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Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (

Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company. © 2020 Elsevier Ltd

Summary report on the fist season of digital recording of temple architecture and wall paintings in Shanxi Province, China.

The risk of transfusion-transmitted infection (TTI) for severe fever with thrombocytopenia syndrome virus (SFTSV) is a concern because person-to-person transmission resulting from contact with SFTSV-contaminated blood has been reported. To obtain information regarding the risk of TTI-SFTSV, antibody testing was performed for blood samples donated in an severe fever with thrombocytopenia syndrome-endemic area in Japan. No antibody-positive samples were detected among 3990 samples. This finding suggested that there were few cases of SFTSV infection among donors and that the risk of TTI-SFTSV was also estimated low in Japan.

Rituximab (RIT) is effective as a part of the desensitization therapy before ABO-incompatible kidney transplantation (ABOi-KTx), and a single dose of RIT at 375 mg/mForty-four consecutive ABOi-KTx recipients were enrolled in this retrospective study. Before transplantation, subjects were treated with RIT at various doses, ranging from 65 to 400 mg/body (46-263 mg/mThe incidence of AAMR was significantly higher in the high %CD19 group than in the low %CD19 group (44.4% vs 5.7%, P = .006). Furthermore, multivariate analysis showed that %CD191.2% was the only independent factor to predict AAMR, with an odds ratio of 14.31 (P = .038).High %CD19 values after rituximab administration in ABOi-KTx recipients implies insufficient depletion of B cells, which can lead to AAMR.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tickborne virus in the Bunyaviridae family. This virus has recently been found in China, Japan and Korea. The risk of transfusion-transmitted SFTSV infection (TTI-SFTSV) is a concern because person-to-person transmission resulting from contact with SFTSV-contaminated blood has been reported. Therefore, we investigated the efficacy of the Mirasol pathogen reduction technology (PRT) system for inactivating SFTSV in vitro. The Mirasol PRT system achieved a > 4.11 log10 reduction value (LRV) for SFTSV. In conclusion, we showed that the Mirasol PRT system could potentially be used to reduce the risk of TTI-SFTSV.

The trapped-flux dependence of bulk high-temperature superconductors between two typical working temperatures of 77 and 30 K was investigated by a field-cooling magnetization (FCM) method under a limited excitation field of 5 T to approach actual application conditions. An exponential trapped-flux dependence between the two temperatures was obtained by fitting the experimental data. Its effectiveness was checked from the theoretical temperature relationship of the critical current density and trapped-field data in the literature. It was found that the achievable trapped flux at 30 K is closely dependent on the excitation field. The bulk samples with moderate performance around the trapped-field range of 1.0–1.5 T at 77 K can be efficiently activated to reach a trapped field over 4.6 T at 30 K. Bulk samples with better performance at 77 K will get saturation and cannot be fully excited by the 5 T excitation field. The presented results are useful for the appropriate estimation of trapped-flux performance from 77 to 30 K and may support some basic references for the applications of bulk HTS magnets.

Background Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab—a human IgG1 VEGFR-2 antagonist—or placebo in this patient population. Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 sites in 23 countries. Previous treatment with one immune-checkpoint inhibitor was permitted. Patients were randomised (1:1) using an interactive web response system to receive intravenous docetaxel 75 mg/m2 plus either intravenous ramucirumab 10 mg/kg or matching placebo on day 1 of repeating 21-day cycles, until disease progression or other discontinuation criteria were met. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat in the first 437 randomised patients. This study is registered with ClinicalTrials.gov, number NCT02426125. Findings Between July, 2015, and April, 2017, 530 patients were randomly allocated either ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267). Progression-free survival was prolonged significantly in patients allocated ramucirumab plus docetaxel versus placebo plus docetaxel (median 4·07 months [95% CI 2·96–4·47] vs 2·76 months [2·60–2·96]; hazard ratio [HR] 0·757, 95% CI 0·607–0·943; p=0·0118). A blinded independent central analysis was consistent with these results. An objective response was achieved by 53 (24·5%, 95% CI 18·8–30·3) of 216 patients allocated ramucirumab and 31 (14·0%, 9·4–18·6) of 221 assigned placebo. The most frequently reported treatment-emergent adverse events, regardless of causality, in either treatment group (any grade) were fatigue, alopecia, diarrhoea, decreased appetite, and nausea. These events occurred predominantly at grade 1–2 severity. The frequency of grade 3 or worse adverse events was similar for patients allocated ramucirumab and placebo (156 [60%] of 258 vs 163 [62%] of 265 had an adverse event), with no unexpected toxic effects. 63 (24%) of 258 patients allocated ramucirumab and 54 (20%) of 265 assigned placebo had a serious adverse event that was judged by the investigator to be related to treatment. 38 (15%) of 258 patients allocated ramucirumab and 43 (16%) of 265 assigned placebo died on treatment or within 30 days of discontinuation, of which eight (3%) and five (2%) deaths were deemed related to treatment by the investigator. Sepsis was the most common adverse event leading to death on treatment (four [2%] vs none [0%]). One fatal event of neutropenic sepsis was reported in a patient allocated ramucirumab. Interpretation To the best of our knowledge, ramucirumab plus docetaxel is the first regimen in a phase 3 study to show superior progression-free survival over chemotherapy in patients with platinum-refractory advanced urothelial carcinoma. These data validate inhibition of VEGFR-2 signalling as a potential new therapeutic treatment option for patients with urothelial carcinoma. Funding Eli Lilly and Company. © 2017 Elsevier Ltd

Diagnosis and treatment of bone metastasis requires various types of measures, specialists and caregivers. To provide better diagnosis and treatment, a multidisciplinary team approach is required. The members of this multidisciplinary team include doctors of primary cancers, radiologists, pathologists, orthopaedists, radiotherapists, clinical oncologists, palliative caregivers, rehabilitation doctors, dentists, nurses, pharmacists, physical therapists, occupational therapists, medical social workers, etc. Medical evidence was extracted from published articles describing meta-analyses or randomised controlled trials concerning patients with bone metastases mainly from 2003 to 2013, and a guideline was developed according to the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014. Multidisciplinary team meetings are helpful in diagnosis and treatment. Clinical benefits such as physical or psychological palliation obtained using the multidisciplinary team approaches are apparent. We established a guideline describing each specialty field, to improve understanding of the different fields among the specialists, who can further provide appropriate treatment, and to improve patients’ outcomes.

The top-seeded melt-growth process with multi-seeding technique provides a promising way to fabricate large-sized bulk superconductors in an economical way. To understand the essential characteristics of the multi-seeded bulks, the paper reports the influence of the grain boundary (GB) coupling or connectivity on the total trapped magnetic flux. The coupling ratio, the lowest trapped flux density in the GB area to the averaged top value of the two neighboring peak trapped fields, is introduced to reflect the coupling quality of GBs inside a multi-seeded bulk. By the trapped flux density measurement of four different performance multi-seeded YBCO bulk samples as representatives, it was found that the GB coupling plays an important role for the improvement of the total trapped magnetic flux; moreover, somewhat more significant than the widely used parameter of the peak trapped fields to evaluate the physical performance of bulk samples. This characteristic is different with the case of the well-grown single-grain bulks.

Pulsed-field magnetization (PFM) is one of the practical activation techniques for bulk applications, especially as an inexpensive, small-volume, and mobile experimental setup. To utilize the method, its effectiveness to excite the bulk superconductors was examined by four samples with different trapped-flux performance as representatives. The PFM experiments were conducted with a pair of vortex-type copper coils at liquid nitrogen temperature (77 K). The utmost trapped-flux performance of the four samples was obtained by a multi-PFM method with progressively increased applied fields. By comparison with their trapped-flux results of static field-cooling magnetization (FCM), the effectiveness of PFM according to different performance bulk superconductors was analyzed. It was found that with the improvement of the bulk performance, the PFM results start to deviate from the FCM ones more and more, indicating a harder tendency to excite the bulk samples by the PFM method. The possible explanations from heat generation during the pulse and some suggestions to the improvement of the PFM process for practical applications are discussed.

Aiming at exploiting the high trapped field ability of bulk high-temperature RE-Ba-Cu-O (RE: rare-earth elements) superconductors, a brushless axial-gap type superconducting synchronous motor has been successfully developed as a technology demonstrator using eight melt-textured GdBa2Cu3Oy (Gd-123) bulks as pole-field magnets. An output power of 10 kW at 720 rpm was realized by an average trapped field peak of 0.56 T reaching the armature coils, under a pulsed field excitation at the liquid nitrogen temperature. For such motors, to improve the trapped flux of bulks is a direct way to enhance the motor performance. In order to obtain a high trapped flux density with a regular shape for a high performance motor utilization, the pulsed field magnetization (PFM) properties of two kinds of bulk superconductors have been investigated. By a reasonable multi-PFM process with a pair of vortex-type pulsed coils, it was found that the multi-seed Y-Ba-Cu-O bulk can bring a high average trapped field, while the single-grain Gd-Ba-Cu-O bulk under a size-adjustable pulsed coil can obtain a very regular trapped field distribution. These results will be useful to the following optimization of the rotating machine system.

A synchronous rotation study with eight field rotor pole of Gd123 bulks was performed with the axial-type motor. The field pole of Gd123 packs with and without doped amorphous magnetic particles Fe-B-Si-Nb-Cr-Cu (MP) were employed. Before and after the synchronous operation, the change of the trapped magnetic flux on the bulk was investigated at the operating temperature of 40 K. The observed decay of the trapped integrated flux on the surface of Gd123 packs after 5 hours synchronous rotation were 7.2% for the Gd123 pack without MP doping and 4.1% for the Gd123 bulk doped with MP. The present result indicates that the lowering operation temperature may be beneficial to avoid the AC loss. This also leads to another complementally conclusion that the employment of the condensed neon gas cooling system is a suitable choice from the viewpoint of practical applications of the HTS bulks in contrast to liquid nitrogen cooling. In addition, the Gd123 doped with MP alloy particles provide a practical magnetic flux trapping function at 40 K.

Temperature Superconductors (HTS) applied to rotating machines require an efficient cooling system. It is necessary to increase the maximum trapped flux density in the bulk HTS magnets and decrease the overall cooling time. In this paper, we added a gaseous helium phase to a condensed-neon closed-cycle thermosyphon. The latent heat of neon-film cooling is combined with helium's high thermal conductivity. Different mixture proportions were evaluated in terms of resistance to variable heat loads. More helium decreased the temperature variation of the evaporator. The mixture was then used to cool down a 30 kW-grade gadolinium-bulk HTS synchronous motor. The eight bulk HTS conductors of the rotor were cooled to 40 K in less than six hours. The application of this thermosyphon is envisioned for larger rotating machines.

Aiming at examining the trapped-flux dependence between single and combined bulk superconductors for field-pole applications, three rectangular Y1.65Ba2Cu3O7−x (YBCO) bulks with a possibly compact combination were employed to investigate the trapped-flux characteristics of single and combined bulks with a field-cooling magnetization (FCM) method. A gap-related dependence was found between them. At lower gaps of 1 mm and 5 mm, the peak trapped fields and total magnetic flux of combined bulks are both smaller than the additive values of each single bulk, which can be ascribed to the demagnetization influences of the field around the bulk generated by the adjacent ones. While, at larger gaps like 10 mm, the situation becomes reversed. The combined bulks can attain bigger peak trapped fields as well as total magnetic flux, which indicates that the magnetic field by the bulk combination can reach higher gaps, thanks to the bigger magnetic energy compared with the single bulk. The presented results show that, on one hand, it is possible to estimate the total trapped magnetic flux of combined bulks by an approximate additive method of each single bulk while considering a demagnetization factor; on the other hand, it also means that the performance of combined bulks will be superior to the addition of each single bulk at larger gaps, thus preferable for large-scaled magnet applications.

A neutron capture cross section for the 112Cd(n, γ)113Cdm reaction has been measured with neutrons provided from a nuclear reactor in order to study the astrophysical origin of a rare p-process isotope 115Sn, which may be produced by a nucleosynthesis flow through 113Cdm in the s-process. We have obtained the thermal neutron capture cross section of 0.028 ± 0.009 [b] and the resonance integral of 1.1 ± 0.3 [b] using a cadmium difference method. The cross section ratio of the isomer to the ground state has been calculated as a function of the incident neutron energy, E, by using a statistical model. The calculated ratios are almost constant over a wide range of E < 100 keV. We have evaluated the s-process contribution to the solar abundance of 115Sn using the classical steady-flow model with various astrophysical parameters. This calculated result has shown that the production through 113Cdm may give minor contribution to 115Sn.

The bit-error rate (BER) performance of the generalized partial response maximum likelihood with autoregressive (GPRML-AR) channel model system in perpendicular magnetic recording (PMR) channel with thermal decay is obtained. The 128/130(0,16/8) run-length-limited (RLL) code is used as a recording code. The GPR channel consists of the PR1 channel followed by the reduction circuit of predicted noise. The BER performance is evaluated by computer simulation using a thermal decay model. The model has been obtained by using an approximate equation that represents amplitude degradation of the reproducing waveform with elapsed time based on the experimental data for CoPtCr-SiO 2 PMR media. The Viterbi detector with an AR channel model is employed. Furthermore, long-term degradation of the required SNR to achieve a BER of 10 −4 with elapsed time is obtained and the performance is compared with that of PR1ML system. The results show that the poorer the thermal stability of the medium becomes, the larger the SNR gain of the GPR1ML-AR system over the PR1ML system becomes. The SNR gain also increases with elapsed time.

T cells mediating chronic rejection (CR) of human kidney allografts were characterized by comparing them with those mediating acute rejection (AR). Two lines of analysis were performed using biopsy specimens (23 CR and 8 AR). First, the extent of infiltration of CD4+ and CD8+ T cells into allografts was assessed from mRNA expression of CD4 and CD8. The group of CR specimens was not significantly different from the group of AR specimens in terms of the extent of CD4+ and CD8+ T cell infiltration, underlining the importance of the immunological contribution to the progress of CR. Second, Th1/Th2 polarization in infiltrating T cells was investigated by measuring mRNA expression of interferon gamma (IFN-gamma; a Th1 cytokine) and interleukin 4 (IL-4; a Th2 cytokine). IFN-gamma expression was detected in most CR specimens, and was not significantly different between the group of CR specimens and the group of AR specimens. On the other hand, IL-4 expression was detected in only two CR specimens and one AR specimen; from its pathological features, the AR in this last case was concomitant with CR. These results suggest that most cases of CR and of AR are mediated by Th1 mechanisms, although some cases of CR show features of both Th1 and Th2.

The clonality of T-cell populations mediating acute and chronic rejection (AR and CR, respectively) of kidney allografts was ascertained by investigating the diversity of TCRBV genes expressed by allograft-infiltrating T cells. Both oligoclonality and polyclonality cases were found in biopsy specimens of AR as well as CR. These results indicated that the T-cell clonality in each specimen did not correlate directly with the mode of rejection. When AR and CR specimens were compared, however, the CR specimen group was significantly more polyclonal (or less oligoclonal) than the AR group. This result may reflect the higher chance of epitope spreading in the more slowly progressing CR than in AR.

We investigate the feasibility of estimating an in situ three-dimensional stress field by using data of drilling-induced tensile fractures (DTFs) observed in a single inclined borehole. The principal assumptions in this investigation are that the rock is isotropic, homogeneous and elastic. A DTF is a longitudinal crack consisting of many small parallel cracks which are oblique to the borehole axis. A DTF is characterized by its circumferential position ( θ mD ) along the borehole surface and the inclination ( γ m ) of the small cracks with respect to the borehole axis. We show how it is possible to estimate the three-dimensional stress field by using the variation of θ mD and γ m with respect to borehole orientation (i.e. azimuth and inclination of a borehole). Based on the variation of θ mD and γ m as functions of borehole orientation which changes with depth, an inverse problem is formulated to estimate the three-dimensional stress field. Tests with synthetic data sets ( θ mD and γ m ) show that it is feasible to estimate the three-dimensional stress field and that the statistical approach is appropriate for the inversion practically. Finally, we discuss a DTF data set ( θ mD and γ m ) measured in a real borehole in the northern area of Japan Main Island and apply the inversion technique to estimate the stress field.

The effectiveness of the lipopolysaccharide-mixed chloroform-killed cell (LPS-CKC) vaccine against pasteurellosis was examined in yellowtail, Seriola quinqueradiata. Vaccination stimulated the production of serum agglutinating antibodies against Pasteurella piscicida. Production of a Superoxide anion, as determined by reduction of nitroblue tetrazolium (NBT), was increased in head kidney leucocytes of vaccinated fish. Fish vaccinated with the LPS-CKC bacterin showed a relative percentage survival (RPS) of 60% or greater when challenged by the immersion method using three different live P. piscicida strains and the efficacy of this bacterin continued for at least 35 days after vaccination. In addition to providing protection against an artificial challenge, the LPS-CKC bacterin also provided protection against natural infection by P. piscicida.

The effect of 14 days of spaceflight on the vertebrae of rapidly growing rats was studied. The hardness of the vertebrae was measured with a Knoop microhardness tester, and bone mineral density was measured from X-ray photographs. Histomorphometric examination was performed with a microcomputer-aided system. No significant difference (P > 0.05) was observed between flight rats and ground controls with regard to mechanical hardness or bone mineral density. However, histological examination revealed irregular thickening of the endosteal surface of cortical bone in the flight rats, whereas it was uniform in the ground controls. The relative area of lamellar bone showed a significant reduction (P < 0.001) in the flight rats. These findings suggest that the structural disturbances were due to retardation of endosteal modeling and remodeling. We conclude that delay of vertebral maturation can occur in rapidly growing rats after even short-term exposure to microgravity.

Perforin- and Fas-based cytolytic pathways are two major mechanisms of cell-mediated cytotoxicity. Recently, we have shown that an inhibitor of vacuolar type H+-ATPase, concanamycin A (CMA), inhibits perforin-based cytotoxic activity, mostly due to accelerated degradation of perforin by an increase in the pH of lytic granules. Here we show that CMA failed to inhibit the cytolytic activity of CD4+ CTL clone and perforin-deficient CD8+ CTL clone, which exclusively mediate Fas-based cytotoxicity, although CMA inhibited acidification and induced drastic vacuolation of cytoplasmic granules in these clones. In a wide range of alloantigen-specific CTL, a significant amount of the lysis of Con A blasts from normal mice and of Fas-positive tumor cells remained unaffected even in excess concentrations of CMA. However, CMA almost completely inhibited the lysis of Con A blasts from lpr mice and of Fas low expressing or negative tumor cells. Cytolysis by alloantigen-specific CD8+ CTL derived from gld mice was completely prevented by CMA. Furthermore, CMA-insensitive cytolysis exerted by CD8+ CTL clone was completely inhibitable by soluble Fas molecules. Thus, these data clearly indicate not only that CMA-insensitive cytolysis mediated by alloantigen-specific CTL is Fas dependent, but also that CMA is a selective inhibitor to block only the perforin-based killing pathway. In contrast, brefeldin A blocked the Fas-based cytotoxicity, but only marginally reduced the perforin-based cytotoxicity. Moreover, CMA and brefeldin A in combination completely abrogated all cytolytic activity of alloantigen-specific CTL. Taken together, these results reveal that CTL mainly exert perforin-based cytotoxicity and complementary Fas-based cytotoxicity, and that CMA is a powerful tool to clarify the contributions of the two distinct cytolytic pathways.

BACKGROUND In order to make clear the prognostic factors in patients with advanced prostatic cancer (stage D2) whose initial treatment was hormone therapy, we reviewed 34 men with newly diagnosed advanced prostatic cancer for 6 years from May 1987 at the Hospital of Hokkaido University. METHODS All patients had histologically proven prostatic adenocarcinoma. The mean age was 67.9 years (range 54 to 86 years). Median follow-up period was 26 months (range 5 to 66 months). The parameters studied were age, performance status, histological grade, extent of disease on bone scan, pretreatment values of PSA, gamma-Sm, PAP and PSA/gamma-Sm ratio, posttreatment values of PSA, gamma-Sm and PAP at 6th month, and the ratio of PSA at 3rd month to PSA at 6th month. RESULTS Univariate analysis revealed that performance status (PSO vs. PS2, p = 0.006, PS1 vs. PS2, p = 0.016) and extent of disease on bone scan (p = 0.004) in background factors, gamma-Sm (p = 0.005) among pretreatment values of markers, PAP at 6th month (p < 0.001) and the ratio of PSA at 3rd month to PSA at 6th month (p < 0.001) among posttreatment values of markers, significantly related with the cause-specific survival. Based on multivariable analysis, PAP at 6th month and the ratio of PSA at 3rd month to PSA at 6th month were significantly correlated with the cause-specific survival at 24th month and 36th month, respectively. CONCLUSION We conclude that posttreatment values of markers are more important prognostic factors in patients with advanced prostatic cancer (stage D2) following hormone therapy than pretreatment background factors and values of markers.

The orthopositronium decay rate is measured with an entirely new method, in which the pickoff annihilation rate is directly measured as a function of time with a high-resolution germanium detector. The decay rate can be determined without the ambiguities of the thermalization nor of the extrapolation, which might have been sources of the main systematic errors in all the previous experiments. Two independent measurements are carried out with two different types of SiO2 powder, resulting in decay rate values consistent with each other. The combined result is λ0 = 7.0398 ± 0.0025 (stat.) ± 0.0015 (sys.) μs−1, which is consistent with the QED prediction, and differs by 2.9–4.1Φ from three recent measurements.

We studied the effect of maternal diabetes induced by neonatal streptozotocin treatment on the longevity of the male offspring in spontaneously hypertensive rats (SHR). Maternal diabetes significantly decreased the survival in the offspring as compared with the control (p0.01). Mean age at death was 14.9 +/- 0.6 months in the offspring from the diabetic dams and 17.9 +/- 1.1 months in that from the control. The life span was significantly correlated with the birth weight (rs = 0.55, p = 0.009). These findings suggest that a diabetic pregnancy may accelerate an age-related degenerative process of the offspring in SHR.

Positronium quenching through its collisions with gaseous atoms and molecules is discussed. It is found that the values of the normalized pick-off quenching parameter, 1Zeff, at room temperature are roughly proportional to the geometric collisional cross-sections estimated from the radius of the positronium and those of the atoms and molecules derived from the viscosity. This suggests that the probabilities of the pick-off quenching of the thermalized positronium per collision with various atoms and molecules are almost constant.

The cooling systems used for rotating High-Temperature Superconducting (HTS) machines need a cooling power high enough to ensure a low temperature during various utilization states. Radiation, torque tube or current leads represent hundreds of watts of invasive heat. The architecture also has to allow the rotation of the refrigerant. In this paper, a free-convection thermosyphon using two Gifford-McMahon (GM) cryocoolers is presented. The cryogen is mainly neon but helium can be added for an increase of the heat transfer coefficient. The design of the heat exchangers was first optimized with FEM thermal analysis. After manufacture, they were assembled for preliminary experiments and the necessity of annealing was studied for the copper parts. A single evaporator was installed to evaluate the thermal properties of such a heat syphon. The maximum bearable static heat load was also investigated, but was not reached even at 150 W of load. Finally, this cooling system was tested in the cooling down of a 100-kW range HTS rotating machine containing 12 Bi-2223 double-pancake coils (DPC).

Although the existence of a large number of CD8+ class II MHC-specific CTLs had long been noticed, the origin of such T cells with a discordant combination of specificity and phenotype has been a mystery in the positive selection model. Recent reports suggesting the independency of the positive selection of T cells from coreceptor-mediated signals raised a possibility that they might be the progeny of putative transitional, mismatched, single-positive cells appearing before positive selection as proposed in the stochastic/selective model. By developing transgenic mice carrying TCR alpha and beta chain genes of a CD8+ class II MHC Ag-specific allogeneic CTL clone QM11, the origin of such T cells with mismatched TCR specificity and coreceptor expression was studied. The results indicate that QM11 belongs to a conventional CD8+ T cell population whose maturation is dependent on a class I (or class I-like) MHC product. Consequently, the reactivity of QM11 to I-Ak can be considered to be an accidental cross-reaction.

An inhibitor of vacuolar type H(+)-ATPase, concanamycin A (CMA), inhibited the specific cytolytic activity of a CD8+ CTL clone, OE4. The inhibitory effect was observed when the effector cells, and not the target cells, were pretreated with CMA. CMA did not seem to inhibit early events, inasmuch as effector/target conjugate formation remained unaffected. Although CMA treatment of OE4 resulted in a slight decrease in the efficiency of granule exocytosis in response to anti-CD3 stimulation, the most prominent effect was a marked reduction of perforin activity and DNA degradation activity in lytic granules. Western blotting analysis indicated a drastic decrease in the amount of perforin in CMA-treated cells. Fluorescent microscopic observation of OE4 stained with acridine orange indicated that CMA raised the pH of the lytic granules. Under transmission electron microscopy, striking morphologic changes in cytoplasmic granular structures were observed after CMA treatment of OE4. The lytic granules of OE4 had homogeneously stained large cores and numerous small vesicles that filled peripheral areas. In contrast, the lytic granules of CMA-treated OE4 showed irregular shapes with no small vesicles, but with cores that became rough and loose. Vacuoles with no structure in them were seen occasionally. These results suggest that acidification through vacuolar type H(+)-ATPase is essential to maintain the structure and function of lytic granules.

The early phases of three flares, observed by the Nobeyama Radio Heliograph, are studied. Nonthermal and thermal radio sources are identified by comparison with soft X-ray images taken by the Soft X-ray Telescope onboard the Yohkoh satellite. Two of the flares are mainly of nonthermal origin and their location coincides with one of the footpoints of soft X-ray loops. Another flare has both thermal and nonthermal components which start to brighten simultaneously. This suggests that particle acceleration and plasma compression develop simultaneously.

A new 17-GHz radio interferometer dedicated for solar observations was constructed in two years at Nobeyama, Nagano. It consists of eighty-four 80-cm-diameter antennas arranged in a tee-shaped array extending 490 m in east-west and 220 m in north-south directions. Since late June of 1992, radio full-disk images of the Sun have been observed for 8 h every day. The spatial resolution is 10" and the temporal resolution is 1 s and also 50 ms for selected events. Every 10 s correlator data are synthesized into images in real time and displayed on a monitor screen. The array configuration is optimized to observe the whole Sun with high spatial and temporal resolution and a high dynamic range of images. Image quality of better than 20 dB is realized by incorporation of technical advances in hardware and software, such as (1) low-loss phase-stable optical-fiber cables for local reference signal and IF signals, (2) newly developed phase-stable local oscillators, (3) custom CMOS gate-array LSTs of 1-b quadraphase correlators for 4/spl times/4 combinations, and (4) new image processing techniques to suppress large sidelobe effects due to the solar disk and extended sources. >

The microstructure of pressureless sintered silicon carbide (SiC) materials with alumina (Al2O3) addition was investigated using analytical electron microscopy and nuclear magnetic resonance. A sintered body with a density of higher than 99% theoretical was obtained with an addition of 5 wt.% Al2O3. The sintered body (SiC–Al2O3) has high strength, high fracture toughness, and high fatigue resistance. Its fracture toughness is approximately 5 MPa-m1/2, which is twice as high as that of pressureless sintered SiC materials with boron and carbon additions (SiC–B–C). The correlation between the microstructure and the mechanical properties is presented here. The starting β–SiC powder is mostly transformed to α–SiC with various polytype distributions during the sintering process. The microstructure has homogeneously distributed, fine, plate-like interlocking gains with a high aspect ratio. Well-developed basal planes form parallel and elongated boundaries, and the crystal structure is mostly the 6H polytype (56%) mixed with thin lamellar 4H.