Association between dietary calcium and vitamin D intake and cervical carcinogenesis among Japanese women.

BACKGROUND/OBJECTIVES: To examine the association between dietary calcium and vitamin D intake and cervical neoplasia risk, we conducted a case-control study. SUBJECTS/METHODS: We selected 405 incident cervical neoplasias (333 invasive carcinomas and 72 cervical intraepithelial neoplasias grade III (CIN3)) and 2025 age-matched non-cancer controls. Dietary information was collected using a semiquantitative food-frequency questionnaire (FFQ). The effect on cervical neoplasia risk was evaluated using conditional logistic regression models. RESULTS: The inverse association between invasive carcinoma and milk, yogurt and fish was observed. On the other hand, the marginally significant inverse association between CIN3 and tofu and green leafy vegetables was observed. Compared with the lowest quartile (Q1) of calcium intake, adjusted odds ratios (ORs) for each of the three upper quartiles (Q2, Q3 and Q4) on invasive carcinoma risk were 0.86 (95% confidence interval (CI) 0.63-1.17), 0.50 (95% CI 0.34-0.73) and 0.68 (95% CI 0.48-0.97), respectively (P for trend=0.004). However, no association between calcium and cancer risk was evident among CIN3 cases (P for trend=0.528). Vitamin D intake showed a similar inverse association (Q2: OR 1.03, 95% CI 0.74-1.44; Q3: OR 0.80, 95% CI 0.56-1.15; and Q4: OR 0.64, 95% CI 0.43-0.94; P for trend=0.013). Similar to calcium, no association between vitamin D intake among CIN3 was evident (P for trend=0.109). An inverse association with calcium was evident in women whose vitamin D intake was low. However, this combined effect was not significant (invasive carcinoma: interaction P=0.819; and CIN3: interaction P=0.101). CONCLUSION: We found an inverse association between dietary calcium and vitamin D intake and cervical neoplasia risk among a group of Japanese women.

Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer.

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolising enzyme inducing immune tolerance. The present study aimed to investigate IDO expression and its prognostic significance in endometrial cancer. Indoleamine 2,3-dioxygenase expression in endometrial cancer tissues (n = 80) was immunohistochemically scored as four groups (IDO-, 1+, 2+, and 3+). The high IDO expression (IDO2+ or 3+) in tumour cells was found in 37 (46.3%) of the 80 cases, and was positively correlated with surgical stage, myometrial invasion, lymph-vascular space involvement, and lymph node metastasis, but not with the histological grade. Patients with high IDO expression had significantly impaired overall survival and progression-free survival (PFS) (P = 0.002 and P = 0.001, respectively) compared to patients with no or weak expression of IDO (IDO- or 1+). The 5-year PFS for IDO-/1+, 2+, and 3+ were 97.7, 72.9, and 36.4%, respectively. Even in patients with early-stage disease (International Federation of Gynecology and Obstetrics I/II, n = 64), the PFS for IDO2+/3+ was significantly poor (P = 0.001) compared to that for IDO-/1+. On multivariate analysis, IDO expression was an independent prognostic factor for PFS (P = 0.020). These results indicated that the high IDO expression was involved in the progression of endometrial cancer and correlated with the impaired clinical outcome, suggesting that IDO is a novel and reliable prognostic indicator for endometrial cancer.

Role of hydrophilic interaction in binding of hydroxylated 3-deoxy C(19) steroids to the active site of aromatase.

As part of our investigation into the structure-activity relationship of a novel class of aromatase inhibitors, C(19) steroids having no oxygen function at C-3, we tested aromatase inhibition activity of polar diol compounds 4,19-dihydroxyandrost-5-en-17-ones (25 and 27) and 6,19-dihydroxyandrost-4-en-17-ones (36 and 37). 4alpha,19-Diol 25 was synthesized from tert-butyldimethylsilyoxyandrost-4-ene steroid (9) through its OsO(4) oxidation, giving the 4alpha,5alpha-dihydroxy derivative 12, as a key reaction. Acetylation of 5beta,6alpha-dihydroxy-19-acetate 30 and its 5alpha,6beta-analogue 31 followed by dehydration with SOCl(2) and alkaline hydroxysis gave 6alpha,19-diol 36 and its 6beta-isomer 37, respectively. The stereochemistry of a hydroxy group at C-4 of compound 25 and that at C-6 of compounds 36 and 37 were determined on the basis of (1)H NMR spectroscopy in each case. 4beta,19-Diol 27, previously synthesized, was identified as an extremely powerful competitive inhibitor of aromatase (K(i) = 3.4 nM). In contrast, its 4alpha,19-dihydroxy isomer 25 and other series of diol compounds, 6,19-dihydroxy-4-en-17-one steroids, were moderate to poor competitive inhibitors (K(i) = 110-800 nM). Through this series of analyses, it was concluded that hydrophilic interaction of a 4beta,19-diol function with the active site of aromatase plays a critical role in the tight binding of 3-deoxy-5-ene steroids.

19-oxygenated derivatives of androst-4-ene-6,17-dione and androst-5-ene-4,17-dione as catalytic probes for the active site of aromatase.

To gain insight into the binding manner of androst-4-ene-6,17-dione (4) and its 5-en-4-one analog 9, good competitive inhibitors of aromatase, in the active site of the enzyme, their 19-oxygenated derivatives were evaluated as inhibitors of human placental aromatase. The 19-hydroxy steroids 6, 7, and 10 and the 19-oxo analogs 8 and 12 were much poorer competitive inhibitors than their corresponding parent 19-methyl steroids. Conversion of the 17-keto inhibitors 4, 6, and 10 to the 17beta-ols 5, 7, and 11, respectively, markedly decreased their affinity to the enzyme. The results suggest that steroids 4 and 9 would bind to the active site in a similar manner to that involved in the binding of the substrate androstenedione (1).

Role of patellar tendon on the population of muscle fiber types and the contractile properties of single glycerinated muscle fibers in quadriceps muscles of rats.

The role of the patellar tendon (PT) in the contractile properties of quadriceps muscle was investigated. After PT resection (partial or complete), PT reconstruction, or a sham operation, rats were forced to run on a rodent treadmill. The histochemical and mechanical characteristics of the vastus medialis (VM) and vastus lateralis (VL) muscles were examined 2, 4, and 8 weeks after treatment. There were no significant changes in either fiber type population or the contractile properties of glycerinated single muscle fibers from VM and VL 2 and 4 weeks after partial PT resection. Complete PT resection caused a decrease in the population of type I fibers in VM, while the running training after PT reconstruction increased the population of type I fibers in VM. For both the PT resection and PT reconstruction groups, the Hill coefficient, an indicator of the Ca2+ sensitivity of myofilaments, was calculated from the pCa-tension relationship of glycerinated single muscle fibers. In the PT reconstruction group, the Hill values for fibers isolated from VM were significantly decreased by running training, but the Hill values for VL were not. The effect of running training on the Ca2+ sensitivity of myofilaments in muscle fibers with PT reconstruction was different from that in muscle fibers without PT treatment. Both resection and partial resection of the PT in this animal model had heterogeneous effects on the contractile properties of quadriceps muscles; we presume that, clinically, we must give careful consideration to PT treatment.