Takafumi Nakamura

Change of salivary stress marker concentrations during pregnancy: Maternal depressive status suppress changes of those levels

Aim:  The aim of the present study was to show changes in salivary cortisol and chromogranin A/protein concentrations as stress markers during pregnancy and to clarify the effect of chronic stress on stress markers.

Gene expression profiling of lens tumors, liver and spleen in α-crystallin/SV40 T antigen transgenic mice treated with Juzen-taiho-to

The autogenic lens tumors induced by the Simian vacuolating virus 40 (SV40) T antigen in α-crystallin/SV40 T antigen transgenic (TG) mice, provide a tool to screen anti-tumor reagents in vivo and to clarify the underlying mechanisms. Juzen-taiho-to, a Chinese medicine composed of 10 herbs, was frequently used as an alternative medicine for cancer patients by clinicians and occasionally it was demonstrated to have beneficial effects on the prognosis and general condition of cancer patients. However, it was not scientifically verified. In the present study, the anti-tumor effects and underlying mechanisms of Juzen-taiho-to in the TG mice model was examined using cDNA microarray analysis and the results were confirmed by real-time PCR. The TG mice demonstrated a higher cumulative survival rate after treatment with the drug compared with the control group (P<0.05). Gene chip profiles demonstrated that cell functions involving the membrane, glycoprotein, cell membrane, signal and ionic channel for the lens tumor, the cell cycle, DNA replication, homeobox, mitosis and cell division for the spleen and the acetylation, mitochondrion, ribosomal protein, ribonucleoprotein for the liver, were altered by the administration of Juzen‑taiho-to. The important canonical pathways were those of the mitogen-activated protein kinase (MAPK), the cell cycle and the ribosome for the altered genes of the lens tumor, spleen and liver after drug administration, respectively. From real-time PCR, in the eyeball, epidermal growth factor receptor (Egfr), Rasgrf1 and heat shock protein 1B (Hspa1b) mRNAs were found to be significantly lower in treated lenses than in those not exposed to the drug, while Rps25 mRNA demonstrated the opposite association in the liver. It was suggested that Juzen-taiho-to may prolong the survival time of SV40 T antigen TG mice by improving their nutritional condition, inhibiting the MAPK pathway and strengthening the immune system without causing hepatic toxicity.

Effects of 4-Hydroxy-2-Nonenal, a Major Lipid Peroxidation-Derived Aldehyde, and N-Acetylcysteine on the Cyclooxygenase-2 Expression in Human Uterine Myometrium

Background: Chorioamnionitis is one of the important causes of preterm labor. Preterm labor with chorioamnionitis is associated with oxidative stress. We reported that 4-hydroxy-2-nonenal (4-HNE), a major end product of oxidative fatty acid metabolism, is accumulated in the placenta with chorioamnionitis. The aim of this study was to confirm the effect of 4-HNE on cyclooxygenase-2 (COX-2) and prostaglandin (PG) induction in the uterine myometrial tissues. We also examined the effect of N-acetylcysteine (NAC) on 4-HNE-induced COX-2 expression. Methods: Uterine myometrial tissues were obtained from 5 patients. One of them underwent elective cesarean section without labor, and 4 of them underwent hysterectomy because of placental previa or atonic bleeding. We stimulated the uterine myometrial tissues with 4-HNE. In addition, the tissues were pretreated with NAC before 4-HNE treatment. The expression of COX-2 mRNA was observed by real-time PCR. PGE2 and prostacyclin release into the supernatants of the tissue cultures was measured by ELISA. Results: 4-HNE induced the COX-2 mRNA expression and PGE2 production in the uterine myometrial tissue culture in a dose-dependent and time-dependent manner. NAC inhibited 4-HNE-induced COX-2 expression. Conclusion: 4-HNE may play an important role in preterm labor. NAC might be protective against preterm labor under oxidative stress.

Massive Cystic Degeneration of a Uterine Leiomyoma in a Patient with Autosomal Dominant Polycystic Kidney Disease

Background: A uterine cyst occurring as an extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) is extremely rare. Case: A 46-year-old Japanese woman was referred with a large abdominal mass causing severe abdominal distension. A large uterine cyst as an extrarenal manifestation of ADPKD was strongly suspected. First, we managed this patient by aspirating the cyst fluid through a small laparotomy. A year later, the cyst recurred and the patient underwent hysterectomy. Massive cystic degeneration of a uterine leiomyoma was diagnosed histologically. Conclusion: We described the rare case of massive cystic degeneration of a uterine leiomyoma in a patient with ADPKD, in which a causal relationship was suspected.

Timing of cisplatin administration for chemoradiotherapy in transgenic mice bearing lens tumors.

Cisplatin-based concurrent chemoradiotherapy (CCRT) has become a standard treatment for cancer of the uterine cervix. However, there have been no investigations into the optimum timing for administration of anticancer drugs using animal models. The aim of the present study was to determine the appropriate timing for administration of the anticancer drug cisplatin in relation to delivery of radiation by assessing the antitumor activity and adverse effects of 3 different regimens in αT3 transgenic mice bearing lens epithelial tumors. CCRT showed the strongest antitumor activity. There was a significant difference between CCRT and administration of cisplatin before radiotherapy (neoadjuvant therapy) with regard to the apoptotic effect detected by TUNEL staining, but there was no significant difference between CCRT and administration of cisplatin after radiotherapy (adjuvant therapy). Assessment of adverse effects showed that there were no significant differences in the mortality rate, weight loss, anemia and leukopenia among the 3 regimens. In conclusion, these findings obtained in an animal model suggest that cisplatin should probably not be administered before irradiation, since the antitumor effect is significantly weaker than that of CCRT or administration after irradiation, while adverse effects are similar.

Does local infiltration anesthesia on laparoscopic surgical wounds reduce postoperative pain? Randomized control study

Recently, endoscopic surgeries are widely performed in the gynecological field. Several studies on the use of local anesthesia for pain control after laparoscopic surgery have been conducted; however, its effects remain controversial. Herein, a randomized control study on gynecological laparoscopic surgeries was conducted to analyze the effectiveness of local anesthesia on postoperative pain.

Abstract 4713: A Kampo (Japanese herbal) medicine Juzentaihoto may suppress the expression of indoleamine 2, 3-dioxygenase on macrophages and prolong the survival of transgenic mice bearing lens-epithelial cell carcinoma.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Kampo medicine (the traditional Chinese medicine) is a pharmaceutical grade multi-herbal medicine widely used for immunocompromized patient in Japan. Juzentaihoto is a well known Kampo medicine that comprises 10 different herbs. The effect of a Kampo medicine Juzentaihoto on survival of tumor-bearing mice was measured in this study. We previously reported αT3 transgenic mice carrying αA-SV40Tag transgene (αA denotes murine αA-crystallin promoter). The αT3 mice carry a single copy of transgene, which have been generated from αA-loxP-SV40Tag/Ella-cre double transgenics. The αT3 lens tumors show multi-step carcinogenesis(J Cancer Res Clin Oncol 135:1521-1532 2009). At birth the αT3 lens tumors demonstrate moderate∼severe dysplasia, and in 2-3 month-old they become carcinoma in situ and start to invade lens capsule, and in 4-6 month-old they proliferate in the eyeball and finally they enlarge and destroy eyeballs. The αT3 lens tumor is growing very slow and finally invading and destroying surrounding brain tissue, and some of the αT3 lens tumor, metastasizing to cervical lymph node and lung. Finally αT3 mice died due to cancer cachexia. Carcinogenesis of the αT3 lens tumor induced by SV40 T antigens is pathologically very similar to uterine cervical cancer, which is induced by high-risk human papillomavirus E6 and E7 oncoprotein(Cancer Lett 179:165-173 2002, Oncol Rep 12:253-258 2004, Oncogene 25:3670-3679 2006). We also reported that expression of indoleamine 2, 3-dioxygenase(IDO)increases as tumors progress from carcinoma in situ to microinvasive and invasive cancer, and that tumor associated macrophages(TAMs) localized at the invasive front express IDO in patients with cervical cancer(Cancer Sci 98:874-881 2007). In this study, the αT3 mice were fed bait containing 1.5% Juzentaihoto for more than one year and the survival rate was compared with the untreated control. We also analyzed various biological activities, such as phagocytosis, IL-10 and IL-12 induction, especially IDO-expression on macrophages. Oral administration of Juzentaihoto activated peritoneal exudate macrophages and recruited the IDO-negative macrophages. The number of TAMs also increased as compared with the untreated control. These results suggest that oral administration of Juzentaihoto affect macrophage expression of IDO, possibly through a mechanism mediated by the activation of M1 macrophages and modulate local innate immunity. Citation Format: Takafumi Nakamura. A Kampo (Japanese herbal) medicine Juzentaihoto may suppress the expression of indoleamine 2, 3-dioxygenase on macrophages and prolong the survival of transgenic mice bearing lens-epithelial cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4713. doi:10.1158/1538-7445.AM2013-4713