Search

Purpose: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. Methods: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients. Results: Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition. Conclusions: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D. [ABSTRACT FROM AUTHOR]

Chromosomal abnormalities are good guideposts when hunting for cancer-related genes. We analyzed copy number alterations of 163 primary gastric cancers using array-based comparative genomic hybridization and simultaneously performed a genome-wide integrated analysis of copy number and gene expression using microarray data for 58 tumors. We showed that chromosome 6p21 amplification frequently occurred secondary to ERBB2 amplification, was associated with poorer prognosis and caused overexpression of half of the genes mapped. A comprehensive small interfering RNA knockdown of 58 genes overexpressed in tumors identified 32 genes that reduced gastric cancer cell growth. Enforced expression of 16 of these genes promoted cell growth in vitro, and six genes showing more than two-fold activity conferred tumor-forming ability in vivo. Among these six candidates, GLO1, encoding a detoxifying enzyme glyoxalase I (GLO1), exhibited the strongest tumor-forming activity. Coexpression of other genes with GLO1 enhanced growth-stimulating activity. A GLO1 inhibitor, S-p-bromobenzyl glutathione cyclopentyl diester, inhibited the growth of two-thirds of 24 gastric cancer cell lines examined. The efficacy was found to be associated with the mRNA expression ratio of GLO1 to GLO2, encoding glyoxalase II (GLO2), another constituent of the glyoxalase system. GLO1 downregulation affected cell growth through inactivating central carbon metabolism and reduced the transcriptional activities of nuclear factor kappa B and activator protein-1. Our study demonstrates that GLO1 is a novel metabolic oncogene of the 6p21 amplicon, which promotes tumor growth and aberrant transcriptional signals via regulating cellular metabolic activities for energy production and could be a potential therapeutic target in gastric cancer. [ABSTRACT FROM AUTHOR]

Sgf29, a component of the SPT-ADA-GCN5 acetyltransferase (SAGA) complex, binds H3K4me2/3 marks and leads to histone H3 acetylation. Previously, we found that downregulation of Sgf29 suppresses c-Myc-mediated malignant transformation. Nonetheless, the upstream regulator of the Sgf29 gene is not yet known. Here, we report that Sry (sex-determining region Y), an HMG (high-mobility group) domain containing transcription factor, directly upregulates Sgf29 gene expression. Sry expression was deregulated in two out of the four tested male rodent hepatocellular carcinoma (rHCC) cell lines. Luciferase reporter and chromatin immunoprecipitation assays indicated that Sry could bind HMG-boxes in the proximal promoter region of the Sgf29 gene. Knockdown of Sry robustly lowered anchorage-independent growth, invasiveness and tumorigenicity of rHCC cells, whereas ectopic expression of Sry conferred more malignant properties. Thus, these data show that Sry is involved in male-specific malignant conversion of rHCCs via Sgf29 upregulation. [ABSTRACT FROM AUTHOR]

Background:A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival.Methods:Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m−2 day 5, mitomycin 7 mg m−2 day 5, cisplatin 14 mg m−2 days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival.Results:A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85).Conclusion:Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT. [ABSTRACT FROM AUTHOR]

Background: We previously reported that the primary tumour/vessel tumour/nodal tumour (PVN) classification is significantly superior to the UICC pTNM classification and the Nottingham Prognostic Index for accurately predicting the outcome of patients with invasive ductal carcinoma of the breast in a manner that is independent of the nodal status and the hormone receptor status.Methods: The purpose of the present study was to compare the outcome predictive power of a modified PVN classification to that of the newly devised pathological UICC pTNM classification and the reclassified Nottingham Prognostic Index in a different group of patients with invasive ductal carcinoma (n=1042) using multivariate analyses by the Cox proportional hazard regression model.Results: The modified PVN classification clearly exhibited a superior significant power, compared with the other classifications, for the accurate prediction of tumour recurrence and tumour-related death among patients with invasive ductal carcinoma in a manner that was independent of the nodal status, the hormone receptor status, and adjuvant therapy status.Conclusion: The modified PVN classification is a useful classification system for predicting the outcome of invasive ductal carcinoma of the breast. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CC) is a highly malignant carcinoma. We attempted to clarify the prognostic significance of c-Met overexpression and its association with clinicopathological factors in patients with CC.Patients and Methods: One hundred and eleven patients with intrahepatic CC (IHCC) and 136 patients with extrahepatic CC (EHCC) who had undergone curative surgery were divided immunohistologically into c-Met(high) and c-Met(low) groups. Clinicopathological factors and outcomes were compared between the groups. c-Met and epidermal growth factor receptor (EGFR) expression was also examined in 10 CC cell lines.Results: The positivity of c-Met was 45.0% in IHCC and 68.4% in EHCC; c-Met(high) expression was demonstrated in 11.7% of IHCC and 16.2% of EHCC. c-Met(high) expression was significantly correlated with the 5-year survival rate for CC overall (P=0.0046) and for IHCC (P=0.0013), histopathological classification in EHCC, and for EGFR overexpression in both IHCC and EHCC. Coexpression and coactivation of c-Met and EGFR were also observed in CC cell lines. Multivariate analysis revealed that c-Met(high) expression was an independent predictor of poor overall and disease-free survival in patients with IHCC.Conclusions: c-Met overexpression is associated with EGFR expression and is a poor prognostic factor in CC. [ABSTRACT FROM AUTHOR]

We report a 64-year-old woman with duodenal varices who underwent balloon-occluded retrograde transvenous obliteration (B-RTO) complicated by intraprocedural variceal rupture. The patient developed shivering and a fever higher than 40°C 3 days after the B-RTO procedure. A blood culture grew Entereobacter cloacoe. This case represents a rare septic complication of B-RTO for duodenal varices. [ABSTRACT FROM AUTHOR]

Objective: To compare the accuracy of gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI with that of diffusion-weighted MRI (DWI) in the detection of small hepatic metastases (2 cm or smaller).Methods: Forty-five patients underwent abdominal MRI at 3 T, including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), heavily T2WI (HASTE), DWI with a b-value of 500 s/mm(2) and contrast-enhanced MRI with Gd-EOB-DTPA. Two groups were assigned and compared: group A (T1WI, T2WI, HASTE and contrast-enhanced study with Gd-EOB-DTPA), and group B (T1WI, T2WI, HASTE and DWI). Two observers independently interpreted the images obtained in a random order. For all hepatic metastases, the diagnostic performance using each imaging set was evaluated by receiver-operating characteristic (ROC) curve analysis.Results: A total of 51 hepatic metastases were confirmed. The area under the ROC curve (Az) of group A was larger than that of group B, and the difference in the mean Az values between the two image sets was statistically significant, whereas, there were three metastases that lay near thin vessels or among multiple cysts and were better visualised in group B than in group A.Conclusion: Gd-EOB-DTPA-enhanced MRI showed higher accuracy in the detection of small metastases than DWI. [ABSTRACT FROM AUTHOR]

Lung cancer shows diverse histological subtypes. Large-cell neuroendocrine cell carcinoma and small-cell lung carcinoma show similar histological features and clinical behaviors, and can be classified as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Here we elucidated the molecular classification of pulmonary endocrine tumors by copy-number profiling. We compared alterations of copy number with the clinical outcome of HGNEC and identified a chromosomal gain of the DEK oncogene locus (6p22.3) that was significantly associated with poor prognosis. We further confirmed that DEK overexpression was associated with poor prognosis in a larger set of HGNEC. Downregulation of DEK by small hairpin RNA led to a marked reduction of in vitro colony formation, in vivo tumorigenicity and chemo-resistance, and was associated with loss of lung cancer stem cell markers. Gene expression profiling revealed that DEK downregulation was associated with altered expression of transcriptional regulators, which specifically include known targets of interchromosomal translocations in hematopoietic tumors, and knockdown of these epigenetic modifiers affected colony formation activity. Our study showed that DEK overexpression, partly through an increase in its gene dose, mediates the activity of global transcriptional regulators and is associated with tumor initiation activity and poor prognosis in HGNEC. [ABSTRACT FROM AUTHOR]

The present study is devoted to the design and statistical investigations of dynamical gene expression networks. In our model problem, we aim to design genetic networks which would exhibit stable periodic oscillations with a prescribed temporal period. While no rational solution of this problem is available, we show that it can be effectively solved by running a computer evolution of the network models. In this process, structural rewiring mutations are applied to the networks with inhibitory interactions between genes and the evolving networks are selected depending on whether, after a mutation, they closer approach the targeted dynamics. We show that, by using this method, networks with required oscillation periods, varying by up to three orders of magnitude, can be constructed by changing the architecture of regulatory connections between the genes. Statistical properties of designed networks, including motif distributions and Laplacian spectra, are considered. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the safety and efficacy of dose-dense weekly chemotherapy, followed by resection and/or thoracic radiotherapy.Methods: Patients with histologically documented thymoma with unresectable stage III disease received 9 weeks of chemotherapy: cisplatin 25 mg m(-2) on weeks 1-9; vincristine 1 mg m(-2) on weeks 1, 2, 4, 6 and 8; and doxorubicin 40 mg m(-2) and etoposide 80 mg m(-2) on days 1-3 of weeks 1, 3, 5, 7 and 9. Patients went on to surgery and post-operative radiotherapy of 48 Gy; those with unresectable disease received 60 Gy radiotherapy.Results: total of 23 patients were entered. The main toxicities of the chemotherapy regimen were neutropenia and anaemia, and 57% of patients completed the planned 9 weeks of therapy. There were no toxic deaths. Of the 21 eligible patients, 13 (62%) achieved a partial response (95% confidence interval: 38-82%). Thirteen patients underwent a thoracotomy and nine (39%) underwent complete resection. Progression-free survival at 2 and 5 years was 80 and 43%, respectively. Overall survival at 5 and 8 years was 85 and 69%, respectively. Survival did not seem to be affected by resection.Conclusion: In thymoma patients, weekly dose-dense chemotherapy has activity similar to that of conventional regimens. Although some patients could achieve complete resection, the role of surgery remains unclear. [ABSTRACT FROM AUTHOR]

Background: To evaluate the safety and efficacy of dose-dense weekly chemotherapy in the treatment of advanced thymoma.Methods: Subjects comprised patients with histologically documented chemotherapy-naïve thymoma with stage-IVa or IVb disease. Thymic carcinoma, carcinoid or lymphoma cases were excluded. Patients received 9 weeks of chemotherapy: cisplatin (25 mg m(-2)) on weeks 1-9; vincristine (1 mg m(-2)) on weeks 1, 2, 4, 6 and 8; and doxorubicin (40 mg m(-2)) and etoposide (80 mg m(-2)) on days 1-3 of weeks 1, 3, 5, 7 and 9. Chemotherapy courses were supported by granulocyte colony-stimulating factor. Post-protocol local therapy was allowed.Results: From July 1997 to March 2004, 30 patients were entered. Three were ineligible due to different histology. Chemotherapy-associated toxicity was mainly haematological and was well tolerated, with no deaths due to toxicity, and 87% of patients completed the planned 9-week regimen. Overall response rate was 59%, with 16 of the 27 eligible patients achieving partial response. Median progression-fee survival (PFS) was 0.79 years (95% confidence interval: 0.52-1.40 years), and PFS at 1 and 2 years was 37 and 15%, respectively. Overall survival rates at 2 and 5 years were 89 and 65%, respectively.Conclusion: In stage-IV thymoma patients, weekly dose-dense chemotherapy offers similar activity to conventional regimens. [ABSTRACT FROM AUTHOR]

Induced radioactivity in natural indium (natIn) foils by high energy neutrons was measured at the KENS Facility, KEK, Japan, where a 16.7 cm thick W target was bombarded by protons of 500 MeV. High energy neutrons consequently produced irradiated the In targets placed at different depths inside a 4 m thick concrete shield placed at the beam exit. The measured activities were compared with the results calculated using the nuclear reaction model codes ALICE-91 and EMPIRE-2.18. To estimate the induced activity, excitation functions of the various radionuclides were calculated using the two codes and folded with the appropriate neutron energy distribution at different depths of the concrete shield. The calculated excitation functions of a given nuclide were found to vary widely from one another in some cases. The performances of the codes for different input parameters like level densities and inverse cross-sections are reported in this paper. Our analysis shows that neither of the two codes reproduced all the measured activities satisfactorily, requiring further improvements in the models adopted. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses > or = 12.5 mg kg(-1) day(-1) (P<0.05), but higher doses (50 mg kg(-1) day(-1), P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg(-1) day(-1)) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Safety and efficacy of intrapericardial (i.p.c.) instillation of bleomycin (BLM) following pericardial drainage in patients with malignant pericardial effusion (MPE) remain unclear. Patients with pathologically documented lung cancer, who had undergone pericardial drainage for MPE within 72 h of enrolment, were randomised to either arm A (observation alone after drainage) or arm B (i.p.c. BLM at 15 mg, followed by additional i.p.c. BLM 10 mg every 48 h). The drainage tube was removed when daily drainage was 20 ml or less. The primary end point was survival with MPE control (effusion failure-free survival, EFFS) at 2 months. Eighty patients were enrolled, and 79 were eligible. Effusion failure-free survival at 2 months was 29% in arm A and 46% in arm B (one-sided P=0.086 by Fisher's exact test). Arm B tended to favour EFFS, with a hazard ratio of 0.64 (95% confidence interval: 0.40-1.03, one-sided P=0.030 by log-rank test). No significant differences in the acute toxicities or complications were observed. The median survival was 79 days and 119 days in arm A and arm B, respectively. This medium-sized trial failed to show statistical significance in the primary end point. Although ipc BLM appeared safe and effective in the management of MPE, the therapeutic advantage seems modest. [ABSTRACT FROM AUTHOR]

The purpose of our study was to evaluate the usefulness of diffusion-weighted imaging in predicting the responses to neoadjuvant therapy for head and neck squamous cell carcinomas. Diffusion-weighted, T2-weighted, and gadolinium-enhanced T1-weighted images were obtained from 28 patients with untreated head and neck squamous cell carcinomas with histological proof. A blinded radiologist evaluated the quantitative and qualitative signal intensities and apparent diffusion coefficients (ADCs) in the lesions on each sequence. All patients were treated by neoadjuvant therapies, and the post-therapeutic tumor regression rate was determined. Both the quantitative and qualitative signal intensities on diffusion-weighted images showed positive correlations (r = 0.367 and 0.412, p < .05), and the ADCs showed a weak, inversed correlation (r = -0.384, p < .05) with the tumor regression rates. Diffusion-weighted imaging including an assessment by ADCs may be able to predict tumor response to neoadjuvant therapy for head and neck squamous cell carcinomas. [ABSTRACT FROM AUTHOR]

Preoperative chemotherapy is a promising strategy in patients with early-stage resectable non-small-cell lung cancer (NSCLC); optimal chemotherapy remains unclear. Clinical (c-) stage IB/II NSCLC patients were randomised to receive either two cycles of docetaxel (D)-cisplatin (P) combination chemotherapy (D 60 mg m(-2) and P 80 mg m(-2) on day 1) every 3-4 weeks or three cycles of D monotherapy (70 mg m(-2)) every 3weeks. Thoracotomy was performed 4-5 weeks (DP) or 3-4 weeks (D) after chemotherapy. The primary end point was 1-year disease-free survival (DFS). From October 2002 to November 2003, 80 patients were randomised. Chemotherapy toxicities were mainly haematologic and well tolerated. There were two early postoperative deaths with DP (one intraoperative bleeding and one empyema). Pathologic complete response was observed in two DP patients. Docetaxel-cisplatin was superior to D in terms of response rate (45 vs 15%) and complete resection rate (95 vs 87%). Both DFS and overall survival were better in DP. Disease-free survival at 1, 2 and 4 years were 78, 65 and 57% with DP, and were 62, 44 and 36% with D, respectively. Preoperative DP was associated with encouraging resection rate and DFS data, and phase III trials for c-stage IB/II NSCLC are warranted. [ABSTRACT FROM AUTHOR]

RECK is a novel tumour suppressor gene that negatively regulates matrix metalloproteinases (MMPs) and inhibits tumour invasion, angiogenesis and metastasis. In the present study, we investigated the effects of epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, on the methylation status of the RECK gene and cancer invasion in oral squamous cell carcinoma cell lines. Our results showed that treatment of oral cancer cells with EGCG partially reversed the hypermethylation status of the RECK gene and significantly enhanced the expression level of RECK mRNA. Inhibition of MMP-2 and MMP-9 levels was also observed in these cells after treatment with EGCG. Interestingly, EGCG significantly suppressed cancer cell-invasive ability by decreasing the number of invasive foci (P<0.0001) as well as invasion depth (P<0.005) in three-dimensional collagen invasion model. Although further investigation is required to assess the extent of contribution of RECK on MMPs to the suppression of invasive behaviour, these results support the conclusion that EGCG plays a key role in suppressing cell invasion through multiple mechanisms, possibly by demethylation effect on MMP inhibitors such as RECK. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52-4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05-3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

The 63Ni in copper samples exposed by the Hiroshima atomic bomb was clearly measured for the first time by liquid scientillation method For the measurement, the chemical separation scheme previously developed was improved The obtained result was agreed with that estimated by the new dosimetry system for atomic bomb survivor studies, DS02. [ABSTRACT FROM AUTHOR]

We compared the efficacy and the safety of a carboplatin plus etoposide regimen (CE) vs split doses of cisplatin plus etoposide (SPE) in elderly or poor-risk patients with extensive disease small-cell lung cancer (ED-SCLC). Eligibility criteria included: untreated ED-SCLC; age 70 and performance status 0–2, or age <70 and PS 3. The CE arm received carboplatin area under the curve of five intravenously (IV) on day 1 and etoposide 80 mg m−2 IV on days 1–3. The SPE arm received cisplatin 25 mg m−2 IV on days 1–3 and etoposide 80 mg m−2 IV on days 1–3. Both regimens were given with granulocyte colony-stimulating factor support in a 21–28 day cycle for four courses. A total of 220 patients were randomised. Median age was 74 years and 74% had a PS of 0 or 1. Major grade 3–4 toxicities were (%CE/%SPE): leucopenia 54/51, neutropenia 95/90, thrombocytopenia 56/16, infection 7/6. There was no significant difference (CE/SPE) in the response rate (73/73%) and overall survival (median 10.6/9.9 mo; P=0.54). Palliation scores were very similar between the arms. Although the SPE regimen is still considered to be the standard treatment in elderly or poor-risk patients with ED-SCLC, the CE regimen can be an alternative for this population considering the risk–benefit balance.British Journal of Cancer (2007) 97, 162–169. doi:10.1038/sj.bjc.6603810 www.bjcancer.com Published online 19 June 2007 [ABSTRACT FROM AUTHOR]

For evaluation of radioactivity induced in the concrete samples from accelerator facilities, the residual radioactivity in concrete sample, collected from seven accelerator facilities, was determined by γ-ray spectrometry. The tritium was extracted by the heating method using an IR furnace, and measured with a liquid scintillation counter. It was found that the major radioisotopes activated mainly by neutrons in the concrete samples were 152Eu, 60Co, 134Cs and 3H. The concentrations of radioactivities induced by thermal neutron capture are the highest at a depth of 10 cm in the concrete wall. The correlation between tritium, 60Co and 152Eu activity was investigated by measuring many concrete samples for seven accelerator facilities. The results indicate that their activities are strongly correlated with each other. So it would also be concluded that the total activity in shielding concrete could be estimated on the basis of the activities of 60Co and 152Eu. [ABSTRACT FROM AUTHOR]

Hypoxia is closely associated with the radioresistance of tumours; therefore, targeting hypoxic areas is very important for cancer therapy. The aim of this study is to establish such a targeting strategy by applying a bacterial cytosine deaminase (BCD)/5-fluorocytosine (5-FC) gene therapy system and to examine whether the strategy enhances the efficacy of radiotherapy in a tumour xenograft. The hypoxia-responsive promoter 5HREp, in which five copies of the hypoxia-response element (HRE) enhance transcription from a cytomegalovirus minimal promoter, was employed to induce the expression of BCD under hypoxic conditions. The adenoviral vector Ad/5HREp-BCD, encoding the gene 5HREp-BCD, robustly induced BCD expression under hypoxic conditions and this led to significant cytotoxicity in combination with 5-FC in vitro. Intratumoral Ad/5HREp-BCD administration resulted in the expression of BCD at the border between normoxic and necrotic regions. The BCD/5-FC gene therapy enhanced the therapeutic effects of both single (12.5 Gy) and fractionated (3 Gy x 5 days) radiotherapy with few side effects and significantly increased tumour growth doubling time by up to 2.4-fold (P<0.01) and 2.5-fold (P<0.05), respectively. All of these results suggest that the present BCD/5-FC gene therapy has the ability to specifically target hypoxic tumour cells and significantly improves the control of tumour growth after radiotherapy. [ABSTRACT FROM AUTHOR]

Host genetic factors may play a key role in determining the long-term outcome of the Helicobacter pylori infection. Toll like receptor 4(TLR4) and CD14-mediated recognition of lipo-polysaccharide (LPS) is required for efficient recognition of Gram-negative bacterial infections. We investigated the effects of common polymorphisms of TLR4 Asp299Gly, Thr399Ile and CD14 promoter –C159T on the risk of gastric cancer including its subtypes and clinicopathologic features. We also investigated the effects of these polymorphisms on histologic degree of H. pylori induced gastritis. The study was performed in 149 gastric cancer(GC) cases [mean age 64.0 ±12.4, M:F = 109:40] and 94 patients without evidence of GC (mean age 64.1 ±12.3, M:F = 65:25, Peptic ulcer diseases = 43.6 %, gastritis = 56.4 %) as the control group. TLR4 Asp299Gly, Thr399Ile and CD14 promoter – C159T were determined by PCR-RFLP in all the patients. Gastritis scores of non-cancerous gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects(n = 174). The frequencies of CD14-260 TT and T carrier were significantly lower in patents with intestinal type gastric cancer than in controls (OR = 0.31;95 % CI = 0.12–0.78, OR = 0.38; 95 % CI = 0.18–0.81, respectively) Compared with patients older than 61 years, the atrophy score in antrum was significantly lower in TT and CT patients.TLR4 Asp299Gly, Thr399Ile were not detected in all the patients. Our data suggest that CD14 promoter-159TT and T carrier were associated with lower risk of developing gastric mucosal atrophy in H. pylori infected patients more than 61 years of age, and these genotypes may reduce the risk of intestinal type gastric cancer and TLR4 Asp299Gly, Thr399Ile are very rare in the Japanese population. [ABSTRACT FROM AUTHOR]

Laser-induced fluorescence spectroscopy has been employed to characterize the plume produced in nanosecond laser ablation of metallic neodymium. The kinetic-energy distributions of the neutral and ionized atoms in the plume under both vacuum and gas environments have been investigated. The population distribution of metastable levels in the ablated atoms was also derived. The results show that some metastable states are more heavily populated than predicted by a Boltzmann-type distribution. These investigations provide preliminary data for the design of a new type of resonance photo-ionization laser ion source as well as for high-resolution laser spectroscopy of refractory elements. [ABSTRACT FROM AUTHOR]

An infrared furnace (ULVAC RHL-410P) was newly applied to the extraction of tritium from concrete samples. After studying the tritium recovery yield regarding temperature and time, the best extraction conditions were set to 800 °C (setting temperature) for 30 minutes under Ar-gas flow of 200 ml/min. Tritium was collected in two cold traps and transferred to a vial for liquid scintillation counting. It took about one hour for the extraction of tritium. Reproducibility and recovery yield of tritium were about 100% compared to the values obtained by the ordinary heating method using an electric furnace. Gamma-ray emitters and tritium of concrete samples collected from several accelerator facilities have been determined. The specific activity of tritium strongly correlated with that of 152Eu and 60Co, so it was found that tritium was produced by thermal neutron reaction by the 6Li(n,α)3H reaction. The results indicate that the tritium specific activity in concrete can be estimated from the 60Co specific activity obtained easily by γ-ray measurement. [ABSTRACT FROM AUTHOR]

Dysregulation of apoptosis plays an important role in tumour progression and resistance to chemotherapy. The X-linked inhibitor of apoptosis (XIAP) is considered to be the most potent caspase inhibitor of all known inhibitor of apoptosis-family members. Only recently, an antagonist of XIAP has been identified, termed Smac/DIABLO. To explore the relevance of antiapoptotic XIAP and proapoptotic Smac/DIABLO for tumour progression in renal cell carcinomas (RCCs), we analysed XIAP and Smac/DIABLO mRNA and protein expression in the primary tumour tissue from 66 RCCs of all major histological types by quantitative real-time PCR, Western blot and ELISA. X-linked inhibitor of apoptosis and Smac/DIABLO mRNA expression was found in all RCCs. Importantly, the relative XIAP mRNA expression levels significantly increased from early (pT1) to advanced (pT3) tumour stages (P = 0.0002) and also with tumour dedifferentiation (P = 0.04). Western blot analysis confirmed the tumour stage-dependent increase of XIAP expression on the protein level. In contrast, mRNA and protein expression levels of Smac/DIABLO did not significantly change between early and advanced tumour stages or between low and high tumour grades. Consequently, the mRNA expression ratio between antiapoptotic XIAP and proapoptotic Smac/DIABLO markedly increased during progression from early (pT1) to advanced (pT3) tumour stages. Moreover, RCCs confined within the organ capsule (pT1 and pT2) exhibited a significantly lower XIAP to Smac/DIABLO expression ratio when compared with RCCs infiltrating beyond the kidney (pT3; P = 0.01). Thus, our investigation demonstrates that the delicate balance between XIAP and Smac/DIABLO expression is gradually disturbed during progression of RCCs, resulting in a relative increase of antiapoptotic XIAP over proapoptotic Smac/DIABLO, thereby probably contributing to the marked apoptosis resistance of RCC. [ABSTRACT FROM AUTHOR]

Measurements of aerosols were made in 2001 and 2002 at Dunhuang (40°00′N, 94°30′E), China to understand the nature of atmospheric particles over the desert areas in the Asian continent. Balloon-borne measurements with an optical particle counter suggested that particle size and concentration had noticeable peaks in super micron size range not only in the boundary mixing layer but also in the free troposphere. Super-micron particle concentration largely decreased in the mid tropopause (from 5 to 10 km; above sea level, a.s.l.). Lidar measurements made during August 2002 at Dunhuang suggested the possibility that mixing of dust particles occurred from near the ground to about 6km even under calm weather conditions, and a large depolarization ratio of particulate matter was found in the aerosol layer. The top of the aerosol layer was found at heights of nearly 6km (a.s.l.). It is strongly suggested that nonspherical dust particles (Kosa particles) frequently diffused in the free atmosphere over the Taklamakan desert through small-scale turbulences and are possible sources of dust particles of weak Kosa events that have been identified in the free troposphere not only in spring but also in summer over Japanese archipelago. Electron microscopic experiments of the particles collected in the free troposphere confirmed that coarse and nonspherical particles observed by the mineral particle were major components of coarse mode (diameter larger than 1 μm) below about 5 km over Dunhuang, China. [ABSTRACT FROM AUTHOR]

A novel glycoprotein, dysadherin, has an anti-cell — cell adhesion function through downregulating F-cadherin. In this study, we investigated the expressions of dysadherin and E-cadherin in 82 patients with stage II and III colorectal carcinomas to determine the correlation between the two molecules and the clinicopathologic features of each tumour. Dysadherin was not expressed in normal colorectal epithelium. Fifty-one per cent of tumours showed dysadherin immunopositivity in over 50% of cancer cells. Thirty-eight per cent of tumours showed reduced E-cadherin immunopositivity. The increased expression of dysadherin was significantly associated with lung metastasis (P = 0.003). The increased expression of dysadherin had a significant impact on patient survival (P=0.0099 and 0.0036, log-rank test for overall and recurrence-free survival rate, respectively). Furthermore, tumour with increased expression of dysadherin and reduced expression of E-cadherin showed the worst prognosis (P = 0.0043 and 0.0028, log-rank test for overall and recurrence-free survival rate, respectively). These results suggest that increased dysadherin expression is a significant indicator of poor prognosis for patients with advanced colorectal carcinoma. [ABSTRACT FROM AUTHOR]

For decommissioning of the cyclotron and electron synchrotron facilities, the residual radioactivity in surface and core samples of concrete, collected from various parts of buildings, was determined by gamma-ray spectrometry. It was found that the concrete samples were activated mainly by neutrons and that the major radioisotopes were 152Eu, 60Co, 134Cs, 22Na and 54Mn. The maximum activity induced by thermal neutron capture was observed at the depth of 10 cm in the concrete wall near the deflector of the cyclotron. Tritium was also produced by the neutron reaction, because its concentration was proportional to the activities of 152Eu and 60Co. The surface dose rates inside the accelerator room were also monitored to define the decontamination area. The surface dose rate was proportional to the residual radioactivity, such as 60Co. A careful evaluation was very useful in order to minimize the radioactive waste during decontamination. [ABSTRACT FROM AUTHOR]

Measurements of aerosol were made in August and October 2001, and January 2002, at Dunhuang, China (40°00′N, 94°30′E), to understand the nature of atmospheric particles over the desert areas in the Asian continent. Balloon-borne measurements with an optical particle counter suggested that particle size and concentration had a noticeable peak in size range of super micron in not only the boundary mixing layer but also the free troposphere. Thickness of the boundary mixing layer, from distributions of particle concentration, was about 4 km in summer (17 August 2001), about 2.5 km in fall (17 October 2001), and about 3 km in winter (11 January 2002), which suggest active mixing of particles near the boundary in summer. Number-size distribution of particle showed a noticeable peak in the super micron particles size range in the mixing boundary layer: 0.4–2 particles cm-3 at diameter >1.2 μm in summer, 0.05–4 particles cm-3 at diameter >1.2 μm in fall, and 0.1–5 particles cm-3 at diameter >1.2 μm in winter. In winter strong inversion of atmospheric temperature was found in the height range from the boundary to about 3 km and vertical distribution of particle concentration well corresponded with the temperature distribution. Chemical elements of individual aerosols, which were collected in the boundary layer atmosphere at Dunhuang (18 October 2001) were analyzed with an electron microscope equipped with EDX. Those single particle analysis suggested that most of the particles with super micron size were soil particles, and those particles had little sulfate on its surface. This is a very important different point, comparing with the chemical state of soil particles, which were transported from the desert area of China to Japan, and showed frequently the existence of sulfate on the particle surface. Therefore, it is strongly suggested that dust particles can be chemically modified during their long-range transport from desert areas to Japan. [ABSTRACT FROM AUTHOR]

Vertical changes of aerosol concentration and size in the free troposphere over the Asian desert areas were firstly observed using a balloon-borne optical particle counter at DunHuang, China (40°00′N, 94°30′E) (17 August and 17 October 2001, and 11 January 2002). In the free troposphere highly concentrated aerosol layers were frequently observed, suggesting the importance of regional scale particle transportation over the Asian continent. Concentration of particles with a diameter larger than 0.15 μm was about 5–10 particles cm-3 in the free troposphere. Particle number-size distribution in the free troposphere shows important contribution of super micron particles. Regional scale transportation, in addition to diffusion of soil particles from the lower atmosphere to the free troposphere through local and small scale air motions, is suggested by backward trajectory analysis of air masses containing super micron particles. The importance of horizontal transport of coarse size particles in the free troposphere was strongly suggested. Thickness of the boundary mixing layer, from distributions of particle concentration, was about 4 km in summer (17 August 2001) and apparently higher than the height of layers in fall (17 October 2001) and in winter (11 January 2002), which suggest an active mixing of particles near the boundary in summer. In winter measurement (11 January 2002), strong inversion was found in the vertical profile of temperature, suggesting cold ground surface and vertically stable atmosphere near the ground. [ABSTRACT FROM AUTHOR]

Acute cerebral ischemia causes hypoxic neuronal cell death by necrosis and apoptosis. Expression of anti-apoptotic transgenes in ischemic brain may provide a useful therapeutic strategy for alleviation of postischemic damage. The present study investigates liposome-mediated transfer of the human bcl-2 protein in a rat model of focal transient ischemia due to middle cerebral artery (MCA) occlusion. Two different types of plasmid vectors were used for bcl-2 expression: one driven by the constitutive cytomegalovirus promoter (pCMV) and another based on the hypoxiainducible human vascular endothelial growth factor promoter (pHRE). Cationic liposome/plasmid DNA complexes (lipoplexes) were injected directly into the cerebrospinal fluid (CSF) of rats immediately after MCA occlusion. The brains of treated and control animals were analyzed 48 h later. Infarct volumes and numbers of apoptotic cells were quantified. Occlusion of the MCA resulted in ipsilateral cerebral infarcts in all study animals. Transfer of the bcl-2 gene resulted in high level widespread protein expression in the case of the pCMV-bcl2 plasmid, while animals treated with the pHREbcl2 vector showed lower expression levels of bcl2 which were in addition limited to the ischemic area. Treatment with pCMV-bcl2, but not with pHRE-bcl2, was able to significantly reduce the infarct volume, which was 109 ± 8 mm³ for pCMV-bcl2, 152 ± 29 mm³ for pHRE-bcl2, and 155 ± 18 mm³ for control animals. Animals transfected with either vector showed a significant reduction in numbers of apoptotic cells in the infarct and penumbra area compared with controls. There were no short-term neurological side-effects of the CSF injection of lipoplexes or of bcl-2 expression. In conclusion, the hypoxia-inducible bcl-2 expression mediated by intrathecal lipoplexes may represent a novel, biologically safe and lesion-selective therapeutic approach for neuroprotection after acute cerebral ischemia. [ABSTRACT FROM AUTHOR]

The crystal structures and microstructures of AlN $$(11\overline 2 0)$$ /GaN $$(11\overline 2 0)$$ epitaxial films on just-cut and ±4° off-cut Al2O3 $$(1\overline 1 02)$$ substrates grown by metal organic chemical vapor deposition (MOCVD) are investigated using high-resolution X-ray diffractometry and transmission electron microscopy, and are compared with those of AlN $$(11\overline 2 0)$$ film on +4° off-cut Al2O3 $$(1\overline 1 02)$$ substrate. In the AlN/Al2O3(+4° off-cut) film and the AlN/GaN/Al2O3 (just-cut, −4° off-cut) films, cracks parallel to the $$[1\overline 1 00]$$ AlN direction and perpendicular to the interfaces of the films and the substrates are observed. The AlN/Al2O3 and AlN/GaN interfaces exhibit low crystallinity in which moiré fringes are observed. On the other hand, in the AlN/GaN/Al2O3(+4° off-cut) film, no cracks form. The GaN layer buffers the lattice mismatch between the AlN film and the Al2O3 substrate, and moiré fringes are not observed in the GaN/Al2O3 and AlN/GaN interfaces. On the basis of these results, the effects of the interface structures on cracking are discussed. [ABSTRACT FROM AUTHOR]

Background. The problem of whether surgical or conservative treatment is indicated for ruptured hepatocellular carcinoma (HCC) has not been analyzed from the viewpoint of long-term development of hepatitis viral infection from liver fibrosis to liver cirrhosis. Although transcatheter arterial embolization (TAE) for hemostasis followed by two-stage hepatectomy has been established as the best treatment for ruptured HCC, there still remain difficulties in the treatment of some patients. Methods. Twelve patients with ruptured HCC who were surgically or conservatively treated were retrospectively analyzed in terms of modality of treatment, liver function, extension of HCC, complications, survival rate, and cause of death. Results. Tumor rupture can occur either in the early phase or in the terminal phase during the development from liver fibrosis to liver cirrhosis, while tumor rupture occurs at the advanced stage in terms of HCC extension. TAE for emergent hemostasis or prevention of re-bleeding was performed in ten patients, while TAE was contraindicated in one patient and emergent laparotomy for hemostasis was performed in one patient. In four patients, elective extended surgical resection was performed, because liver function was evaluated as clinical stage 1 according to the General rules for the clinical and pathological study of primary liver cancer of the Liver Cancer Study Group of Japan. In seven patients, conservative or medical treat-ment was selected, because liver function was evaluated as poor. The surgically treated group, who could tolerate extensive operation, survived longer than the conservatively treated group. Conclusions. While TAE remains the best method to employ for hemostasis, it still has limitations. Hence, we should be mindful of other possible modalities for hemostasis and their outcomes. Rupture of HCC at an early phase in the development of liver fibrosis is a good indication for elective surgical treatment and should be distinguished from rupture in the terminal phase of liver cirrhosis, which should be treated conservatively. Although elective surgical treatment can be performed in selected patients, tumor size and location of HCC, in addition to liver function, should be taken into consideration. [ABSTRACT FROM AUTHOR]

The cracking mechanism in AlN(11―20)/α-Al2O3(1―102) heteroepitaxial film grown by MOCVD is discussed. The crystal structure and microstructure of an AlN/Al2O3 film and an AlN/GaN/Al2O3 film are compared using high-resolution X-ray diffractometry, optical microscopy, scanning electron microscopy, and transmission electron microscopy. In the AlN/Al2O3 film, cracks parallel to the [1―100]AlN direction and perpendicular to the interface of the film and the substrate are observed. The cracks do not propagate to the AlN film surface. The tips of the cracks are widest in the AlN film, and the cracks narrow as they penetrate deeply into the substrate. On the other hand, in the AlN/GaN/Al2O3 film, no cracks are observed. A concave curvature is observed in the AlN film with cracks on the Al2O3 substrate along the [0001]AlN direction, whereas a convex curvature is observed in the AlN film without cracks. On the basis of these results, the cracks, formed in the AlN film due to the tensile stress along the [0001]AlN direction during the epitaxial growth, propagate to the AlN film surface and into the Al2O3 substrate. On the other hand, in the AlN/GaN/Al2O3 film, it seems that the GaN buffer layer suppresses the tensile stress; as a consequence, no cracks occur. [ABSTRACT FROM AUTHOR]

Expression of anti-apoptotic or neurotrophic transgene proteins in hypoxic neurons may provide a novel therapeutic strategy for neuroprotection and alleviation of damage to ischemic brain areas. NT2, a human neoplastic cell line which terminally differentiates into postmitotic neurons (NT2N) by treatment with retinoic acid was used in this study as a cell culture model for human neuronal cells. The hypoxia-inducible VEGF promoter in plasmid vectors was employed to drive the expression of marker genes (luciferase) and therapeutic genes (bcl2) in hypoxic NT2 cells and NT2N neurons in culture. Cationic liposomes complexed with plasmid DNA were used for transfection of vectors with the constitutive cytomegalovirus promoter (pCMV) or the hypoxia-inducible VEGF promoter (pHRE). Hypoxic or normoxic control NT2 cells transfected with pCMV-luciferase showed high transgene expression (2.4 × 10[sup 8] relative light units (RLU)/mg protein). Control NT2 cells transfected with pHRE-luciferase had a rather low activity (4.9 × 10[sup 6] RLU/mg protein), which was induced 34-fold under hypoxic conditions. Four-fold induction of luciferase expression was obtained in hypoxic NT2N neurons transfected with pHRE compared with normoxic controls. The hypoxia-induced luciferase expression in NT2N cells was 34% of the activity of pCMV-luciferase under the same conditions. Transfection of NT2N neurons with pCMV-bcl2 or pHRE-bcl2 was demonstrated to reduce significantly the numbers of apoptotic cells after hypoxia. These results demonstrate efficient VEGF promoter-mediated induction of transgene expression in hypoxic human neurons. This cell culture model may be employed for the further investigation of therapeutic proteins against ischemic brain damage due to neuronal loss. [ABSTRACT FROM AUTHOR]

We consider the nonlinear Sturm-Liouville problem¶¶ $ -u''(t) = \mid u(t)\mid^{p-1}u(t) - \lambda u(t), t \in I :=(0,1), u(0) = u(1) = 0 $, ¶¶ where p > 1 and $ \lambda \in {\bf R} $ is an eigenvalue parameter. To investigate the global L 2-bifurcation phenomena, we establish asymptotic formulas for the n-th bifurcation branch $ \lambda = \lambda_n (\alpha) $ with precise remainder term, where $ \alpha $ is the L 2 norm of the eigenfunction associated with $ \lambda $ . [ABSTRACT FROM AUTHOR]

We are developing new gene therapy vectors whose expression is selectively activated by hypoxia, a unique feature of human solid tumors. As vascular endothelial growth factor (VEGF) is upregulated by hypoxia, such regulatory mechanisms would enable us to achieve hypoxia-inducible expression of therapeutic genes. Constructs with five copies of hypoxia-responsive elements (HREs) derived from the 5'untranslated region (UTR) of the human VEGF showed excellent transcriptional activation at low oxygen tension relevant to tumor hypoxia. In an attempt to achieve higher responsiveness, various combinations of HREs and promoters were examined. In addition, we also investigated whether the 3' UTR of the VEGF gene would confer increased post-transcriptional mRNA stability under hypoxic conditions. However, despite increases in the hypoxic/aerobic ratio of luciferase activity, gene expression with 3' UTR was lower due to mRNA destabilization by AUrich elements (AREs). Thus, we found no benefit from the inclusion of the 3' UTR in our vectors. Of all the vectors tested, the combination of 5HRE and a CMV minimal promoter exhibited hypoxia responsiveness (over 500-fold) to the similar level to the intact CMV promoter. We propose that this vector would be useful for tumor selective gene therapy. [ABSTRACT FROM AUTHOR]

We describe the isolation of a new type of RecQ homologue in Drosophila melanogaster, RECQE. The Recqe gene consists of five exons and four introns, and encodes a protein of 1058 amino acids with a predicted molecular weight of 120,000 Da. The RECQE protein has seven helicase motifs. The helicase domain shows 42% identity overall to that of Escherichia coli RecQ DNA helicase, and is most closely related to Homo sapiens RecQL5 and Caenorhabditis elegans E03A3.2. The C-terminal region of RECQE protein is unique and the longest known among members of the RecQ superfamily. We demonstrate that the RECQE protein has DNA helicase activity and that the C-terminal region is dispensable for this activity. The RECQE mRNA accumulates in oocytes and is expressed at high levels in early embryos. We show for the first time that the expression of a RecQ homologue is developmentally regulated in embryos. These data suggest that the DNA helicase activity of RECQE might be involved in the DNA metabolism of early embryos. [ABSTRACT FROM AUTHOR]

Copyright of Der Orthopäde is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The excitation function for the 63Cu(n, p) 63Ni reaction were measured using neutrons produced by the T(p, n) reaction at En=∼1.5 MeV, D(d, n) at En=∼6.5 MeV and T(d, n) at En=∼14 MeV, respectively. Irradiations were performed using the dynamitron accelerator at the Fast Neutron Laboratory of Tohoku University. After irradiation, the nickel was separated by anion-exchange and solvent extraction. The 63Ni was measured by liquid scintillation method. The cross sections obtained were compared with the calculated values of JENDL-3. [ABSTRACT FROM AUTHOR]

We have isolated a Saccharomyces cerevisiae mutant that shows an increased tendency to form cytoplasmic petites (respiration-deficient ρ− or ρ0 mutants) in response to treatment of cells growing on a solid medium with the DNA-damaging agent methyl methanesulfonate or ultraviolet light. The mutation in this strain, atm1-1, was found to cause a single amino acid substitution in ATM1, a nuclear gene that encodes the mitochondrial ATP-binding cassette (ABC) transporter. When the mutant cells were grown in liquid glucose medium, they accumulated free iron within the mitochondria and at the same time gave rise to spontaneous cytoplasmic petite mutants, as seen previously in cells carrying a mutation in a gene homologous to the human gene responsible for Friedreich's ataxia. Analysis of the effects of free iron and malonic acid (an inhibitor of oxidative respiration in mitochondria) on the incidence of petites among the mutant cells indicated that spontaneous induction of petites was a consequence of oxidative stress rather than a direct effect of either a defect in the ATM1 gene or the accumulation of free iron. We observed an increase in the incidence of strand breaks in the mitochondrial DNA of the atm1-1 mutant cells. Furthermore, we found that rates of induction of petites and accumulation of strand breaks in mitochondrial DNA were enhanced in the atm1-1 mutant by the introduction of another mutation, mhr1-1, which results in a deficiency in mitochondrial DNA repair. These observations indicate that spontaneous induction of petites in the atm1-1 mutant is a consequence of oxidative damage to mitochondrial DNA mediated by enhanced accumulation of mitochondrial iron. [ABSTRACT FROM AUTHOR]

The mitochondrial single-stranded DNA-binding protein (SSB) encoded by a nuclear gene, RIM1, is a homolog of Escherichia coli SSB. The addition of glucose decreased the amount of RIM1-mRNA in cells growing in a glycerol medium, but increased the amount of the immature RIM1-mRNA. The changes in the amounts of both mature and immature RIM1-mRNAs were dependent on SRN1/REG1/HEX2, a gene relating to pre-mRNA-splicing and glucose repression. These observations suggest that the expression of the mitochondrial SSB is regulated, at least in part, by pre-mRNA splicing under the control of glucose repression. [ABSTRACT FROM AUTHOR]

The surface tension of refrigerant mixtures, i.e., R-410A (50 mass% R-32/50 mass% R-125), R-410B (45 mass% R-32/55 mass% R-125), R-407C (23 mass% R-32/25 mass% R-125/52 mass% R-134a), R-404A (44 mass% R-125/52 mass% R-143a/4 mass% R-134a), and R-507 (50 mass% R-125/50 mass% R-143a), has been measured and correlated in the present study. Although the first three mixtures are very important as promising replacements for R-22 in air-conditioners and heat-pumps and the last two are promising replacements for R-502, surface tension data for these mixtures were not previously available. The measurements were conducted under conditions of coexistence of the sample liquid and its saturated vapor in equilibrium. The differential capillary rise method (DCRM) was used, with two glass capillaries with inner radii of 0.3034±0.0002 and 0.5717±0.0002 mm. The temperature range covered was from 273 to 323 K, and the uncertainty of measurements for surface tensions and temperatures is estimated to be at most ±0.2 mN·m−1 and ±20 mK, respectively. A mixing rule was selected for representing the temperature dependence of the resultant data. These data were successfully represented by a mixing rule using mass fraction based on the van der Waals correlation. [ABSTRACT FROM AUTHOR]

A newly synthesized antidiabetic agent, JTT-501 is an isoxazolidinedione rather than a thiazolidinedione. An oral dose of JTT-501 (100 mg · kg–1· day–1) given to 12-week-old male Zucker fatty rats for 7 days led to the amelioration of both hyperinsulinaemia (40 % of non-treated) and hypertriglyceridaemia (23 % of non-treated) as well as a 2.4-fold increased insulin sensitivity as determined by a euglycaemic insulin clamp. In our study, we further evaluated the acute effect of JTT-501 on both the glucose infusion rates (GIR) and insulin signalling in skeletal muscle. Male Sprague-Dawley (SD) rats aged 10 weeks were injected intravenously with JTT-501 (5 mg/kg) and then a euglycaemic insulin clamp was initiated and glucose infusion rates monitored for 150 min. We found that this treatment increased the glucose infusion rate by 33 % during the last 30 min in SD rats. After the clamp had been initiated for 30 min, the insulin-stimulated phosphatidylinositol 3-kinase (PI3-kinase) activities co-immunoprecipitated with insulin receptor substrate 1 (IRS-1) were also enhanced, resulting in increased glycogen synthase activities in the soleus muscles. Treatment with JTT-501 also enhanced the phosphorylation of insulin receptors and insulin receptor-substrate 1 rapidly as well as the phosphatidylinositol 3-kinase activities, which were stimulated by a bolus injection of insulin. Similarly, JTT-501 stimulated the glucose infusion rate by 30 % and enhanced insulin signalling in Zucker fatty rats. In conclusion, a newly developed isoxazolidinedione, JTT-501, rapidly potentiates the insulin sensitivity of skeletal muscle by enhancing insulin signalling and could be useful for the treatment of insulin-resistant diabetic subjects. [Diabetologia (1999) 42: 151–159] [ABSTRACT FROM AUTHOR]

We isolated six clones of weakly tumorigenic fibrosarcoma (QR) from the tumorigenic clone BMT-11 cl-9. The QR clones were unable to grow in normal C57BL/6 mice when injected s.c. (1 x 10[SUP5] cells). However, they formed aggressive tumours upon co-implantation with a 'foreign body', i.e. a gelatin sponge, and the rate of tumour take ranged from 8% to 58% among QR clones. The enhanced tumorigenicity was due to host cell-mediated reaction to the gelatin sponge (inflammation). Immunoblot analysis and enzyme activity assay revealed a significant inverse correlation between the frequencies of tumour formation by QR clones and the levels of manganese superoxide dismutase (Mn-SOD, P<0.005) and glutathione peroxidase (GP[SUBX], P<0.01) in the respective tumour clones. Electron spin resonance (ESR) revealed that superoxide-scavenging ability of cell lysates of the QR clone with high level of Mn-SOD was significantly higher than that with low level of the antioxidative enzyme in the presence of potassium cyanide, an inhibitor for copper-zinc superoxide dismutase (CuZn-SOD) (P<0.001). Minisatellite mutation (MSM) induced by the inflammatory cells in tumour cells were investigated by DNA fingerprint analysis after QR clones had been co-cultured with gelatin-sponge-reactive cells. The MSM rate was significantly higher in the subclones with low levels of Mn-SOD and GP[SUBX] (P<0.05) than in the subclones with high levels of both enzymes. The MSM of the subclones with low levels of both enzymes was inhibited in the presence of mannitol, a hydroxyl radical scavenger. The content of 8-hydroxydeoxyguanosine (8-OHdG) by which the cellular DNA damage caused by active oxygen species can be assessed was significantly low in the tumours arising from the QR clone with high levels of Mn-SOD and GP[SUBX] even if the clone had been co-implanted with gelatin sponge, compared with the arising tumour from the QR clone with low levels of those antioxidative enzymes (P<0.001). In contrast,... [ABSTRACT FROM AUTHOR]