The effects of HSP90 inhibition were proven using proliferation, migration and invasion assay in angiosarcoma cells. The mechanism of antitumour effect by HSP90 inhibition was investigated by the transfection of small interfering RNA (siRNA). RESULTS: The levels of HSP90 protein expression in cultured angiosarcoma cell lines were markedly increased compared with those in normal tissue cell lines. Immunohistochemical analyses revealed that the expression of HSP90 protein was strongly detected in angiosarcoma tissues compared with that in normal dermal vessels or senile angioma tissues. Ganetespib, an HSP90 inhibitor, with or without taxanes, inhibited the proliferation of angiosarcoma cells via apoptosis in a dose-dependent manner. HSP90 siRNA suppressed the proliferation, migration and invasion of angiosarcoma cells. Knock-down of HSP90 did not suppress vascular endothelial growth factor receptor 2 directly, but selectively suppressed several downstream targets of vascular endothelial growth factor signalling in angiosarcoma cells. CONCLUSIONS: HSP90 could be a novel therapeutic target for angiosarcoma.

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.

Protooncogene TCL1b functions as an Akt kinase co-activator that exhibits oncogenic potency in vivo.

Protooncogene T-cell leukemia 1 (TCL1), which is implicated in human T-cell prolymphocytic leukemia (T-PLL), interacts with Akt and enhances its kinase activity, functioning as an Akt kinase co-activator. Two major isoforms of TCL1 Protooncogenes (TCL1 and TCL1b) are present adjacent to each other on human chromosome 14q.32. In human T-PLL, both TCL1 and TCL1b are activated by chromosomal translocation. Moreover, TCL1b-transgenic mice have never been created. Therefore, it remains unclear whether TCL1b itself, independent of TCL1, exhibits oncogenicity. In co-immunoprecipitation assays, both ectopic and endogenous TCL1b interacted with Akt. In in vitro Akt kinase assays, TCL1b enhanced Akt kinase activity in dose- and time-dependent manners. Bioinformatics approaches utilizing multiregression analysis, cluster analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway mapping, Venn diagrams and Gene Ontology (GO) demonstrated that TCL1b showed highly homologous gene-induction signatures similar to Myr-Akt or TCL1. TCL1b exhibited oncogenicity in in vitro colony-transformation assay. Further, two independent lines of ß-actin promoter-driven TCL1b-transgenic mice developed angiosarcoma on the intestinal tract. Angiosarcoma is a rare form of cancer in humans with poor prognosis. Using immunohistochemistry, 11 out of 13 human angiosarcoma samples were positively stained with both anti-TCL1b and anti-phospho-Akt antibodies. Consistently, in various cancer tissues, 69 out of 146 samples were positively stained with anti-TCL1b, out of which 46 were positively stained with anti-phospho-Akt antibodies. Moreover, TCL1b structure-based inhibitor 'TCL1b-Akt-in' inhibited Akt kinase activity in in vitro kinase assays and PDGF (platelet-derived growth factor)-induced Akt kinase activities-in turn, 'TCL1b-Akt-in' inhibited cellular proliferation of sarcoma. The current study disclosed TCL1b bears oncogenicity and hence serves as a novel therapeutic target for human neoplastic diseases.

Efficacy of selective transarterial chemotherapy using a port systemfor angiosarcomas of the face and scalp.

SUMMARY: Angiosarcoma is a rare, highly malignant tumor with a poor clinical outcome. From January 2004 to September 2005, we advocated transarterial chemotherapy using a port system for four patients with angiosarcomas of the face and scalp. A heparin coated ANTHRON P-Ucatheter was introduced into the feeding artery. The proximal part of the P-U catheter was connected to the port system and buried in subcutaneous tissue. The amount of chemotherapeutic drug applied using the port system was almost the same as the conventional intravenous dose. Paclitaxel was the standard agent, at 50-100 mg/diluted in 15-30 ml of physiological saline fluid slowly injected over 0.5-1 hour. For immunotherapy where appropriate, r-IL2 was mainly used at a dose of 70.000U/ diluted in 5 ml of physiological saline fluid injected into the port system over 30 seconds. This was continued for two to three weeks (five days/week) until recognition of a disappearance of the tumor. Macroscopic size reduction of the tumor was achieved in three out of the four cases. One case could not be evaluated because of eruptions induced by immunotherapy. Unfortunately two patients died after placement of port system, but the other two are still alive and are enjoying useful lives. Transarterial infusion chemotherapy using such a port system may be particularly effective for angiosarcoma in the early stages because small lesions with limited invasion mean a small territory of blood supply to be covered, and useful life was possible because the port system embedded in subcutaneous tissue allows treatment in an out-patient clinic.

Inhibitory effect of propofol on ketamine-induced c-Fos expression in the rat posterior cingulate and retrosplenial cortices is mediated by GABAA receptor activation.

BACKGROUND: Non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, including ketamine, have psychotomimetic activities and cause neuronal damage in the posterior cingulate and retrosplenial cortices (PC/RS), which are suggested to be the brain regions responsible for their psychotomimetic activities. We previously demonstrated that ketamine induced marked c-Fos (c-fos protein) expression in the rat PC/RS, which was inhibited by propofol, and the expression was closely related to ketamine-induced abnormal behavior. In the present study, we investigated whether the inhibition by propofol was mediated by GABAA receptor receptor activation. METHODS: Using Wistar rats, propofol alone, propofol with bicuculline or propofol with flumazenil was injected intravenously and then continuously infused. Fifteen minutes later, 100 mg kg-1 of ketamine or normal saline was injected intraperitoneally. Two hours after the ketamine or saline injection, the brain was extracted and brain sections were prepared, and c-Fos expression was detected using immunohistochemical methods. RESULTS: Ketamine induced marked c-Fos expression in the PC/RS (171 +/- 9/0.4 mm2), which was significantly inhibited by propofol (5 +/- 5/0.4 mm2). The inhibition by propofol was disinhibited dose-dependently by both bicuculline (0.5 and 1.0 mg kg-1 bicuculline groups: 46 +/- 15 and 143 +/- 16, respectively) and flumazenil (0.1 and 1.0 mg kg-1 flumazenil groups: 79 +/- 6 and 130 +/- 15, respectively). CONCLUSION: These results demonstrate that the inhibitory effect of propofol on ketamine-induced c-Fos expression in the PC/RS is mediated by GABAA receptor activation, and suggests that ketamine-induced psychoneuronal adverse effects may be suppressed by propofol via the activation of GABAA receptors.

Significance of serum soluble Fas antigen level in chronic hepatitis C patients treated with interferon: relationship to the therapeutic response.

BACKGROUND AND AIM: Fas system-mediated cytotoxicity is thought to be involved in the development of liver injury in hepatitis C virus (HCV) infection. In this study, we investigated serum soluble Fas antigen levels in chronic hepatitis C patients treated with interferon and their correlation with the therapeutic response. METHODS: The subjects were 67 chronic hepatitis C patients who underwent a 24-week course of alpha-interferon therapy. Patients were categorized into three groups; sustained responders (n = 22), transient responders (n = 24), and non-responders (n = 21), according to changes in the serum alanine aminotransferase level during and after therapy. The viral genotype, viremic level and diversity in the hypervariable region were examined before therapy. Serum soluble Fas antigen levels were assayed by using serum samples taken at the beginning and the end of therapy. RESULTS: In the univariate analysis, serum soluble Fas antigen levels tended to be higher in non-responders (10.0 +/- 3.4 ng/mL) than in sustained responders (8.5 +/- 3.0 ng/mL) and transient responders (8.2 +/- 2.1 ng/mL; P = 0.13 and P < 0.05). The non-response to therapy was observed in eight of the 15 (53%) patients with serum soluble Fas antigen > or = 11 ng/mL, compared with 13 of the 52 (25%) patients with serum soluble Fas antigen < 11 ng/mL (P < 0.05). As for the multivariate analysis, the only significant factor contributing to the sustained response was a low HCV viremic level (P = 0.0046). Significant factors contributing to the non-response were a high serum alanine aminotransferase (P = 0.0407) and a high serum soluble Fas antigen level (P = 0.0483). CONCLUSIONS: High production levels of soluble Fas antigen may be associated with a poor response to interferon therapy in chronic hepatitis C patients.

Evaluation of recombinant interleukin-2 immunotherapy for human hemangiosarcoma in a SCID mice model (WB-SCID).

We treated the patients with cutaneous hemangiosarcoma with recombinant interleukin-2 (rIL-2) immunotherapy that showed clear therapeutic effects. This immunotherapy is popular for the treatment of hemangiosarcoma in Japan. The purpose of this study is to clarify the clinical effects in an animal experiment. After establishing a SCID mouse model of human hemangiosarcoma WB-SCID, we used this model to investigate anti-tumor effects of rIL-2 and LAK cells. We demonstrated that hemangiosarcoma cells are LAK-sensitive, and LAK cells induced by rIL-2 suppress the growth of hemangiosarcoma. Our results may assure the clinical effects of rIL-2 immunotherapy on hemangiosarcoma.

[Two-step interferon rebound therapy for refractory chronic hepatitis C].

In almost all patients in whom interferon(IFN) treatment dose not result in persistent negative findings for HCV-RNA, HCV-RNA levels show a rebound after discontinuing the administration. In most patients, HCV-RNA levels after administration are increased compared to pretreatment values. When a rapid increase in HCV-RNA levels causes transient exacerbation of transaminase levels, HCV-RNA levels then rapidly decrease. In two-step interferon rebound therapy(TIRT), IFN is additionally administered when HCV-RNA levels are decreased. We previously reported that TIRT was useful for treating type 1b patients with an HCV-RNA level of 1 Meq/ml or more who did not respond to IFN treatment. In the year 2000, health insurance covered the additional administration of IFN. The use of TIRT for additional administration may further improve treatment response in patients who do not respond to IFN treatment.

Expression of vascular endothelial growth factor in a human hemangiosarcoma cell line (ISO-HAS).

Vascular endothelial growth factor (VEGF), in addition to being a specific mitogen of endothelial cells in vitro, is also known to induce angiogenesis in vivo. These functions suggest that VEGF may play an important role in the growth of hemangiosarcomas. Previous studies have demonstrated the expression of VEGF and its receptors, flt-1 or KDR/flk-1, in hemangiosarcomas by immunohistochemical staining and in situ hybridization. In the present study, however, we demonstrated that tumor cells of the hemangiosarcoma cell line ISO-HAS express mRNA of VEGF and its two receptors, flt-1 and KDR, and secrete VEGF protein. VEGF mRNA expression and protein secretion were found to be enhanced by phorbol 12-myristate 13-acetate. In addition, we demonstrated that ISO-HAS cells respond to recombinant human VEGF165 with a dose-dependent up-regulation of cell proliferation and growth. These results suggest that the VEGF-VEGF receptor system plays a role in proliferation and growth of hemangiosarcoma cells.

Immunological response to interferon-gamma priming prior to interferon-alpha treatment in refractory chronic hepatitis C in relation to viral clearance.

The aim of this study was to clarify the immunological and virological responses to pre-administration of interferon-gamma prior to initiation of interferon-alpha treatment in patients with refractory chronic hepatitis C. Twenty-two nonresponders to 6-months of IFN-alpha treatment were enrolled. The hepatitis C virus (HCV) genotype was Ib in all. Natural IFN-gamma (1 MIU/day) was administered daily for 14 days followed by natural IFN-alpha (5 MIU/day) daily for 14 days and then three times weekly for 22 weeks. Serum immunological parameters (IL-10, neopterin, BMG, sCD8, sCD4, IL-6, IL-12) were measured as were the levels of several cytokines (IFN-gamma, TNF-alpha, IL-2, IL-4, IL-5, IL-6, IL-10). Three patients dropped out; two because of the occurrence of other diseases and one because of an adverse effect. At the end of the period of IFN-alpha treatment, HCV-RNA had become negative in six of 19 patients (end-of treatment response; ETR). Six months after the completion of IFN administration, a virological sustained response (SR) was seen in two of 19 patients. The mean serum levels of IL-10 were significantly decreased 6 weeks after the start of treatment. Other immunological parameter levels increased significantly during the period of IFN-gamma administration, and tended to return to the pretreatment level after the start of IFN-alpha administration. Univariate logistic regression analysis showed that the initial change in the levels of these parameters or the change in the ratios of Th1/Th2 parameter levels are useful factors indicative of the end of the treatment response. These findings suggest that priming with IFN-gamma prior to the initiation of IFN-alpha treatment in patients with refractory chronic hepatitis C can modulate the host immune response and this might contribute to viral clearance.

Xenon inhibits but N(2)O enhances ketamine-induced c-Fos expression in the rat posterior cingulate and retrosplenial cortices.

Both nitrous oxide (N(2)O) and xenon are N:-methyl-D-aspartate receptor antagonists that have psychotomimetic effects and cause neuronal injuries in the posterior cingulate and retrosplenial cortices. We investigated the effect of xenon, xenon with ketamine, N(2)O, and N(2)O with ketamine on c-Fos expression in the rat posterior cingulate and retrosplenial cortices, a marker of psychotomimetic effects. Brain sections were prepared, and c-Fos expression was detected with immunohistochemical methods. A loss of microtubule-associated protein 2, a marker of neuronal injury, was also investigated. The number of Fos-like immunoreactivity positive cells by ketamine IV at a dose of 5 mg/kg under 70% N(2)O (128 +/- 12 cells per 0.5 mm(2)) was significantly more than those under 30% (15 +/- 2 cells per 0.5 mm(2)) and 70% xenon (2 +/- 1 cells per 0.5 mm(2)). Despite differences in c-fos immunoreactivity, there was no loss of microtubule-associated protein 2 immunoreactivity in any group examined. Xenon may suppress the adverse neuronal effects of ketamine, and combined use of xenon and ketamine seems to be safe in respect to neuronal adverse effects.

Retreatment with interferon for chronic hepatitis C after transient response.

Approximately half of all patients with chronic hepatitis C show an initial biochemical response to interferon, but only 15% to 20% of patients achieve a sustained response. We studied the efficacy of retreatment with interferon for patients with chronic hepatitis C who showed transient biochemical responses to initial treatment. Thirty patients who relapsed were retreated 1 to 52 months (median 14) after the end of initial treatment, according to the previously used regimens. The responses were correlated with the pre-retreatment patient data. The liver histologic grades, compared with those found before the initial treatment, were better in eight (27%) patients but worse in six (20%), whereas the fibrosis stage was improved in five (17%) but worsened in eight (27%). All patients displayed end-of-retreatment biochemical responses. Of the 30 patients, 10 (33%) achieved sustained aminotransferase normalization and serum hepatitis C virus (HCV) RNA clearance, but the remaining 20 patients showed relapse within 1 year after cessation of retreatment. Univariate analysis associated the sustained response with low pre-retreatment viral loads (0.8 +/- 0.7 MEq/mL vs. 9.1 +/- 6.5 MEq/mL; p = 0.006), short treatment intervals (13 +/- 13 months vs. 22 +/- 14 months; p = 0.031), and low histologic grades (1.3 +/- 0.7 vs. 1.9 +/- 0.7; p = 0.039). However, multivariate analysis indicated that only the pre-retreatment viral load was predictive of the sustained response (p = 0.049). These findings suggest that transient responders to interferon are likely to respond to retreatment but the achievement of a sustained response depends on the HCV viral load before retreatment.

Treatment of murine angiosarcoma with etoposide, TNP-470 and prednisolone.

To develop effective therapies for angiosarcoma, we investigated the anti-tumor effects of etoposide (ETO), TNP-470 and prednisolone (PSL) using an established murine angiosarcoma cell line (ISOS-1). We examined the direct anti-tumor and anti-angiogenic effects of these drugs on ISOS-1 cells and normal murine microvascular endothelial cells (mECs) in vitro. Cell growth of ISOS-1 was inhibited significantly by ETO, moderately by TNP-470, and not at all by PSL (IC(50): 0.25 microg/ml, 10 microg/ml, >8000 microg/ml, respectively). One the other hand, cell growth of mECs was inhibited significantly by TNP-470, slightly by PSL, and negligibly by ETO (IC(50): 0.85 ng/ml, 0.7 microg/ml, 10 microg/ml, respectively). In an in vivo assay, tumor growth of ISOS-1 was significantly inhibited by more than 2.5 mg/kg of ETO dose-dependently, and by more than 30 mg/kg of TNP-470, and 100 mg/kg of PSL individually. Combination treatments of ETO+TNP-470 and TNP-470+PSL showed synergistic enhancement of inhibition (% control inhibition: ETO vs. TNP-470 vs. ETO+TNP-470: 55 versus 55 vs. 16%) (% control inhibition: TNP-470 vs. PSL vs. TNP-470+PSL: 41 vs. 86 vs. 21%). ETO+PSL combination treatment, however, failed to show significant enhancement of anti-tumor effects. In conclusion, our results indicated that TNP-470 may be a very effective drug for angiosarcoma treatment, especially in combination with ETO or PSL. We eagerly anticipate the use of TNP-470 in clinical treatment of angiosarcoma.

Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C: a retrospective cohort study of 738 patients.

The effect of interferon on the long-term clinical outcome of patients with chronic hepatitis C remains unclear. This study included 594 patients with chronic hepatitis C who received interferon-alpha therapy (Interferon group) and 144 patients with chronic hepatitis C who did not receive interferon (Control group). The patients in the Interferon group were classified into the following three groups based on the response of the serum aminotransaminase level of the patient during and after completion of the therapy protocol: sustained responders (n = 175), transient responders (n = 165), and non-responders (n = 254). The age, sex, serum aminotransaminase level, platelet count, histological staging, hepatitis C virus (HCV) subtype, and HCV concentration at baseline were adjusted with the Cox proportional hazards model. The length of follow-up for assessment of the risk for developing hepatocellular carcinoma (HCC) was 57.2 +/- 13.9 months in the Interferon group and 67.7 +/- 28.7 months in the Control group. Multivariate analysis showed that interferon therapy decreased the risk for developing HCC by 48% compared with that in the Control group (P = 0.064). The older the age, being male, having a low platelet count, and higher histological stage were independent factors associated with the development of HCC. The hazard rate ratio for development of HCC in the sustained responders, transient responders, and non-responders was 0.16 (95% confidence interval [CI]: 0.04-0.62), 0.27 (95% CI: 0. 09-0.79), and 0.74 (95% CI: 0.37-1.48), respectively. During follow-up, 18 patients in the Interferon group died (10 from liver-related diseases) and 17 patients in the Control group died (10 from liver-related diseases). No sustained responder or transient responder in the Interferon group died of liver-related disease. The cumulative survival rates of the Interferon and Control groups were nearly identical during the first 5 years following diagnosis. Thereafter, the cumulative survival rate of the Control group declined, resulting in an 8-year survival rate in the Interferon and Control groups of 97% and 81%, respectively (P = 0. 061). Similar trends were seen in the survival analysis of those who had died of liver disease: the 8-year survival rates of the Interferon and Control groups were 98% and 88%, respectively (P = 0. 32). Our study demonstrated that interferon therapy significantly lowered the incidence of HCC among patients with chronic hepatitis C who showed sustained normalization and among patients who showed transient normalization of the serum aminotransferase level after completion of interferon therapy. The survival analyses and determination of cause of death suggested that interferon therapy improves the long-term survival of chronic hepatitis C patients who respond to this therapy, possibly by decreasing mortality from liver-related diseases.

Reappraisal of biochemical hepatitis C activity in hemodialysis patients.

We reappraised biochemical hepatitis C activity in hemodialysis patients in comparison with normal controls. A total of 111 hemodialysis patients and 66 healthy volunteer blood donors with hepatitis C virus (HCV) infection were consecutively enrolled. Serum alanine aminotransferase (ALT) levels were normal (< or =45 U/L) in 103 (93%) hemodialysis patients and 34 (52%) donors (p < 0.001). HCV viremic levels were lower in the hemodialysis group (p = 0.044), with no difference in the HCV genotype prevalence. During two-year follow-up, 60 (67%) of 90 hemodialysis patients and 13 (26%) of 50 donors showed persistently normal ALT levels (p < 0.001). For hemodialysis patients, however, the upper normal limit of ALT activity was reset at 25 U/L corresponding to the mean + 2 x SD for the normalized ALT distribution in 400 control patients. The adjusted ALT levels were initially normal in 73 (66%) hemodialysis patients and persistently normal in 19 (21%). Thus, ALT levels were the same for the two groups. GB virus C (GBV-C)/hepatitis G virus (HGV) coinfection found only in the hemodialysis group (10/111) had no influence on the disease. A relationship was noted between low disease activity and female gender in both groups. These findings indicate that biochemical hepatitis C activity in hemodialysis patients is similar to that in normal controls and should be monitored based on adjusted ALT levels.