Randomised phase III study of neoadjuvant chemotherapy with methotrexate, doxorubicin, vinblastine and cisplatin followed by radical cystectomy compared with radical cystectomy alone for muscle-invasive bladder cancer: Japan Clinical Oncology Group Study JCOG0209.

BACKGROUND: This study aimed to determine the clinical benefit of neoadjuvant methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy. PATIENTS AND METHODS: Patients with MIBC (T2-4aN0M0) were randomised to receive two cycles of neoadjuvant MVAC followed by radical cystectomy (NAC arm) or radical cystectomy alone (RC arm). The primary end point was overall survival (OS). Secondary end points were progression-free survival, surgery-related complications, adverse events during chemotherapy, proportion with no residual tumour in the cystectomy specimens, and quality of life. To detect an improvement in 5-year OS from 45% in the RC arm to 57% in the NAC arm with 80% power, 176 events were required per arm. RESULTS: Patients (N = 130) were randomly assigned to the RC arm (N = 66) and the NAC arm (N = 64). The patient registration was terminated before reaching the initially planned number of patients because of slow accrual. At the second interim analysis just after the early stoppage of patient accrual, the Data and Safety Monitoring Committee recommended early publication of the results because the trial did not have enough power to draw a confirmatory conclusion. OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant [hazard ratio 0.65, multiplicity adjusted 99.99% confidence interval 0.19-2.18, one-sided P = 0.07]. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (P < 0.01). In subgroup analyses, OS in almost all subgroups was in favour of NAC. CONCLUSIONS: This trial showed a significantly increased pT0 proportion and favourable OS of patients who received neoadjuvant MVAC. NAC with MVAC can still be considered promising as a standard treatment. UMIN CLINICAL TRIALS REGISTRY IDENTIFIER: C000000093.

RISING beamline (BL28XU) for rechargeable battery analysis.

The newly installed BL28XU beamline at SPring-8 is dedicated to in situ structural and electronic analysis of rechargeable batteries. It supports the time range (1 ms to 100 s) and spatial range (1 µm to 1 mm) needed for battery analysis. Electrochemical apparatus for battery charging and discharging are available in experimental hutches and in a preparation room. Battery analysis can be carried out efficiently and effectively using X-ray diffraction, X-ray absorption fine-structure analysis and hard X-ray photoelectron spectroscopy. Here, the design and performance of the beamline are described, and preliminary results are presented.

Radiation environment in high-altitude Antarctic plateau: Recent measurements and model studies.

Polar regions are the most exposed to secondary particles and radiation produced by primary cosmic rays in the atmosphere, because naturally they are with marginal geomagnetic shielding. In addition, the secondary particle flux contributing to the complex radiation field is enhanced at high-mountain altitudes compared to sea level because of the reduced atmospheric attenuation. At present, there are very few systematic experimental measurements of environmental dose at high southern latitudes, specifically at high-altitude region. Here, we report a campaign of measurements with different devices, that is passive and Liulin-type dosimeters, of the radiation background at high-mountain Antarctic station Vostok (3488 m above sea level, 78° 27' S; 106° 50' E). We compare the measurements with a Monte Carlo-based model for the propagation of the cosmic rays through the atmosphere and assessment of the radiation field in the atmosphere. We employed the model to estimate the radiation dose at Vostok station during the ground-level enhancement at 28 October 2021. As in previous studies by other teams, we show that the annual dose equivalent at high-altitude Antarctic facilities can significantly exceed the limit of 1 mSv established for the general population by the ICRP.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with prostate cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of prostate cancer was published in 2020. It was therefore decided, by both the ESMO and the Singapore Society of Oncology (SSO), to convene a special, virtual guidelines meeting in November 2021 to adapt the ESMO 2020 guidelines to take into account the differences associated with the treatment of prostate cancer in Asia. These guidelines represent the consensus opinions reached by experts in the treatment of patients with prostate cancer representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with prostate cancer across the different regions of Asia.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with renal cell carcinoma.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of renal cell carcinoma was published in 2019 with an update planned for 2021. It was therefore decided by both the ESMO and the Singapore Society of Oncology (SSO) to convene a special, virtual guidelines meeting in May 2021 to adapt the ESMO 2019 guidelines to take into account the ethnic differences associated with the treatment of renal cell carcinomas in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with renal cell carcinoma representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate.

The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells.

The natural killer T (NKT) cell ligand alpha-galactosylceramide (alpha-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12-mediated antitumor activities. Because of these similarities between the activities of alpha-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by alpha-GalCer. We first established, using purified subsets of various lymphocyte populations, that alpha-GalCer selectively activates NKT cells for production of interferon (IFN)-gamma. Production of IFN-gamma by NKT cells in response to alpha-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, alpha-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1(-/-) or Valpha14(-/-) mice. This effect of alpha-GalCer required the production of IFN-gamma by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of alpha-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-gamma production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by alpha-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.

Hyper IgM syndrome and complement Clq deficiency in an individual with systemic lupus erythematosus-like disease.

Many immunedeficiency syndromes are associated with autoimmune disorders. We here report on a girl with a systemic lupus erythematosus-like disease who suffered from both hyperimmunoglobulin M syndrome (HIGMS) and C1q deficiency. Despite severe central nervous system-lupus like disease, probably due to C1q deficiency, kidney function was relatively spared. IgM autoantibody might play a protective role against lupus-glomerulonephritis.

Quantum distribution of protons in solid molecular hydrogen at megabar pressures

Solid hydrogen, a simple system consisting only of protons and electrons, exhibits a variety of structural phase transitions at high pressures. Experimental studies based on static compression up to about 230 GPa revealed three relevant phases of solid molecular hydrogen: phase I (high-temperature, low-pressure phase), phase II (low-temperature phase) and phase III (high-pressure phase). Spectroscopic data suggest that symmetry breaking, possibly related to orientational ordering, accompanies the transition into phases II and III. The boundaries dividing the three phases exhibit a strong isotope effect, indicating that the quantum-mechanical properties of hydrogen nuclei are important. Here we report the quantum distributions of protons in the three phases of solid hydrogen, obtained by a first-principles path-integral molecular dynamics method. We show that quantum fluctuations of protons effectively hinder molecular rotation--that is, a quantum localization occurs. The obtained crystal structures have entirely different symmetries from those predicted by the conventional simulations which treat protons classically.

Identification of novel helper epitopes of MAGE-A4 tumour antigen: useful tool for the propagation of Th1 cells.

MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumour immunotherapy. It has been well accepted that T-helper type 1 (Th1) cell-dominant immunity is critical for the successful induction of antitumour immunity in a tumour-bearing host. The adoptive Th1 cell therapy has been shown to be an attractive strategy for inducing tumour eradication in mouse systems. However, Th1-cell therapy using human tumour-specific Th1 cells, which were expanded from peripheral blood mononuclear cells (PBMCs) in a clinically useful protocol, has never been performed. Here, we first identified MAGE-A4-derived promiscuous helper epitope, peptide (MAGE-A4 280-299), bound to both HLA-DPB1(*)0501 and DRB1(*)1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 cells in vitro. Culture of CD4(+) T cells with IFN-gamma-treated PBMC-derived adherent cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th cells producing IFN-gamma , but not IL-4. Moreover, it was shown that ligation of MAGE-A4-reactive Th1 cells with the cognate peptide caused the production of IFN-gamma and IL-2. Thus, our identified MAGE-A4 helper epitope peptide will become a good tool for the propagation of tumour-specific Th1 cells applicable to adoptive immunotherapy of human cancer.

A prolonged course of Group A streptococcus-associated nephritis: a mild case of dense deposit disease (DDD)?

We herein report the case of a 12-year-old boy with dense deposit disease (DDD) evoked by streptococcal infection. He had been diagnosed to have asymptomatic hematuria syndrome at the age of 6 during school screening. At 12 years of age, he was found to have macrohematuria and overt proteinuria with hypocomplementemia 2 months after streptococcal pharyngitis. Renal biopsy showed endocapillary proliferative glomerulonephritis with double contours of the glomerular basement membrane. Hypocomplementemia and proteinuria were sustained for over 8 weeks. He was suspected to have dense deposit disease due to intramembranous deposits in the first and the second biopsies. 1 month after treatment with methylprednisolone pulse therapy, proteinuria decreased to a normal level. Microscopic hematuria disappeared 2 years later, but mild hypocomplementemia persisted for more than 7 years. Nephritis-associated plasmin receptor (NAPlr), a nephritic antigen for acute poststreptococcal glomerulonephritis, was found to be positive in the glomeruli for more than 8 weeks. DDD is suggested to be caused by dysgeneration of the alternative pathway due to C3NeF and impaired Factor H activity. A persistent deposition of NAPlr might be one of the factors which lead to complement dysgeneration. A close relationship was suggested to exist between the streptococcal infection and dense deposit disease in this case.

[Coronary artery bypass in octogenarians; how to reduce operative mortality and enhance long-term quality of life].

Octogenarians are at increased risk for perioperative morbidity and mortality after coronary artery bypass. This study is aimed to elucidate the suitable operative strategy and perioperative management. A retrospective analysis was conducted of 54 consecutive patients with 80-years of age or older, who underwent elective isolated coronary artery bypass between May 1999 and May 2008. Mean follow-up was 43.3 months and 96.3% complete. Operavive mortality was 3.7% and the incidence of stroke was 3.7%. The 7-year cardiac survival was 80.4% and the 7-year cardiac event free was 65.0%. The use of arterial graft to the right coronary artery was identified as independent predictor of late cardiac event. Neither total arterial revascularization nor bilateral internal thoracic artery grafting was a significant cardiac event factor. This retrospective study suggests a benefit of the less invasive strategy in terms of operative mortality and morbidity. Application of fast-track treatment in octogenarians appears to be an effective approach to reduce perioperative morbidity and enhance long-term quality of life.

Investigation of cynomolgus monkey complement.

BACKGROUND: The cynomolgus monkey is one of the most popular recipient animals in xenotransplantation experiments. However, studies of the cynomolgus monkey complement are rare. In the present study, based on the study that compared the hemolytic complement titer in cynomolgus monkeys with that in humans, the complement regulatory function of human decay accelerating factor (CD55) in both human and cynomolgus monkey sera was studied. METHODS: Hemolytic complement titers in cynomolgus monkeys were calculated using the same methods as are used in humans. Next, the complement regulatory function of human DAF (CD55) in cynomolgus monkey serum was studied using porcine endothelial cells (PECs) and human DAF. RESULTS: Of the complement titers tested, such as CH50, ACH50, C4, C2, and C3, the values were relatively high, except for the C4 titer. Human DAF on the surface of PEC resulted in nearly identical complement regulatory function in the human and cynomolgus monkey sera. CONCLUSIONS: Human DAF showed nearly the same complement regulatory function in both human and cynomolgus monkey sera.

Mixed chimerism and tolerance without whole body irradiation in a large animal model.

Mixed hematopoietic chimerism may provide a treatment for patients with nonmalignant hematologic diseases, and may tolerize patients to organ allografts without requiring chronic immunosuppression. However, the toxicity of the usual conditioning regimens has limited the clinical applicability of this approach. These regimens generally include some level of whole body irradiation (WBI), which is thought to facilitate engraftment either by making room for donor hematopoietic stem cells or by providing sufficient host immunosuppression to enable donor cells to engraft. Here, we have established mixed chimerism across both minor and major histocompatibility barriers in swine, by using high doses of peripheral blood stem cells in the absence of WBI. After mixed chimerism was established, swine leukocyte antigen-matched (SLA-matched) donor skin grafts were tolerated and maintained for a prolonged period, whereas third-party SLA-matched skin was rejected promptly. Donor-matched kidney allografts were also accepted without additional immunosuppression. Because of its low toxicity, this approach has potential for a wide range of clinical applications. Our data may indicate that niches for engrafting stem cells are filled by mass action and that WBI, which serves to empty some of these niches, can be omitted if the donor inoculum is sufficiently large and if adequate host T-cell depletion is achieved before transplant.

A 13-week oral dose subchronic toxicity study of gardenia yellow containing geniposide in rats.

Gardenia yellow powders A, B and C, containing geniposide at 0.284%, 0.938% and 2.783%, respectively, were administered orally to male and female SD rats as 3% feed admixtures for 13-weeks to evaluate any potential toxicity. Mean geniposide intake values were 5.72, 18.9 and 56.3mg/kg/day in groups receiving these feed admixtures, respectively. All animals survived the duration of the study. The following findings were evident in the gardenia yellow C group: chromatouria, slightly increased plasma total bilirubin, blackish brown discoloration of the kidneys and liver, brown pigments in the proximal tubular epithelium of the kidneys. Slightly increased plasma total bilirubin was considered to be due to interference of metabolite of geniposide with the system of measurement and not to be a toxic effect since there were no related changes in histopathology of the liver or in any blood chemistry parameters. Other findings were limited to pigmentations or discolorations attributable to metabolites of geniposide. No treatment-related effects were evident on body weight, food consumption, ophthalmology, hematology or organ weights in any group. Therefore, it was concluded that 3-month ingestion of the gardenia yellow powder containing geniposide at 2.783% (approximately 60 mg/kg/day as geniposide intake) does not cause any severe toxic effects.

IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model.

The interaction between cancer cells and their microenvironment is an important determinant of the pathological nature of cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human cancers forming solid tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients, including those with lung and breast cancers. Multiple lines of evidence suggest that aberrantly activated NRF2 in cancer cells drives their malignant progression and that the cancer cells consequently develop 'NRF2 addiction.' Although the downstream effectors of NRF2 that are responsible for cancer malignancy have been extensively studied, mechanisms of how NRF2 activation contributes to the aggressive tumorigenesis remains to be elucidated. In this study, we found a significant correlation between NRF2 and IL-11 status in breast cancer patients. Based on a recent report demonstrating that IL-11 is induced downstream of NRF2, we examined the significance of IL-11 in NRF2-driven tumorigenesis with a newly established NRF2 addiction cancer model. Expression of Il11 was elevated during the tumorigenesis of the NRF2 addiction cancer model, but intriguingly, it was hardly detected when the cancer model cells were cultured in vitro. These results imply that a signal originating from the microenvironment cooperates with NRF2 to activate Il11. To the best of our knowledge, this is the first report showing the influence of the microenvironment on the NRF2 pathway in cancer cells and the contribution of NRF2 to the secretory phenotypes of cancers. Disruption of Il11 in the NRF2 addiction cancer model remarkably inhibited the tumorigenesis, suggesting an essential role of IL-11 in NRF2-driven tumorigenesis. Thus, this study suggests that IL-11 is a potential therapeutic target for NRF2-addicted breast cancers.

Two types of autophagy in the podocytes in renal biopsy specimens: ultrastructural study.

Two types of autophagy in the podocytes were found in renal biopsy specimens by electron microscopy. Type I autophagy (about 1 microm in diameter) was found in 10 out of the 100 cases with renal diseases, and showed a condensed ribosome area with a limiting membrane. The origin of limiting membrane appeared to be from degenerated mitochondria. During type I autophagy formation, the thickness of limiting membrane changed from 5-6 nm to about 8-10 nm thickness. Type I autophagy did not transform to autophagosomes and autophagic vacuoles. On the other hand, many cases (90 out of the 100 cases) showed type II autophagy. Type II autophagy (3-8 microm in diameter) showed that many ribosomes were aggregated, formed condensed ribosome area, which always included many aggregated lipid droplets at first. Next, during the formation of autophagosome, rough ER connected to condensed ribosome area, and partly formed limiting membranes from dilated ER membrane. Finally, the limiting membrane of autophagic vacuoles was completely formed, and this membrane changed from about 5-6 nm to 8-10 nm thickness. Ribosomes and lipid droplets were resolved in autophagic vacuoles. Thus, type II autophagy might play a significant role in clearance of proteins and lipids in comparison with type I autophagy. The occurrence of type I autophagy in the renal biopsy specimens was not clearly associated with age, sex or pathological diagnosis. However, cases with type I autophagy may show a tendency to poor prognosis.

Expression of nestin in rat and human glomerular podocytes.

Nestin is a neuroepithelial precursor cell marker expressed in a variety of human cell types during development. However, no information exists on the expression of nestin in mature glomeruli as well as during the glomerular development. Here, we examined nestin expression in rat and human glomerular tissues in quiescent states using RT-PCR and immunohistochemical methods. Nestin mRNA was detected in the rat glomeruli in parallel with its expression in developing rat brains. In the normal mature rat glomeruli, WT-1 positive cells expressed nestin. Co-expression of nestin and vimentin was observed in mature rat podocytes. Immunoelectron microscopy revealed nestin localization in the cell bodies and primary processes of podocytes. A similar expression pattern was observed for vimentin. In matured glomeruli, nestin was not expressed by mesangial and endothelial cells. In the newborn rat, early developing glomeruli (metanephric cap, metanephric vesicle, comma-shaped vesicle and S-shaped body phases) expressed nestin. In the capillary loop stage, Bowman's capsules also expressed nestin. Immunoelectron microscopy demonstrated that developing podocytes and endothelial cells in S-shaped phase glomeruli expressed nestin. Additionally, in immature glomeruli, the mesangial cells in capillary stage of glomerulus also expressed nexin. As in the rat, WT-1 positive cells in human glomeruli also expressed nestin and immunoelectron microscopy confirmed nestin expression in human glomerular podocytes. These results reveal that in normal condition nestin is expressed in several glomerular cell types at early stage of development and becomes confined to podocytes in mature glomeruli, thus implicating nestin in podocyte functions.

The intercomparison of cosmic rays with heavy ion beams at NIRS (ICCHIBAN) project.

The ICCHIBAN-2 experiment, the first dedicated to the ground-based intercomparison of passive space dosemeters, was carried out between 23 May and 28 May 2002 at the National Institute of Radiological Sciences in Chiba, Japan. The primary objective of the ICCHIBAN-2 experiment was to intercompare the response of passive dosemeters used in space crew dosimetry to monoenergetic heavy ions of charge and energy spanning a significant portion of the galactic cosmic ray (GCR) spectrum. During the ICCHIBAN-2 experiment, dosemeters from 12 different laboratories in 9 countries were irradiated under identical conditions to heavy ion beams of 150 MeV n(-1) (4)He, 400 MeV n(-1) (12)C, 490 MeV n(-1) (28)Si and 500 MeV n(-1) (56)Fe at the NIRS Heavy Ion Medical Accelerator.