Expression level of enzymes related to in situ estrogen synthesis and clinicopathological parameters in breast cancer patients

In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17β-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor β, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues.     

Steroid sulfatase and estrogen sulfotransferase in normal human tissue and breast carcinoma

Steroid sulfatase (STS) hydrolyzes inactive estrone sulfate (E1-S) to estrone (E1), while estrogen sulfotransferase (EST; SULT 1E1 or STE gene) sulfonates estrogens to estrogen sulfates. They are considered to play important roles in the regulation of local estrogenic actions in various human tissues, however, their biological significance remains largely unknown. Therefore, we examined the expression of STS and EST in non-pathologic human tissues and breast carcinomas. STS expression was very weak except for the placenta, while EST expression was markedly detected in various tissues examined. In breast carcinoma tissues, STS and EST immunoreactivity was detected in carcinoma cells in 74 and 44% of cases, respectively, and was significantly associated with their mRNA levels and enzymatic activities. STS immunoreactivity was significantly correlated with the tumor size, and an increased risk of recurrence. EST immunoreactivity was inversely correlated with the tumor size or lymph node status. Moreover, EST immunoreactivity was significantly associated with a decreased risk of recurrence or improved prognosis. Our results suggest that EST is involved in protecting various peripheral tissues from excessive estrogenic effects. In the breast carcinoma, STS and EST are suggested to play important roles in the regulation of in situ estrogen production in the breast carcinomas.     

One host—one parasitoid system: Seasonal life cycles ofPryeria sinica (Ledipoptera) andAgrothereutes Minousubae (Hymenoptera)

The zygaenid Pryeria sinicaMoore and the ichneumonid Agrothereutes minousubaeNakanishi form a one host—one parasitoid system in nature. Their seasonal life cycles were investigated by laboratory experiments and field observations, and the life-cycle adaptation of the parasitoid to its host was examined. The moth is univoltine. The larva hatches from mid-February to mid-March and feeds on leaf buds and young leaves of ever green Euonymus japonicusThunb . The thermal constants for completing the 1st, 2nd, 3rd, 4th larval instars and prepupal stage were 85.6, 80.5, 85.2, 177,0 and 197.6 degree-days, respectively. The prepupa and pupa vulnerable to the attack by the parasitoid occurred from mid-April to early May and from mid- to late May, respectively. Diapause in the parasitoid is facultative and occurs in the eonymphal stage. The photoperiodic response for this diapause was a long-day type with a critical photoperiod of 13 hr 40 min at 20°C, but it was not expressed at 25°C, most larvae entering diapause irrespective of photoperiod. About 19, 120, 82 and 112 degree-days above 7°C were required to complete the egg, larval, prepupal and pupal development, respectively. These data were superimposed on the photothermograph of Fukuoka, and it is predicted that the 1st adult eclosion would occur in late April and the partial 2nd adult eclosion in early June. The prediction was supported by field observations. The adult eclosion of the parasitoid synchronized well with the apperance of prepupae and pupae of the moth. The parasitoid has two types of seasonal life cycle, one generation and two generations a year. Both types have an extremely long dormant period of 10–11 months due to aestivo-hibernation. This seasonal life cycle enables the parasitoid to maintain its population when the host is in short supply.     

One-host one-parasitoid system: Population dynamics of a zygaenid mothPryeria sinica Moore in an undisturbed habitat

Population Ecology - The population dynamics ofPryeria sinica was investigated in an undisturbed area in 1976–1979. We analyzed the process stabilizing the local population by the life table...     

Association between Hemoglobin Concentration and the Progression or Development of Albuminuria in Diabetic Kidney Disease

Aims

Anemia, which might contribute to pathogenesis of kidney dysfunction, is a common finding in patients with type 2 diabetes. The aim of this study was to investigate if hemoglobin concentration is associated with the degree of change in urinary albumin-creatinine ratio or the development of albuminuria in patients with type 2 diabetes.

Methods

We measured hemoglobin concentration in 470 (296 men and 174 women) consecutive type 2 diabetic patients without albuminuria. We performed a follow-up study to assess the progression or development of albuminuria, the interval of which was 3.0 years. Then we evaluated relationships between hemoglobin concentration and albuminuria, using multivariate linear regression analyses and logistic regression analyses.

Results

Eighty four patients developed albuminuria during follow-up duration. In multivariate analyses, hemoglobin concentration was negatively associated with a change in urinary albumin-creatinine ratio in men (ß = -0.259, P = 0.0002) and women (ß = -0.194, P = 0.030). Moreover, multivariate adjusted odds ratio associated with 1 g/L in hemoglobin for the development of albuminuria was 0.93 (95% confidence interval; 0.89-0.96) in men and 0.94 (95% confidence interval; 0.88-0.99) in women, respectively. And, multivariate analyses revealed that adjusted odds ratios for the development of albuminuria were 4.78 (95% confidence interval; 1.65-13.91) in men and 4.62 (95% confidence interval; 1.34-16.68) in women with anemia (hemoglobin < 130 g/L for men and < 120 g/L for women), which were higher than those without anemia.

Conclusions

Low hemoglobin concentration could be a predictor for the progression and development of albuminuria in patients with type 2 diabetes.     

Novel and orally active 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives as selective FLT3 inhibitors

5-(1,3,4-Oxadiazol-2-yl)pyrimidine derivative 1 was identified as a new class of FLT3 inhibitor from our compound library. With the aim of enhancement of antitumor activity of 2 prepared by minor modification of 1, structure optimization of side chains at the 2-, 4-, and 5-positions of the pyrimidine ring of 2 was performed to improve the metabolic stability. Introduction of polar substituents on the 1,3,4-oxadiazolyl group contributed to a significant increase in the metabolic stability. As a result, a series of compounds showed increased efficacy against MOLM-13 xenograft model in mice by oral administration.     

Role of steroid sulfatase in local formation of estrogen in post-menopausal breast cancer patients

More than two-thirds of breast cancers occur in post-menopausal women, and depend on the estrogens for their proliferation and survival. For the treatment of estrogen-dependent breast cancers, two major treatment options are now available. One is selective estrogen receptor modulator (SERM) such as Tamoxifen and another is aromatase inhibitor such as Anastrozole, Letrozole and Exemestane, which reduce local in situ formation of estrogens. Although these therapies are clinically active for advanced and early breast cancers, de novo and/or acquired resistance to SERM and/or aromatase inhibitors are also clinical problem. Recent studies suggest that local formation of estrogens in the breast tumors is more important than circulating estrogen in plasma for the growth and survival of estrogen-dependent breast cancer in post-menopausal women. The rationale for the importance of local formation of estrogens is based on the following evidences. Estradiol (E2) levels in breast tumors are equivalent to those of pre-menopausal patients, although plasma E2 levels are 50-fold lower after menopause. E2 concentrations in breast tumors of post-menopausal women are 10–40 times higher than serum level. Biosynthesis of estrogens in breast tumors tissues occurs via two major different routes, one is aromatase pathway and another is steroid-sulfatase (STS) pathway. Whereas many studies has been reported about aromatase inhibitor and its clinical trial results in breast cancer patients, limited information are available regarding to other estrogen regulating enzymes including STS, its role in breast tumors and STS inhibitors. STS is the enzyme that hydrolyses estrone 3-sulfate (E₁S) and dehydroepiandrosterone-sulfate (DHEA-S) to their active un-sulfoconjugated forms, thereby stimulating the growth and survival of estrogen-dependent breast tumors. It has been well known that E₁S level are much higher than E2 level both in plasma and tumor of post-menopausal patients. Recent reports show that more than 80% of breast tumors are stained with anti-STS antibody and the expression of STS is an independent prognostic factor in breast cancer. Taking these findings into consideration, local formation of estrogens could be partially synthesized from large amount of E₁S by STS, which exist in breast cancer. On the other hand, aromatase localizes in stroma and adipocyte surrounding breast cancer. Furthermore, since estrogen formation from E₁S and DHEA-S (STS pathway) cannot be blocked by aromatase inhibitors, STS is thought to be a new molecular target for the treatment of estrogen-dependent tumor post-SERM and/or aromatase inhibitors. In this symposium, these recent rationale for the importance of STS in post-menopausal breast cancer patients is reviewed as well as STS inhibitor.     

Group feeding as a strategy for exploiting food resources in the burnet moth Pryeria sinica

Summary Pryeria sinica (Zygaenidae) larvae feed on young and growing leaves of Euonymus japonicus in groups. The larvae often defoliate their host plant. Hence, the larvae are occasionally subject to serious shortage in food resources. We hypothesize that larval aggregation is an adaptation for the economical utilization of limited food resources. To test this hypothesis, the patterns of resource utilization were studied on larvae settled on shoots of host plant in various group sizes. The amount of food resources in a shoot was affected by the following three factors; (1) shoot growth, (2) food consumption of larvae, and (3) inhibition of growth or degeneration of shoot by larval activity on it. These factors were measured and the efficiency in resource utilization was compared among groups of varied sizes. The loss in resources caused by the third factor was found to be decreased with group size, i.e., the larger the group size, the larvae utilized the food resources more economically. The advantages of group feeding in survival and reproduction of this species were discussed using a simple graphical model.