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To assess the efficacy and prognostic factors after superselective intra-arterial chemoradiation (RADPLAT) for maxillary sinus squamous cell carcinoma (MS-SCC). Prognostic significance of age, gender, T and N factors, gross tumor volume of the primary-site (GTV), total cisplatin dosage, and total cisplatin dosage per GTV (CDDP/GTV) for primary-site recurrence-free survival rate (PRFS) were analyzed. RADPLAT was administered to 27 patients. The median follow-up period was 42.1 months. The 3-year rates of overall survival and PRFS were 59.2% and 53.9%, respectively. In univariate analysis, age, male, and total cisplatin dosage were significant factors for PRFS. In multivariate analysis, lymph node metastasis was significant factors for PRFS, and gender and total cisplatin dosage weakly influenced PRFS. In acute phase, no patient showed ≥ grade 3 hematologic toxicity, and grade 3 mucositis developed in 5 patients. Late toxicities were recognized in 3 patients (grade 2 phlegmon of the face, grade 3 maxillofacial osteonecrosis, and retinopathy). Twelve patients (44%) experienced recurrences. Of them, 8 patients showed recurrence at the primarysite. RADPLAT was effective for MS-SCC, with acceptable toxicity. Total cisplatin dosage is suggested to be important for primary tumor control.

The aim of this study was to evaluate the effects of treatment with both three-dimensional radiotherapy (3DRT) and weekly 40-mg/mWe conducted a retrospective multi-institutional chart review of postoperative uterine cervical cancer patients with high-risk prognostic factors who had been treated with both 3DRT and weekly 40-mg/mThe eligible 96 patients were analyzed. The median follow-up period was 61 months. The 3-year relapse-free survival, overall survival (OS), and locoregional relapse-free survival (LRFS) rates were 76%, 90%, and 88%, respectively. In multivariate analysis, the histological finding of either adenocarcinoma or adenosquamous carcinoma was a significant risk factor for both OS and LRFS. The percentage of patients with grade ≥ 3 acute hematologic toxicity, acute lower gastrointestinal toxicity (GIT), and late lower GIT were 45%, 19%, and 17%, respectively.The outcomes of concurrent chemoradiotherapy (CCRT) using weekly 40-mg/m

Radiotherapy is an essential component of cancer therapy. Despite advances in cancer genomics, the mutation signatures of radioresistant tumors have not yet been fully elucidated. To address this issue, we analyzed a unique set of clinical specimens from a uterine cervical cancer that repeatedly locally recurred after multiple rounds of radiotherapy. Exon sequencing of 409 cancer-related genes in the treatment-naive tumor and the tumors that recurred after initial and secondary radiotherapy identified (i) activating mutations in PIK3CA and KRAS, and putative inactivating mutations in SMAD4, as trunk mutation signatures that persisted over the clinical course; and (ii) mutations in KMT2A, TET1, and NLRP1 as acquired mutation signatures observed only in recurrent tumors after radiotherapy. Comprehensive mining of published in vitro genomics data pertaining to radiosensitivity revealed that simultaneous mutations in KRAS and SMAD4, which have not been described previously in uterine cervical cancer, are associated with cancer cell radioresistance. The association between this mutation signature and radioresistance was validated by isogenic cell-based experiments. These results provide proof-of-principle for the analytical pipeline employed in this study, which explores clinically relevant mutation signatures for radioresistance, and demonstrate that this approach is worth pursuing with larger cohorts in the future.

BACKGROUND/AIM We investigated whether laryngopharyngeal reflux (LPR) is a risk factor for radiation-induced mucositis. PATIENTS AND METHODS This was a retrospective cohort study using our departmental database. The study included patients with stage I or II laryngeal and hypopharyngeal cancers treated with radiation therapy alone between April 2009 and March 2014. Based on endoscopic findings, baseline laryngeal signs were evaluated using the reflux finding score (RFS), and the severity of mucositis was assessed during and after radiation therapy. RESULTS Fifty-eight patients were enrolled. Thirty-one patients were categorized as high RFS (LPR-likely), while 27 patients were categorized as low RFS (LPR-unlikely). Grade 3 mucositis occurred more frequently in the high RFS group (p

Background and purpose The aim of the study was to evaluate the therapeutic gain of carbon ion (C-ion) radiotherapy using a mouse model. Materials and methods Transplanted fibrosarcoma (NFSa) growing in C3H/He mice and murine small intestine were irradiated with 290MeV/nucleon C-ion beams (C-ions) in 1–12 fractions separated by 4h. The cell killing efficiencies of C-ions were measured using jejunum crypt survival and tumor growth delay (TGD) assays. Results The equieffect dose for crypt survival and TGD increased with increasing number of fractions after X-rays and 20keV/μm C-ions, whereas TGD after 77keV/μm C-ions rather decreased. Crypts showed stronger LET-dependent increase in α terms than the tumor while β terms less depended on LET irrespective of tissues. Therapeutic gain factor, i.e., a ratio of tumor RBE over crypt RBE, of 77keV/μm C-ions was more than unity at any doses while that of 20keV/μm C-ions increased with an increase in dose per fraction. Conclusions These specific data imply that use of large dose per fraction would be suitable for C-ion radiotherapy irrespective of LET from the point of view of therapeutic gain, though small dose per fraction by high-LET radiation decreases total dose for tumor.

X-ray radiotherapy activates tumor antigen-specific T-cell responses, and increases in the serum levels of high mobility group box 1 (HMGB1) induced by X-ray irradiation play a pivotal role in activating anti-tumor immunity. Here, we examined whether carbon-ion beams, as well as X-rays, can induce HMGB1 release from human cancer cell lines. The study examined five human cancer cell lines: TE2, KYSE70, A549, NCI-H460 and WiDr. The proportion of cells surviving X- or carbon-ion beam irradiation was assessed in a clonogenic assay. The D10, the dose at which 10% of cells survive, was calculated using a linear-quadratic model. HMGB1 levels in the culture supernatants were assessed by an ELISA. The D10 dose for X-rays in TE2, KYSE70, A549, NCI-H460 and WiDr cells was 2.1, 6.7, 8.0, 4.8 and 7.1 Gy, respectively, whereas that for carbon-ion beams was 0.9, 2.5, 2.7, 1.8 and 3.5 Gy, respectively. X-rays and carbon-ion beams significantly increased HMGB1 levels in the culture supernatants of A549, NCI-H460 and WiDr cells at 72 h post-irradiation with a D10 dose. Furthermore, irradiation with X-rays or carbon-ion beams significantly increased HMGB1 levels in the culture supernatants of all five cell lines at 96 h post-irradiation. There was no significant difference in the amount of HMGB1 induced by X-rays and carbon-ion beams at any time-point (except at 96 h for NCI-H460 cells); thus we conclude that comparable levels of HMGB1 were detected after irradiation with iso-survival doses of X-rays and carbon-ion beams.

BACKGROUND This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial. METHODS The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions. RESULTS Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively. CONCLUSIONS Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy. Cancer 2014;120:1663–1669. © 2014 American Cancer Society.

Objective The authors performed phase I/II clinical trial to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced squamous cell carcinoma of the uterine cervix. Methods Between April 2000 and January 2006, 22 patients for Protocol 9902 were treated with C-ion RT. The number of patients with stage IIB, IIIB, and IVA diseases was 1, 18, and 3, respectively. All patients had bulky tumors measuring 4.0–12.0cm (median 6.2cm). The whole pelvic dose was fixed at 39.0GyE for 13 fractions, and additional 15.0GyE for 5 fractions was given to the gross tumor volume (GTV) and surrounding tissues. With regard to local boost, a dose–escalation study was planned for 2 fractions to GTV. Total dose to the cervical tumor was 64.0–72.0GyE for 20 fractions. Results All patients completed the scheduled therapy and no patient developed Grade 2 or higher acute toxicity. There was no Grade 3 or higher late complications at each dose. The 5-year overall survival rate and local control rate were 50.0% and 68.2%, respectively. Seven out of the 16 patients who received 64.0–68.0GyE developed local recurrences, but all patients who received 72.0GyE maintained local control. Conclusions There were no severe acute or late complications in this trial. C-ion RT has the potential to improve the treatment for locally advanced bulky cervical cancer by applying a total dose of 72.0GyE, with the results lending incentive to further investigations to confirm the therapeutic efficacy.

Radiation therapy (RT) for metastatic pelvic lymph nodes (PLNs) is not well established in cervical cancer. In this study the correlation between size of lymph nodes and control doses of RT was analyzed. Between January 2002 and December 2007, 245 patients with squamous cell carcinoma of the cervix treated with a combination of external beam irradiation with or without boost irradiation and high-dose rate brachytherapy were investigated. Size of lymph node was measured by computed tomography before RT and just after 50 Gy RT. Of the 245 patients, 78 had PLN metastases, and a total of 129 had enlarged PLNs diagnosed as metastases; 22 patients had PLN failure. The PLN control rate at 5 years was 79.5% for positive cases and 95.8% for negative cases. In cases with positive PLNs, 12 of 129 nodes (9.3%) developed recurrences. There was significant correlation between PLN control rate and size of PLN after 50 Gy ( 58 Gy had recurrence (P = 0.0003). These results suggested that the response of lymph nodes after RT was a more significant predictive factor for recurrence than size of lymph node before RT, and poor-response lymph nodes might require boost irradiation at a total dose of > 58 Gy.

To compare the incidence and degree of hematological toxicity between innovator and generic cisplatin formulations, decreases in white blood cell (WBC) count (leukopenia) and platelet counts (thrombocytopenia) were retrospectively examined, using the Common Toxicity Criteria for Adverse Events ver. 4.0, in patients with uterine cervical cancer treated with concurrent chemoradiotherapy using innovator (innovator group, n = 22) or generic (generic group, n = 22) cisplatin formulations. There were no significant differences in patient characteristics except in the technique of external irradiation; larger numbers of patients in the innovator and generic groups were irradiated using the parallel-opposed two-field technique and the four-field box technique, respectively (P = 0.00012), which is in line with the historical progress of external beam radiation therapy. The numbers of patients showing Grade 1, 2, 3 and 4 leukopenia were 1 (4.5%), 14 (64%), 7 (32%) and 0 (0.0%) in the innovator group, and 1 (4.5%), 6 (27%), 13 (59%) and 2 (9.0%) in the generic group, respectively. The number of patients showing Grade 3–4 leukopenia was significantly greater in the generic group than in the innovator group (P = 0.034). There was no significant relationship between the incidence of Grade 3–4 leukopenia and the technique of external irradiation. There were no significant differences in the incidence and degree of thrombocytopenia between the two groups. These results indicate the possibility that the generic cisplatin formulation may have a different toxicity profile compared to the innovator formulation in terms of the incidence of leukopenia.

We propose a new application of adaptive radiotherapy using a scanning beam, taking into account the daily regression of a tumor. No patient-specific hardware (such as collimators and compensating filters) is needed for the scanning technique; thus, it allows re-planning immediately before each fractional irradiation using the sophisticated conformations of dose distributions. We retrospectively modeled the tumor volume regression curves as a function of the dose from the CT images which were taken three times during the treatment course. The daily shape of the tumor was mathematically interpolated assuming constant continuity of the tumor deformation. We simulated the adaptive radiotherapy by optimizing the dose distribution on the estimated daily tumor volume for every fraction. The dose–volume histogram (DVH) for the organ at risk in the adaptive radiotherapy was compared with that of the current clinical protocol. We performed analysis using the CT images of cervical cancer patients who received carbon-ion radiotherapy in broad-beam irradiation. The DVH for the rectum and the sigmoid colon was improved by adaptive radiotherapy considering the inter-fractional tumor regression. The result shows that this approach has possible advantages.

Lactoferrin (LF) has been implicated in innate immunity. Here we reveal the signal transduction pathway responsible for human LF (hLF)-triggered nuclear factor-kappaB (NF-kappaB) activation. Endotoxin-depleted hLF induces NF-kappaB activation at physiologically relevant concentrations in the human monocytic leukemia cell line, THP-1, and in mouse embryonic fibroblasts (MEFs). In MEFs, in which both tumor necrosis factor receptor-associated factor 2 (TRAF2) and TRAF5 are deficient, hLF causes NF-kappaB activation at a level comparable to that seen in wild-type MEFs, whereas TRAF6-deficient MEFs show significantly impaired NF-kappaB activation in response to hLF. TRAF6 is known to be indispensable in leading to NF-kappaB activation in myeloid differentiating factor 88 (MyD88)-dependent signaling pathways, while the role of TRAF6 in the MyD88-independent signaling pathway has not been clarified extensively. When we examined the hLF-dependent NF-kappaB activation in MyD88-deficient MEFs, delayed, but remarkable, NF-kappaB activation occurred as a result of the treatment of cells with hLF, indicating that both MyD88-dependent and MyD88-independent pathways are involved. Indeed, hLF fails to activate NF-kappaB in MEFs lacking Toll-like receptor 4 (TLR4), a unique TLR group member that triggers both MyD88-depependent and MyD88-independent signalings. Importantly, the carbohydrate chains from hLF are shown to be responsible for TLR4 activation. Furthermore, we show that lipopolysaccharide-induced cytokine and chemokine production is attenuated by intact hLF but not by the carbohydrate chains from hLF. Thus, we present a novel model concerning the biological function of hLF: hLF induces moderate activation of TLR4-mediated innate immunity through its carbohydrate chains; however, hLF suppresses endotoxemia by interfering with lipopolysaccharide-dependent TLR4 activation, probably through its polypeptide moiety.

We previously demonstrated that FGD1, the Cdc42 guanine nucleotide exchange factor (GEF) responsible for faciogenital dysplasia, and its homologue FGD3 are targeted by the ubiquitin ligase SCF(FWD1) upon phosphorylation of two serine residues in their DSGIDS motif and subsequently degraded by the proteasome. FGD1 and FGD3 share highly homologous Dbl homology (DH) and adjacent pleckstrin homology (PH) domains, both of which are responsible for GEF activity. However, their function and regulation are remarkably different. Here we demonstrate extracellular signal-responsive translocation of FGD1, but not FGD3. During the wound-healing process, translocation of FGD1 to the leading edge membrane occurs in cells facing to the wound. Furthermore, epidermal growth factor (EGF) stimulates the membrane translocation of FGD1, but not FGD3. As the most striking difference, FGD3 lacks the N-terminal proline-rich domain that is conserved in FGD1, indicating that proline-rich domain may play a crucial role in signal-responsive translocation of FGD1. Indeed, there is a faciogenital dysplasia patient who has a missense mutation in proline-rich domain of FGD1, by which the serine residue at position 205 is substituted with isoleucine. When expressed in cells, the mutant FGD1 with S(205)/I substitution fails to translocate to the membrane in response to the mitogenic stimuli. Thus we present a novel mechanism by which the activity of FGD1, a GEF for Cdc42, is temporally and spatially regulated in cells.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been shown to play pivotal roles in bile acid homeostasis by regulating the biosynthesis, conjugation, secretion and absorption of bile acids. Accumulating data suggest that FXR signaling is involved in the pathogenesis of liver and metabolic disorders. Here we show that FXR expression is significantly suppressed in HepG2 cells exposed to hypoxia. Concomitantly, the expression of the bile salt export pump, known as an FXR target gene product and responsible for the excretion of bile acids from the liver, is also decreased under hypoxia. Overexpression of hypoxia-inducible factor (HIF)-1alpha does not mimic the suppressive effect of hypoxia on FXR expression. Furthermore, simultaneous knockdown of HIF-1alpha, HIF-2alpha and HIF-3alpha fails to restore the FXR expression level under hypoxia, indicating that HIF is not involved in hypoxia-evoked FXR downregulation. Instead, we demonstrate that p38 mitogen-activated protein kinase is an indispensable factor for FXR downregulation under hypoxia. Thus, we propose a novel liver disorder model in which two signaling molecules, p38 mitogen-activated protein kinase and FXR, may contribute to the linkage of two pathogenic conditions, i.e. ischemia, a condition accompanying hypoxia, and cholestasis, a condition with intrahepatic accumulation of cytotoxic bile acids.

We previously demonstrated that FGD1, the Cdc42 guanine nucleotide exchange factor (GEF) responsible for faciogenital dysplasia, is targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. Here we show that FGD3, which was identified as a homologue of FGD1 but has been poorly characterized, has conserved the same motif and is down-regulated similarly by SCF(FWD1/beta-TrCP). Although FGD3 and FGD1 share strikingly similar Dbl homology (DH) domains and adjacent pleckstrin homology (PH) domains, both of which are responsible for guanine nucleotide exchange, there also exist remarkable differences in their structures. Indeed, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells: whereas FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. Furthermore, FGD1 and FGD3 reciprocally regulated cell motility: when inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration whereas FGD3 inhibited it. Thus we demonstrate that the highly homologous GEFs, FGD1 and FGD3 play different roles to regulate cellular functions but that their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP).

Identification of substances with specific toxicity for carcinoma cells promises to facilitate the development of cancer chemotherapeutics that cause minimal side effects. Here, we show that knockdown of the farnesoid X receptor (FXR) effectively suppresses the proliferation of human hepatocellular carcinoma cell lines HepG2 and HLE accompanied by elevated expression of cyclin-dependent kinase (CDK) inhibitor p16/INK4a and p21/Cip1 proteins. On the other hand, the growth of the primary human hepatocyte-derived cell line Fa2N-4 is not affected by the treatment with FXR siRNA irrespective of marked increases in the mRNAs of p16/INK4a and p21/Cip1. Surprisingly, the expression levels of p16/INK and p21/Cip1 proteins are left unchanged in Fa2N-4 cells that are subjected to the FXR siRNA treatment. Since the expression levels of these CDK inhibitor proteins in FXR-knockdown Fa2N-4 cells were elevated in the presence of proteasomal inhibitor MG132, these CDK inhibitors may be subjected to the proteasomal degradation, thereby counteracting the increased expression of their cognate mRNAs, therefore similar levels of p16 and p21 proteins were observed in control and FXR-knockdown Fa2N-4 cells. These results suggest that FXR-knockdown is effective for inhibiting the proliferation of hepatocellular carcinoma cells, not interfering with the regulatory mechanism of normal hepatocyte growth.

After >60 years since the first treatment, particle radiation therapy (RT) is now used to treat various types of tumors worldwide. Particle RT results in favorable outcomes, especially in local control, because of its biological properties and excellent dose distribution. However, similar to other types of cancer treatment, metastasis control is a crucial issue. Notably, immunotherapy is used for cancer treatment with high risk for recurrence and/or metastasis. These 2 cancer therapies could be ideal, complementary partners for noninvasive cancer treatment. In this review, we will focus on preclinical studies combining particle RT, especially carbon ion RT, and immunotherapy.

Background The prognostic value of rectal invasion is still unclear in stage IVA cervical cancer. The objective of this study is to evaluate patient outcome and prognostic factors in stage IVA cervical cancer treated with radiation therapy. Methods A retrospective review of the medical records of patients treated with definitive photon radiation therapy for pathologically proven stage IVA cervical cancer between 1980 and 2010 was performed. Eligible patients for the present study were diagnosed with clinical stage IVA cervical cancer by cystoscopy or/and proctoscopy, and they received definitive radiation therapy consisting of a combination of external beam radiotherapy and high-dose-rate brachytherapy. All patients underwent CT scans of the abdomen and pelvis. Results Among the 67 stage IVA patients studied, 53 patients were stage IVA on the basis of bladder invasion, 7 according to rectal mucosal invasion, and 7 because of both bladder and rectal mucosal invasion. Median follow-up of all patients and surviving patients was 19 months (range, 2–235 months) and 114 months (range, 14–223 months), respectively. The 5-year local control (LC), disease-free survival (DFS), and overall survival (OS) rate were 55, 17, and 24 %, respectively. Rectal invasion had significant impact on DFS, but bladder invasion had the opposite effect (p = 0.00006 and 0.005, respectively). There were significant differences of LC, DFS and OS rates between patients with and without rectal invasion (p = 0.006, 0.00006 and 0.05, respectively). Conclusions Patients with stage IVA cervical cancer had poor prognosis, with 5-year survival of only 24 %. Furthermore, in stage IVA, rectal invasion might be a worse prognostic factor than bladder invasion.

We investigated the first site of distant failure after carbon ion radiotherapy (C-ion RT) for locally advanced cervical cancer in three clinical trials. A total of 91 cases were enrolled in the three trials (Protocol 9702, 9704 and 9902). Histologically, 36 cases had squamous cell carcinoma (SqCC) and 55 cases had adenocarcinoma (AC), including 13 with adenosquamous cell carcinoma. The number of cases with Stage IIB, IIIB and IVA disease was 21, 59 and 11, respectively. Of the 91 cases, 42 had positive pelvic lymph nodes (PLNs). The median tumor size was 6.0 cm (range, 3.0–12.0 cm). The median follow-up duration for all cases was 40 months (range, 7–181 months). A total of 40 cases developed distant failure as the first site of failure: 13 of 36 (36.1%) SqCC cases had distant failure, with 9 of them with para-aortic lymph node (PALN) failure; 27 of 55 (44.0%) AC cases had distant failure, and 23 of them had distant failure excluding PALN metastasis. Distant failure rates of SqCC cases who had positive and negative PLNs before C-ion RT were 61.1% and 11.1%, respectively (P = 0.0045). Those of AC cases were 54.2% and 45.2%, respectively (P = 0.507). In conclusion, there were high rates of distant failure after C-ion RT in AC cases regardless of PLN status, and there were high rates of distant failure after C-ion RT, especially PALN failure, in SqCC cases with positive PLNs.

We have reported that high exogenous vitamin E (0.1-1 mM) inhibits thioglycollate-induced mouse peritoneal macrophages from binding and uptake of oxidized low density lipoprotein (oxLDL). However, in the present study, we found the amount of oxLDL bound to mouse macrophages increased with increasing levels of endogenous vitamin E in macrophages. Different vitamin E levels in macrophages were obtained by feeding mice with vitamin E deficient-, adequate- or rich-diet for 3 weeks;0.02, 0.12 and 0.14 μg/mg protein, respectively. Exogenous vitamin E dose-dependently (up to 1 μM) increased the amount of oxLDL bound to macrophages from mice fed vitamin E adequate-diet and the numbers of lipid droplet positive macrophages. An increase of oxLDL binding with increasing of exogenous vitamin E was also observed in macrophages from mice fed vitamin E deficient-diet. Above results suggest that vitamin E at physiological levels enhances macrophages to bind and incorporate oxLDL.

Effect of oxidative stress induced by vitamin E-deficiency and/or nitrogen dioxide (NO2) inhalation on Type IV and Type I allergy responses of mice was investigated. Mice were fed a vitamin E-adequate diet (control: C group) or a vitamin E-deficient diet (‐E group). The vitamin E content in the blood of C and ‐E groups was 1.58 and 0.3 µg/ ml, respectively. Mice of the C and ‐E groups were exposed to air or air containing NO2 (5‐6 ppm) (C + NO2 and ‐E + NO2 groups) by feeding them the corresponding diets for 1‐2 week. In the sensitization with 2,4-dinitrochlorobenzene (DNCB), the degree of lymph node cell proliferation of mice of the C + NO2 group, as assessed by lymph node assay, was similar to that of mice of the C group. While the degree of cell proliferation of mice of the ‐E group was lower than that of mice of the C group, the degree of cell proliferation of mice of the ‐E + NO2 group was higher than that of mice of the C and C + NO2 groups. While the DNCB-sensitized IgE levels of mice of the C + NO2 group were similar to those of mice of the C group, the IgE levels of mice of the ‐E and ‐E + NO2 groups were higher than those of the C and C + NO2 groups. While the trimellitic anhydride (TMA)-sensitized IgE levels of mice of the ‐E group were similar to those of mice of the C group, the IgE levels of mice of the C + NO2 and ‐E + NO2 groups were much higher. These results suggest that allergen-sensitized type IV and I allergy responses of mice are enhanced by oxidative stress induced by vitamin E-deficiency and/or NO2 inhalation.

The mammalian target of rapamycin (mTOR) correlates with cell survival under hypoxia and regulates hypoxia-inducible factor-1α (HIF-1α), a key protein in hypoxia-related events. However, the role of mTOR in radio-resistance has not been fully investigated. Therefore, the effect of mTOR on the radio-resistance of cancer cells under hypoxia was evaluated using the mTOR inhibitor temsirolimus. Clonogenic survival was examined in the A549 human lung adenocarcinoma cell line under normoxia or hypoxia, with or without temsirolimus. An oxygen enhancement ratio (OER) was calculated using the D(10) values, the doses giving 10% survival. Western blotting was performed to investigate the effect of temsirolimus on mTOR and the HIF-1α pathway under normoxia and hypoxia. A549 cells showed a radio-resistance of 5.1 and 14.2 Gy, as indicated by D(10) values under normoxia and hypoxia, respectively; the OER was 2.8. The cell survival rates under hypoxia and with temsirolimus remarkably decreased compared with those under normoxia. The D(10) values of the cells under normoxia and hypoxia were 4.8 and 5.4 Gy, respectively (OER = 1.1). mTOR expression was suppressed by temsirolimus under both normoxia and hypoxia. HIF-1α expression decreased under hypoxia in the presence of temsirolimus. These results suggest that temsirolimus can overcome the radio-resistance induced by hypoxia. When the fact that mTOR acts upstream of HIF-1α is considered, our data suggest that the restoration of radiation sensitivity by temsirolimus under hypoxia may be associated with the suppression of the HIF-1α pathway. Temsirolimus could therefore be used as a hypoxic cell radio-sensitizer.

The effect of long-term supplementation of food reductones, 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF) (2%, w/w), detected in many foodstuffs including soy sauce, and hydroxyhydroquinone (1,2,4-benzenetriol) (HHQ) (1.2%, w/w), detected in coffee, on mouse lipid peroxidation and type IV and I allergy responses was investigated. The effect of supplementation of these reductones combined with NO(2) inhalation (5-6 ppm) was also investigated. Levels of thiobarbituric acid-reactive substances in lung were remarkably increased, and those in kidney and liver were slightly decreased by supplementation of DMHF or HHQ. The degree of 2,4-dinitrochlorobenzene (DNCB)-sensitized lymph node cell proliferation as assessed by lymph node assay was remarkably enhanced by supplementation of DMHF or HHQ. Both the DNCB-sensitized and the trimellitic anhydride-sensitized increases in IgE levels of mice were enhanced to greater extent by supplementation of DMHF or HHQ. In no cases were additive effects of NO(2) inhalation observable. Allergen-sensitized type IV and I allergy responses of mice may be enhanced by supplementation of food reductones, DMHF or HHQ.

The present study was undertaken in order to evaluate the effect of feeding plant polyphenolics on fatty acid composition, the vitamin E level and degree of lipid peroxidation in rat organs. Male Wistar rats were fed a diet containing safflower or fish oil at 50g/kg diet and vitamin E at 59mg/kg diet in the absence and presence of plant polyphenolics at 7.5g/kg diet for 6 wk. Fatty acid composition of total lipids, vitamin E levels, the levels of phospholipid hydroperoxides and the levels of thiobarbituric acid-reactive substances (TBARS) in the TBA assay with butylated hydroxytoluene in each organ were measured. Feeding plant polyphenolics decreased the level of arachidonate content in the liver of rats fed safflower oil. Comsumption of vitamin E in heart, lung and testies was slightly prevented, but that in stomach was enchanced by feeding plant polyphenolics in both safflower and fish oil diet groups. Phospholipid hydroperoxide levels in brain and liver of rats fed both safflower and fish oil were lowered, whereas those in lung, kidney and spleen of rats fed both the oils were greatly increased by feeding plant polyphenolics. In determination of the hydroperoxides, the possibility that the values include artificial ones associated with sample handling cannot be excluded. TBARS levels in brain of the fish oil diet group and in liver of both tha safflower and fish oil diet groups were decreased, but those in heart, lung and kidney in both the safflower and fish oil diet groups and those in spleen in the safflower oil diet group were increased by feeding plant polyphenolics. It is likely that feeding plant polyphenolics had little effect in preventing lipid peroxidation in rat organs.

The present study was undertaken in order to reexamine the effect of n-3 polyunsaturated fatty acid (PUFA)-rich diet supplementation on lipid peroxidation and vitamin E status of rat organs. Male Wistar rats were fed a diet containing safflower or fish oil at 50 g/kg diet and an equal amount of vitamin E at 59 mg/kg diet (1.18 g/kg oil; and 1.5 g/kg PUFA in safflower oil diet, and 4.3 g/kg PUFA in fish oil diet) for 6 wk. Fatty acid composition of total lipids of brain, liver, heart, and lung of rats fed fish oil was rich in n-3 PUFA, whereas that of each organ of rats fed safflower oil was rich in n-6 PUFA. The vitamin E levels in liver, stomach, and testis of the fish oil diet group were slightly lower than those of the safflower oil diet group, but the levels in brain, heart, lung, kidney, and spleen were not different between the two diet groups. The levels of phospholipid hydroperoxides were determined by the high-performance liquid chromatography-chemiluminescence method and the levels of thiobarbituric acid-reactive substances (TBARS) were determined at pH 3.5 in the presence of butylated hydroxytoluene with or without EDTA. Levels of phospholipid hydroperoxides and TBARS in the brain, liver, heart, lung, kidney, spleen, stomach and testis of the fish oil diet group were similar to those of the safflower oil diet group. The results indicate that high fish oil intake does not induce increased levels of phospholipid hydroperoxides and TBARS in rat organs.

Human erythrocytes in the circulation undergo dynamic oxidative damage involving membrane lipid peroxidation and protein aggregation during aging. The present study was undertaken to determine the effect of n−3 fatty acid supplementation on lipid peroxidation and protein aggregation in the circulation and also the in vitro susceptibility of rat erythrocyte membranes to oxidative damage. Wistar male rats were fed a diet containing n−6 fatty acid-rich safflower oil or n−3 fatty acid-rich fish oil with an equal amount of vitamin E for 6 wk. n−3 Fatty acid content in erythrocyte membranes of rats fed fish oil was significantly higher than that of rats fed safflower oil. The degree of membrane lipid peroxidation and protein aggregation of rats fed fish oil was not significantly higher than that of rats fed safflower oil when the amounts of phospholipid hydroper-oxides, thiobarbituric acid-reactive substances, and detergent-insoluble protein aggregates were measured. When isolated erythrocytes were oxidized under aerobic conditions in the presence of Fe(III), the degree of membrane lipid peroxidation of erythrocytes from rats fed fish oil was increased to a greater extent than that of rats fed safflower oil, whereas the degree of membrane protein aggregation of both groups was increased in a similar extent. Hence, n−3 fatty acid supplementation did not affect lipid peroxidation and protein aggregation in membranes of circulating rat erythrocytes, and the supplementation increased the susceptibility of isolated erythrocytes to lipid peroxidation, but not to protein aggregation, under the aerobic conditions. If a sufficient amount of vitamin E is supplied, n−3 fatty acid supplementation may give no undesirable oxidative effects on rat erythrocytes in the circulation.

Reactivity of a commercially available test kit (LPO-586), based on N-methyl-2-phenylindole, toward aldehydes was characterized and compared with that of thiobarbituric acid (TBA). In hydrochloric acid, LPO-586 produced a violet pigment with malonaldehyde (MA) but not with other tested aldehydes. In methane sulfonic acid, LPO-586 produced the violet pigment with MA and 4-hydroxynonenal (HNE), but not with other tested aldehydes. Pigment formation with MA was not inhibited by other aldehydes, but that with HNE was inhibited by alka-2,4-dienals. TBA produced a red pigment with MA but not with other tested aldehydes in hydrochloric acid or in acetate with ethylenediaminetetraacetic acid (EDTA). Both the LPO-586 test in hydrochloric acid and the TBA test in hydrochloric acid or in acetate with EDTA can be used for specific measurement of MA in oxidized lipid samples.

Involvement of band 3 aggregation in the mechanism of anti-band 3 autoantibody binding to the cell surface carbohydrate epitopes of band 3 was investigated. When erythrocytes were treated nonoxidatively with a known protein-aggregating agent acridine orange, protein aggregates of the cell membrane which are insoluble in a nonionic detergent C 12 E 8 solution were remarkably increased. Analysis of the protein aggregates by SDS–PAGE indicated that they were composed of several species of noncovalently associated membrane proteins including band 3. 125 I-labeled anti-band 3 bound to the acridine orange-treated cells, and the binding increased depending on the concentrations of acridine orange used. The binding was inhibited by band 3 and its oligosaccharides but not by the oligosaccharides pretreated with endo-β-galactosidase, an enzyme specifically cleaves poly- N -acetyllactosaminyl saccharide chains of band 3. When erythrocytes were pretreated with endo-β-galactosidase to remove poly- N -acetyllactosaminyl saccharide chains from cell surface prior to acridine orange treatment, the cells did not become susceptible to anti-band 3 binding. The results indicate that induction of band 3 aggregation in erythrocyte membrane leads to anti-band 3 binding to the poly- N -acetyllactosaminyl saccharide chains of band 3. Consistently, membrane proteins including band 3 were found to be aggregated when erythrocytes were oxidized with ADP-chelated Fe 3+ under the conditions that induce anti-band 3 binding to the cells. Similar band 3 aggregation was observed on senescent erythrocytes whose carbohydrate epitopes of band 3 had been occupied with anti band 3. These results indicate that anti-band 3 binds to the carbohydrate epitopes of band 3 on erythrocytes when band 3 is aggregated by oxidative and nonoxidative mechanisms.

We have performed precise, experimental and theoretical studies of the quench propagation velocities of the YBa2Cu3Ox (YBCO) high-temperature superconducting film prepared on oxide single-crystal substrates by pulsed laser deposition. In the experimental studies, we determined the quench propagation velocities using strip-shaped YBCO films prepared on LaAlO3 single-crystal substrate with many voltage terminals. That is, the quench propagation velocities were measured from the time that the voltage occurred at each terminal after quenching in part of the strip by a heater. We previously examined the influence of the temperature increase by the heater in order to estimate the correct value of the quench propagation velocity. We then used the data obtained in the region of small temperature increase by the heater. The quench propagation velocities of YBCO film obtained in this study were lower than that of the metallic superconducting wire by an order of 2-3. In a theoretical analysis, the quench propagation velocities were found to be expressed by a function of the specific heat, the density and the thermal conductivity of the substrate, a temperature difference between the operation temperature and Tc, the strip width of the superconducting film and the power of joule heating for the unit area. The theoretical estimations were in good agreement with the obtained quench propagation velocities from this experiment. Therefore, the theoretical analysis in this study is appropriate for the quench propagation characteristics of the superconducting film, and the quench propagation velocity can be estimated when the experimental conditions are determined.

This study sought to evaluate the toxicity and efficacy of carbon ion radiotherapy (C-ion RT) for locally advanced adenocarcinoma of the uterine cervix in a phase 1/2 clinical trial.The treatment consisted of whole-pelvic irradiation of 36.0 gray equivalents (GyE) in 12 fractions and local boost with dose escalation from 26.4 to 38.4 GyE in 8 fractions. The dose escalation was performed with careful observation of acute normal tissue responses. Total dose to the cervical tumor was 62.4 to 74.4 GyE in 20 fractions.Between April 1998 and February 2010, 58 patients were treated with C-ion RT in this clinical trial. The number of patients with stage IIB, IIIB, and IVA disease were 20, 35, and 3, respectively. Median tumor size was 5.5 cm (range, 3.0-11.8 cm). Twenty-seven patients had pelvic lymph node metastases. The median follow-up period was 38 months. All patients completed the treatment schedule. Grade 2 or higher late toxicity was found in 8 patients: 5 with bladder and 2 with small intestine grade 2 toxicities, and 1 patient had grade 4 rectal complication, which was surgically salvaged. The 5-year local control rate, local control rate including salvage surgery, and overall survival rate in all cases were 54.5%, 68.2%, and 38.1%, respectively.Dose escalation of C-ion RT for adenocarcinoma of the uterine cervix was accomplished without severe toxicities except in 1 case. Although the number of patients in this study was small, the results support continued investigation and analysis to confirm therapeutic efficacy.

Background Interstitial brachytherapy (ISBT) is an optional treatment for locally advanced gynecological tumours for which conventional intracavitary brachytherapy (ICBT) would result in suboptimal dose coverage. However, ISBT with Martinez Universal Perineal Interstitial Template (MUPIT), in which ~10-20 needles are usually applied, is more time-consuming and labor-intensive than ICBT alone, making it a burden on both practitioners and patients. Therefore, here we investigated the applicability of a combined intracavitary/interstitial (IC/IS) approach in image-guided adaptive brachytherapy for bulky and/or irregularly shaped gynecological tumours for which interstitial brachytherapy (ISBT) was performed. Methods Twenty-one consecutive patients with gynecological malignancies treated with computed tomography-guided ISBT using MUPIT were analyzed as cases for this dosimetric study. For each patient, the IC/IS plan using a tandem and 1 or 2 interstitial needles, which was modeled after the combined IC/IS approach, was generated and compared with the IS plan based on the clinical ISBT plan, while the IC plan using only the tandem was applied as a simplified control. Maximal dose was prescribed to the high-risk clinical target volume (HR-CTV) while keeping the dose constraints of D2cc bladder

Recurrences of cervical cancer after definitive radiotherapy often occur at common iliac or para-aortic lymph nodes as marginal lymph node recurrences. Patients with these recurrences have a chance of long-term survival by optimal re-treatment with radiotherapy. However, the re-irradiation often overlaps the initial and the secondary radiotherapy fields and can result in increased normal tissue toxicities in the bowels or the stomach. Carbon-ion radiotherapy, a form of particle beam radiotherapy using accelerated carbon ions, offers more conformal and sharp dose distribution than X-ray radiotherapy. Therefore, this approach enables the delivery of high radiation doses to the target while sparing its surrounding normal tissues. Marginal lymph node recurrences in common iliac lymph nodes after radiotherapy were treated successfully by carbon-ion radiotherapy in two patients. These two patients were initially treated with a combination of external beam radiotherapy and intracavitary and interstitial brachytherapy. However, the diseases recurred in the lymph nodes near the border of the initial radiotherapy fields after 22 months and 23 months. Because re-irradiation with X-ray radiotherapy may deliver high doses to a section of the bowels, carbon-ion radiotherapy was selected to treat the lymph node recurrences. A total dose of 48 Gy (RBE) in 12 fractions over 3 weeks was given to the lymph node recurrences, and the tumors disappeared completely with no severe acute toxicities. The two patients showed no evidence of disease for 75 months and 63 months after the initial radiotherapy and for 50 months and 37 months after the carbon-ion radiotherapy, respectively. No severe late adverse effects are observed in these patients. The two presented cases suggest that the highly conformal dose distribution of carbon-ion radiotherapy may be beneficial in the treatment of marginal lymph node recurrences after radiotherapy. In addition, the higher biological effect of carbon-ion radiotherapy and its superior dose distribution may provide more effective tumor control in treatment for re-irradiation of the marginal recurrences in radiation resistant tumors other than cervical cancer.

Binding specifically of naturally occurring anti-band 3 IgG antibody isolated from human plasma was investigated in a cell-free binding system. 125I-labeled human anti-band 3 IgG specifically bound to band 3 glycoprotein and lactoferrin, a glycoprotein that has poly-N-acetyllactosamine-type sugar chains like band 3, on the polyvinylidene difluoride blotting membrane. Binding was decreased by 50-70% when band 3 and lactoferrin were pretreated with N-glycosidase F, endo-beta-galactosidase, or neuraminidase. Binding of 125I-anti-band 3 IgG to band 3-Sepharose gel was partially inhibited by band 3 oligosaccharides or lactoferrin, but was less inhibited by them after they had been treated with N-glycosidase F or endo-beta-galactosidase. A significant part of 125I-anti-band 3 IgG that bound to the band 3-Sepharose gel was released upon treatment of the gel with N-glycosidase F or endo-beta-galactosidase. IgG that binds to lactoferrin (anti-lactoferrin IgG) was isolated from normal human plasma. 125I-Anti-lactoferrin IgG bound to the band 3-Sepharose gel as effectively as to the lactoferrin-Sepharose. The antibody specifically bound to the band 3- and lactoferrin-blotted membrane depending on the poly-N-acetyllactosaminyl sugar chains of the blotted glycoproteins. The results indicate that a major part (about 70%) of anti-band 3 IgG recognizes the sialylated poly-N-acetyllactosaminyl sugar chains of band 3 and lactoferrin, and the remaining part (about 30%) of the antibody may recognize the polypeptide portion of band 3. This was supported by the observation that anti-band 3 IgG effectively bound to lactoferrin-Sepharose but 33% of the antibody did not. Anti-band 3 IgG with the carbohydrate-binding property was equally obtained whether fully denatured or barely denatured band 3 was used for isolation of anti-band 3 IgG by affinity chromatography. These results provide further evidence for our proposal that the binding sites of anti-band 3 IgG to oxidized and senescent erythrocytes reside on the locally condensed sialylated poly-N-acetyllactosaminyl sugar chains of band 3 on the cell surface.

[1] The accurate characterization of fractured geologic medium, imaging of fracture patterns and their connectivity have been a challenge for decades. Recently, hydraulic tomography has been proposed as a new method for imaging the hydraulic conductivity (K) and specific storage (Ss) distributions of fractured geologic media. While encouraging results have been obtained in the field, the method has not been rigorously assessed in a controlled laboratory setting. In this study, we assess the performance of transient hydraulic tomography (THT) in a fractured dolomitic rock block. The block is characterized through flow-through tests and multiple pumping tests. The pumping test data were then analyzed with the THT code of Zhu and Yeh (2005) to image the fracture patterns and their connectivity through the delineation of K and Ss distributions (or tomograms). Results show that the THT analysis of pumping tests yields high-K and low-Ss zones that capture the fracture pattern and their connectivity quite well and those patterns become more vivid as additional pumping test data are added to the inverse model. The performance of the estimated K and Ss tomograms are then assessed by: (1) comparing the tomograms obtained from synthetic to real data; (2) comparing the tomograms from two different pumping configurations; (3) comparing the estimated geometric mean of the hydraulic conductivity (KG) from the K tomogram to the effective hydraulic conductivity (Keff) estimated from the flow-through tests; and (4) predicting five independent pumping tests not used in the construction of the K and Ss tomograms. The performance assessment of the K and Ss tomograms reveals that THT is able to image high-K and low-Ss zones that correspond to fracture locations in the fractured rock block and that the tomograms can be used to predict drawdowns from pumping tests not used in the construction of the tomograms with reasonable fidelity.

Farnesoid X receptor (FXR), a pivotal factor maintaining bile acid homeostasis, has been recently shown to be a critical factor required for liver regeneration. The elucidation of the mechanism how FXR controls the proliferation of hepatocellular carcinoma cells is useful to establish the therapy for liver cancer. Here, we show that FXR plays a crucial role in the proliferation of human hepatocellular carcinoma cell line, HepG2, Huh7 and HLE. The treatment of HepG2 with FXR siRNA elevates the level of p16/INK4a expression resulting in the inhibition of cell proliferation. By contrast, FXR activation reduces p16/INK4a expression and stimulates the cell proliferation. The ectopic expression of the active form of Ras that causes strong activation of extracellular signal-regulated kinase (ERK) leads to the decrease in FXR expression, suggesting that FXR expression is negatively regulated via Ras/ERK pathway. The elevation of p16/INK4a expression and the inhibition of cell proliferation by FXR knockdown are also observed in Huh7 and HLE. In this study, we have suggested a novel mechanism by which hepatocellular carcinoma cell proliferation is regulated: FXR stimulates cell proliferation by suppressing the p16/INK4a expression, whereas Ras/ERK pathway down-regulates the FXR expression, leading to the suppressed cell proliferation in hepatocellular carcinoma cell lines.

Absorption spectra of constituents of fibers are distinguishable by THz spectroscopy, even for fibers in the same category or species. The advantage of this technique is its sensitivity to the structural differences of the fibers, even if they consist largely of the same components. The THz spectra of cellulosic fibers in the category of plant-derived fibers and regenerated cellulose fibers showed an identifiable character, as an example.

When human erythrocytes were incubated with cigarette smoke (CS) exract for 1 h, the cells were oxidized as assessed by the decrease of cytoplasmic glutathione level. Because the ability of the CS extract pretreated with antioxidants and enzymes that destroy superoxide and hydrogen peroxide was lower, various oxidants in the extract may be responsible for the reduction of cytoplasmic glutathione levels. The binding of autologous IgG to the CS extract-treated cells as assessed by enzyme immunoassay was dramatically increased. Autologous IgG responsible for the binding may be anti-band 3 autoantibody, because inhibitors of anti-band 3 autoantibody binding effectively inhibited the IgG binding. The results indicate that oxidants in CS extract rendered erythrocytes susceptible to binding of anti-band 3 autoantibody, a known antibody that binds to senescent erythrocytes.

X-ray lattice parameter measurements of the (Bi, Pb) 2- x Sr 2- y Ca 2- z Cu 3 O 10+δ system show that a continuously varying solid-solution cation nonstoichiometry exists within -0.1 x y z T c , shows a maximum value at the stoichiometric cation composition and decreases to a lower constant value across the nonstoichiometric composition region with increasing alkaline-earth deficiency. Flux pinning in this system is increased by the cation-vacancy concentration only in the low-temperature range, while it decreased in the high-temperature range. The flux-pinning behavior is discussed in view of its two-dimensionality in the superconductivity for this system.

FGD1 encodes a guanine nucleotide exchange factor for Cdc42. Mutations in the FGD1 gene are responsible for an X-linked disorder known as Aarskog-Scott syndrome (AAS). While most mutations were found in the catalytic region, which consists of Dbl homology (DH) domain and adjacent pleckstrin homology (PH) domain, a missense mutation in the proline-rich domain is also found in a patient with typical clinical features as AAS. In this mutant FGD1, the serine residue at 205 is replaced with isoleucine. We recently demonstrated that FGD1 translocated to the membrane in response to extracellular stimuli such as epidermal growth factor (EGF) whereas FGD1 with S(205)/I substitution did not. Here we show that the proline-rich domain is critical for FGD1-induced directionally persistent cell migration. When inducibly expressed in HeLa Tet-Off cells, FGD1 stimulates directional migration whereas FGD1 with S(205)/I substitution does not affect it. We further demonstrate that FGD1 augments EGF-stimulated c-Jun NH(2)-terminal kinase (JNK) activation. In the presence of JNK inhibitor SP600125, motility of FGD1-expressing cells is significantly impaired, indicating a critical role of JNK in cell migration. However, FGD3, an FGD1 homologue lacking the proline-rich domain, and FGD1 with S(205)/I substitution augment EGF-stimulated JNK activation similarly to FGD1, suggesting that the proline-rich domain is not involved in the regulation of JNK. Finally, we show that FGD1, but not FGD1 with S(205)/I substitution, is phosphorylated in response to EGF, suggesting that the phosphorylation of S(205) may trigger the FGD1 translocation to the leading edge membrane and enable cells to undergo directional migration.

A significant enhancement of Jc in a magnetic field for Ag-sheathed Bi-Pb-Sr-Ca-Cu-O (BPSCCO) tapes has been achieved by post-annealing at reduced temperature after processing. This post-annealing at reduced temperature introduced extra oxygen into the oxide superconductor. Weak links were eliminated and Jc has been increased in the post-annealed tapes by a factor of 1.5 to 3 at 0 T over the normally processed tapes without post-annealing. The optimized Jc values for the post-annealed tapes ranged from 30000 to 57000 A cm-2 at 77.3 K and 0 T. The irreversibility lines measured by a DC SQUID exhibited an improvement in flux pinning in the post-annealed tapes compared with that in normally processed tapes. The introduced oxygen ions are responsible for the enhanced Jc and may affect two dimensionality in superconductivity for the BPSCCO system.

The role of oxygen for the hole doping has been investigated for single-phased (Bi,Pb)2Sr2Ca2Cu3O.z Defects introduced by oxygen have been clarified to be interstitial atoms by pycnometric density measurements. The c axis decreases and the modulation periods along the b axis also decrease with increasing oxygen content in the crystal. It is likely that extra oxygen ions exist between the BiO double layers and those oxygen ions are responsible for the modulation. Samples with oxygen content ranging from 9.99 to 10.18 showed superconductivity. The critical temperature Tc, exhibited a maximum value (109 K) at 10.07 oxygen atoms in the formula unit, which coincided with the average Cu valence of 2.13. The data indicated that hole formation was governed by oxygenation reaction in this system.

When human blood was stored in a citrate-phosphate-dextrose (CPD) solution at 4°C, the susceptibility of the erythrocytes to binding of autologous IgG increased. The autologous IgG binding was partially inhibited by purified Band 3 glycoprotein and its oligosaccharides. The susceptibility of the erythrocytes to binding of 125 I-labeled anti-band 3 IgG autoantibody similarly increased. The results indicate that the anti-band 3 binding sites composed of Band 3 oligosaccharides were generated on the cell surface. The rate of the increase in the susceptibility of the stored cells to the antibody binding was lowered when blood was stored in a CPD solution containing L-ascorbic acid or erythorbic acid, suggesting involvement of an oxidative mechanism in the generation of the binding sites. The cytoplasmic glutathione level of erythrocytes gradually decreased during the blood storage. Storing blood in a CPD solution containing glutathione monoethylester or glutathione monoisopropylester resulted in partial prevention of the decrease in cytoplasmic glutathione level and of the increase in the IgG-binding ability of the cells. Similar preventive effect of glutathione monoethylester was observed in the binding of 125 I-labeled anti-band 3 autoantibody to the stored erythrocytes. Thus, the increase in the susceptibility of the stored erythrocytes to anti-band 3 binding may be caused, at least partially, by an oxidative stress resulting in a decreased cytoplasmic glutathione level.

Electrical and magnetic properties of some layered vanadium oxides, such as Sr3V2O7, Sr4V3O8 and NaV6O11, were studied. Metal-insulator transitions, spin-freezing properties and magnetically ordered states, all of which are considered to have relations to the cuprate high Tc superconductivity, were observed in these systems. Nevertheless, they have not shown the superconductivity. These properties are compared with those for the high Tc superconducting cuprates.

We studied double-strand breaks (DSB) induction and rejoining in clamped and non-clamped transplanted tumours in mice leg after exposure to 80 keV µm(-1) carbon ions and X rays. The yields of DSB in the tumours were analysed by a static-field gel electrophoresis. The OER of DSB after X rays was 1.68±0.31, and this value was not changed after 1 h rejoining time (1.40±0.26). These damages in oxygenated conditions were rejoined 60-70% within 1 h in situ. No difference was found between the exposure to X rays and carbon ions for the induction and rejoining of DSB. Thus, the values of OER and rejoined fraction after exposure to carbon ions were similar to those after X rays, and the calculated relative biological effectivenesses of carbon ion were around 1 under both oxygen conditions. The yields of DSB in vivo depend on exposure doses, oxygen conditions and rejoining time, but not on the types of radiation quality.