Reduction of insulin signaling upregulates angiopoietin-like protein 4 through elevated free fatty acids in diabetic mice.

BACKGROUND: Angiopoietin-like protein 4 (Angptl4) is thought to cause an increase in serum triglyceride levels. In the present study, we elucidated Angptl4 expression in the mouse models of type 1 and type 2 diabetes mellitus, and investigated the possible mechanisms involved. METHODS: Type 1 diabetes was induced in C57BL/6 J mice by treating them with streptozotocin (STZ). Type 2 diabetes was induced by feeding the mice a high-fat diet (HFD) for 18 weeks. RESULTS: The levels of Angptl4 mRNA expression in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) were found to increase in the STZ diabetic mice relative to control mice. This effect was attenuated by insulin administration. In the HFD diabetic mice, the Angptl4 mRNA expression levels were increased in liver, WAT, and BAT. Treatment with metformin for 4 weeks attenuated the increased levels of Angptl4 mRNA. Fatty acids (FAs) such as palmitate and linoleate induced Angptl4 mRNA expression in H4IIE hepatoma cells and 3T3-L1 adipocytes. Treatment with insulin but not metformin attenuated FA-induced Angptl4 mRNA expression in H4IIE. Both insulin and metformin did not influence the effect of FAs in 3T3-L1 cells. CONCLUSION: These observations demonstrated that Angptl4 mRNA expression was increased through the elevated free FAs in diabetic mice.

Three-dimensional MR imaging of mammographically detected suspicious microcalcifications.

BACKGROUND: The purpose of this study was to evaluate the diagnostic value and clinical significance of three-dimensional MR imaging of the breast in patients with mammographically detected suspicious microcalcifications. METHODS: Forty patients with suspicious microcalcifications on mammography were evaluated with three-dimensional MR imaging. MR findings were grouped mainly by distribution of abnormal enhancement (linear, focal-clumped, segmental-clumped, segmental-stippled and diffuse-stippled). These findings were compared with the mammography findings according to the criteria of the Breast Imaging Reporting and Data System (BI-RADS) and histopathologic data. RESULTS: Twenty patients had proven malignancies, most frequently ductal carcinoma in situ. For all the cases, linear (100%) and segmental-clumped type (100%) enhancement on MR imaging showed a significantly higher risk for malignancy. Diffuse stippled type (7%) and no enhancement (0%) on MR imaging indicated the lowest possibility of malignancy. 3D-MR imaging showed a sensitivity of 90%, a specificity of 95% and an overall accuracy of 93% in this study. CONCLUSIONS: Three-dimensional MR imaging of the breast can more accurately diagnose ductal carcinoma in situ. Combined with mammography, this procedure is useful for reducing the number of false-positive biopsies and helpful for deciding the better management of patients with mammographically detected suspicious microcalcifications.

Anomaly of 155Gd and 157Gd isotope effects in ligand exchange reactions observed by ion exchange chromatography

The isotope effects of gadolinium in Gd-EDTA ligand exchange system were studied by means of ion exchange chromatography. The separation coefficients of gadolinium isotopes, epsilon, and the local enrichment factors, beta, were calculated from the observed isotopic ratios at the front and rear boundaries of the gadolinium adsorption band. Clear mass independent anomalies were observed in the isotope effects of 155Gd and 157Gd. The relation between the isotope effects of gadolinium isotopes, studied by the three-isotope plot and the separation coefficient methods, and the mass of gadolinium isotopes was found to be related to the change in the mean square radius of the nuclear charge distribution parameter, (r2), of these isotopes, which suggests that the nucleus shape and size highly affect the gadolinium isotope effects in chemical exchange reactions.

Reversal of multidrug resistance by 7-O-benzoylpyripyropene A in multidrug-resistant tumor cells.

7-O-Benzoylpyripyropene A (7-O-BzP), a semi-synthetic analog of pyripyropene, was investigated for its reversing effect on multidrug-resistant (MDR) tumor cells. 7-O-BzP (6.25 microg/ml) completely reversed resistance against vincristine and adriamycin in vincristine-resistant KB cells (VJ-300) and adriamycin-resistant P388 cells (P388/ADR), respectively. 7-O-BzP alone had no effect on the growth of drug sensitive and drug-resistant cells. 7-O-BzP (6.25 microg/ml) significantly enhanced accumulation of [3H]vincristine in VJ-300 cells and completely inhibited the binding of [3H]azidopine to the P-glycoprotein in VJ-300 cells and P388/ADR cells. The result suggests that 7-O-BzP effectively reverses P-glycoprotein-related MDR by interacting directly with P-glycoprotein in drug resistant VJ-300 and P388/ADR cells.

Computer-Aided Diagnosis (CAD) for Mammography: Preliminary Results.

PURPOSE: To evaluate the CAD system for screening mammograms. MATERIALS AND METHODS: Mammograms of patients with asymptomatic breast cancerwere examined retrospectively. A total of 260 screening mammograms from 65 patients (bilateral cranio-caudal and medio-lateral-oblique views from each) were tested by using the CAD system (ImageChecker M1000 system, R2 Technology, Los Altos, CA, USA). Results: With 0.58 microcalcifications marks/film and 0.20 mass marks/film set as the false positive rate, 100% of microcalcifications cases and 79% of mass cases were detected correctly. Conclusion: The CAD system has the potential to become a second reader. Further developments are expected to improve the accuracy of detection of mass lesions

Meta-Analysis of the Second Collaborative Study of Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) in Patients with Stage II, Estrogen-Receptor-Positive Breast Cancer.

The second 5-year study of postoperative adjuvant therapy in patients with breast cancer between 1985 and 1988 was performed by the Study Group for Adjuvant Chemoendocrine Therapy for Breast Canecr (ACETBC). This report describes the results of a meta-analysis of the outcome. A total of 3012 patients with stage II, estrogen-receptor-positive primary breast cancer who underwent radical surgery (total mastectomy with at least axillary dissection) were eligible for the analyses. On the day of surgery, all patients received 13 mg/m(2) of mitomycin C (MMC) intravenously. Patients were then given one of two adjuvant chemoendocrine therapies for 2 years:regimen A, consisting of tamoxifen citrate (TAM) 30 mg/day, or regimen B, consisting of TAM 30 mg/day plus tegafur (Futraful, FT)600 mg/day. The results from all eligible patients were included in a meta-analysis according to the method of Peto et al. The odds reduction rate was 12 +/-13% (log-rank test, P= 0.35)for the 5-year survival rate and 16 +/- 10% (log-rank test, P=0.093)for the 5-year non-recurrence rate. In terms of the 5-year non-recurrence rate. regimen B(with FT)yielded slightly, but not significantly, better results than regimen A. In addition, stratified analyses were carried out with respect to the 5-year non-recurrence rate. Regimen B(with FT)yielded significantly better results than regimen A in patients with four or more positive axillary nodes (log-rank test, P= 0.039) and yielded slightly, but not significantly, better results than regimen A in premenopausal patients (log-rank test, P= 0.079).

Efficacy of Post-operative Adjuvant Therapy for Stage IIIa Berast Cancer: Futraful vs Futraful+Tamoxifen for ER-positive Patients and Futraful vs Futraful+Adriamycin for ER-negative Breast Cancer.

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located thruoughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage III a breast cancer. Patients with estrogen receptor-positive [ ER(+)] breast cancer were treated with two types of regimens, ie, cyclophosphamide+adriamycin+fluorouracil (CAF; 2 cycles) +Futraful(FT) or CAF (2 cycles+FT+tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER(+) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation.The 5-year survival rate was 77.2% for the CAF+FT group and 74.6% for the CAF+FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF+FT+TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF+FT+TAM group was significantly higher than that for the corresponding patients in the CAF+FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF+FT+TAM group than in the CAF+FT group). Patients with estrogen receptor-negative [ ER(-)]breast cancer were treated with two types of regimens, ie, CAF+FT or CAF+FT+adriamycin(ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478(93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF+FT group and 63.0% for the CAF+FT+ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF+FT and CAF+FT+ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF+FT+ADR group than in the CAF+FT group.

BRCA2 germline mutations in Japanese breast cancer families.

Germline mutations of BRCA2 were examined in 20 Japanese breast cancer families without BRCA1 mutations, including one demonstrating cancer development in a male. Three different mutations, resulting in truncation of the BRCA2 protein, were detected in 3 different families. They were 9474insA (exon 24, termination at codon 3110), C8729A (exon 20, S2834 ter) and 982del4 (exon 9, termination at codon 275). The 982del4 mutation was detected in the family with a case of male breast cancer. Age at onset was young, with a range of 28-43 years, in the 2 female breast cancer families with truncation mutations. One probable missense mutation, A10462G (13412V), was further detected in 2 families, although cosegregation of this allele with the breast cancer phenotype was not complete. The rate of BRCA2 mutations in Japanese families was suggested to be almost the same as in Western countries, and larger than it is the case for BRCA1.

Efficacy of postoperative adjuvant therapy for stage ilia breast cancer: Futraful vs futraful+tamoxifen for ER-positive patients and futraful vs futraful + adriamycin for ER-negative breast cancer.

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.

Male breast cancer in patients with a familial history of breast cancer.

We describe herein the clinical characteristics of five male breast carcinoma (MBC) patients with a familial history of breast carcinoma (FHBC). Four of these patients suffered from multiple primary cancers, being gastric and prostate cancer in 1, gastric cancer in 1, and asynchronous bilateral breast cancers in 2. The average age of these patients at diagnosis was not lower than that of MBC patients with no such familial history. The aggregation of cancer in these families had three prominent characteristics: (1) The families included women with early-onset breast cancers which had occurred at the ages of 38, 38, and 35 years, respectively, and/or early-onset uterine cancer which had occurred at the age of 35 years. (2) The incidence of multiple primary cancers was significantly higher in the siblings of MBC patients with a FHBC than without. (3) There were many cancers in hormone-related organs in two families.

[Clinical evaluation of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) on advanced and recurrent breast cancer. Clinical study group of CMF for breast cancer in Japan].

The clinical efficacy of "CMF" chemotherapy, (cyclophosphamide, methotrexate, 5-fluorouracil), was evaluated on advanced and recurrent breast cancer. The response rate was 36.1% in 61 evaluable cases, including four CR and eighteen PR. In terms of efficacy classified by metastatic lesion, the effective rates were 51.4% in soft tissue, 28.6% in viscera, and 20.0% in bone metastases. The main side effects were nausea/vomiting, anorexia, and leucopenia. In this study, CMF chemotherapy resulted in good clinical effects, and its response rate was almost the same as that to CMF chemotherapy in Europe and USA, but slightly lower than that to CAF chemotherapy. As to the side effects, the incidence of leucopenia, thrombocytopenia or alopecia was lower in CMF chemotherapy than in CAF chemotherapy. Also, unlike CAF chemotherapy, CMF chemotherapy had no cumulative dose-limitation and showed no cardiotoxicity. In conclusion, CMF chemotherapy is considered to be one of the most useful treatments for advanced and recurrent breast cancer.

[Correlations between estrogen receptor and prognostic factors of patients with breast cancer. The Kanto Cooperative Study Group of Adjuvant Chemoendocrine Therapy for Breast Cancer, Japan].

We investigated possible correlations between estrogen receptor (ER) and prognostic factors in 3,789 patients with stage II or stage IIIa breast cancer in Japan. The patients with ER-positive tumors showed a significantly better prognosis in the 5-year survival rate and the 5-year disease-free survival rate compared with the patients with ER-negative-tumor. Positivities increased with increasing patient age, with increasing tumor size, and lowering degree of cell differentiation, and no relation was observed between the positivities and tumor sites, obesity index, and lymph-node metastasis.

Evaluation of the critical electron dose on the contractile activity of hydrated muscle fibers in the film-sealed environmental cell.

By using the film-sealed environmental cell (EC) having a liquid-injection function, we observed a contraction reaction of hydrated myofibrils isolated from crab muscle under the transmission electron microscope. Our purpose in this work was to evaluate the critical electron dose at which the hydrated fibers lose the contractile activity. The decision of whether the fibers contracted was done by the existence of contraction band after a contraction reaction. From the observations, it was concluded that its critical dose was 2 x 10(-4) C/cm2 or 12 electrons/nm2 at a protein level.

[Primary lung cancer of the right middle lobe].

During the period from 1973 to 1986, 230 patients with lung cancer were operated on at our Surgical Clinic of Kagoshima University Hospital. There were fourteen patients (6.1%) with lung cancer in the right middle lobe. There were 13 male and 1 female patients. The histological types were adenocarcinoma (10), squamous cell carcinoma (4). Five-year survival rate of 14 patients was 34.9%. Statistically, it was similar to that of the patients with lung cancer in the other lobes. As concerns with the histological type of lung cancer in the right middle lobe, the case of squamous cell carcinoma revealed poorer prognosis than those of adenocarcinoma, because there were many cases of advanced cancer in the former case.

Control of specimen orientation and environment.

Application of electron microscopy in a wide variety of fields of investigation has placed ever-expanding demands on the various components of the instrument. In situ specimen manipulation is one such demand and can often be critical to the success of an experiment. Control of specimen orientation is the most common manipulation, but control of a variety of other physical and chemical parameters may also be important. Temperature, gaseous and/or liquid environment, and mechanical operations are examples. Control and variation of these parameters in a small device (occupying a few cm3) operated in a strong magnetic field inside a vacuum system is often a considerable challenge. This must also be done at extreme stability: at least as good as the resolution limit of the microscope. Optimization of stage performance is too often sacrificed for optical performance or vice versa. The next generation of objective lenses and specimen stages are being designed in concert: an approach which should lead to an improved in situ laboratory, observed with optimum optics.