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Everolimus (EVE) is a drug that improves resistance to hormone therapy but may have adverse effects on EVE‐resistant patients. We indicated that even low concentrations of EVE could increase CIP2A expression in EVE‐resistant breast cancer cells. High CIP2A expression was associated with reduced luminal A breast cancer patient survival. Moreover, the expression of epithelial–mesenchymal transition‐related genes decreased in EVE‐resistant cells., Everolimus (EVE), an inhibitor of mammalian target of rapamycin, is an emerging second‐line therapeutic option for hormone therapy‐resistant breast cancers. However, some patients do not respond to EVE, whereas in others it exacerbates the disease. Cellular inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that can promote cancer cell growth and apoptosis resistance. Although CIP2A is upregulated in hormone‐related cancers, such as breast cancer, little is known about potential anti‐tumor effects of downregulating CIP2A. As a model to study the resistance of breast cancer cells to hormone treatment, we previously established clones of long‐term estrogen depletion‐resistant MCF‐7 (LTED) cells. Here, we selected three clones highly responsive to EVE and three clones poorly responsive to EVE. When cells were treated with EVE, CIP2A mRNA expression was decreased in highly responsive EVE clones (DC‐cells) whereas it was increased in poorly responsive EVE clones (IC‐cells). Using Kaplan–Meier survival plots, we report that high expression of CIP2A was associated with significantly reduced overall survival in patients with luminal A breast cancer. In IC‐cells, cell growth was enhanced upon EVE treatment whereas an EVE range of 0.1–100 nm decreased growth in DC‐cells. The mRNA expression of genes involved in epithelial–mesenchymal transition (EMT) such as CDH1, CLDN3, and CK19 was significantly decreased in IC‐cells, but remained unchanged in DC‐cells. These findings highlight a relationship between CIP2A and EMT in the intrinsic resistance of hormone therapy‐resistant breast cancers to EVE.

Human CYP19 spans a region of chromosome 15 of approximately 130 kb and encodes aromatase, an enzyme required for estrogen synthesis. In the human granulosa cell-line KGN, there are seven open chromatin regions within the CYP19 locus. In this study, we demonstrate that two of these regions ~40 kb upstream and ~15 kb downstream of the CYP19 promoter are cohesin-loading sites, physically interacting with the promoter to negatively and positively regulate transcription, respectively. These observations suggest that CYP19 expression is controlled by a balance between the upstream silencer and downstream enhancer. When cohesin is depleted, CYP19 expression is elevated since the silencer is 2.5-fold further from the promoter than the enhancer and most likely depends on cohesin-mediated tethering to influence expression.

Human CYP19 spans a region of chromosome 15 of approximately 130 kb and encodes aromatase, an enzyme required for estrogen synthesis. In the human granulosa cell-line KGN, there are seven open chromatin regions within the CYP19 locus. In this study, we demonstrate that two of these regions ~40 kb upstream and ~15 kb downstream of the CYP19 promoter are cohesin-loading sites, physically interacting with the promoter to negatively and positively regulate transcription, respectively. These observations suggest that CYP19 expression is controlled by a balance between the upstream silencer and downstream enhancer. When cohesin is depleted, CYP19 expression is elevated since the silencer is 2.5-fold further from the promoter than the enhancer and most likely depends on cohesin-mediated tethering to influence expression., Highlights • Silencer and enhancer elements of CYP19 were identified in the human granulosa cell-line KGN. • The silencer and enhancer elements both interacted with the CYP19 promoter through cohesin-mediated chromosome tethering. • A balance between the activity of the silencer and enhancer element controls CYP19 expression.

Background/aim Although ABO blood group has been reported to be associated with the outcome of patients with pancreatic cancer, little is known about its impact on patients with biliary tract cancer (BTC). We evaluated the prognostic relevance of ABO blood group in patients who had undergone resection of BTC. Patients and methods A total of 154 patients with BTC undergoing pancreatoduodenectomy were retrospectively reviewed. Associations between ABO blood group and patient survival were evaluated by univariate and multivariate analysis. Results The 5-year overall survival rate was higher in group O patients (n=46) than in other blood group patients (n=108) (65.8% vs. 47%, p=0.005). Multivariate analysis revealed that a non-O blood group was an independent risk factor for poor survival (p=0.021). Conclusion ABO blood group is associated with the prognosis of patients with resected BTC; group O patients have a better outcome.

The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.

Background: HER2 (human epidermal growth factor receptor 2) testing performed by IHC (immunohistochemical) methods and FISH (fluorescence in situ hybridization) is semi-quantitative. Exact quantification of HER2 is needed to predict which patients are more or less likely to response to anti HER2 therapy. To improve the method for cancer patients' HER2 status, we developed a novel fluorescence IHC method using new fluorescence nanoparticle. The fluorescent intensity of this new nanoparticles, termed phosphor-integrated dot (PID), was approximately 100-fold brighter than that of Quantum dots. Because of its increased brightness and analyzing technology, this PID-based fluorescent IHC(IHC-PIC) has an ability of quantifying the biomarker protein in the cancer tissue sample at single particle level. In this study, the primary objective was to investigate if pathological complete response (pCR) rate in HER2- positive breast cancer treated by trastuzumab and lapatinib containing neoadjuvant systemic therapy would depend on the level of HER2, EGFR, HER3, Ki67, ER and PgR protein quantified by this new method. Methods: The Neo-LaTH study is a randomized phase II multicenter trial evaluating the efficacy and safety of lapatinib and trastuzumab followed by lapatinib and trastuzumab plus weekly paclitaxel with or without prolongation of anti-HER2 therapy prior to chemotherapy (18 weeks vs. 6 weeks). The primary endpoint was the comprehensive pCR rate. We evaluated the HER2, EGFR, HER3, Ki67, ER and PgR amount by nano-patho method using PID in formalin-fixed paraffin-embedded core biopsy samples taken at diagnosis retrospective analysis. Univariate and multivariate analyses were performed to determine the association between pCR and variables, including HER2, EGFR, HER3, Ki67, ER and PgR nano-patho score and clinicopathological factors including histological grade, tumor status, nodal status and HER2 FISH ratio. Results: A total of 96 tumor samples from patients were used for the present analysis.The pCR rate was 60.4%. We obtained the images of only PID signal by the image analyses, and calculated the number of PID particles in a cell and defined it as IHC-PID score that reflects the level of HER2, EGFR, HER3, Ki67, ER and PgR protein expression in cancer cells. Univariate analysis showed that HER2 IHC-PID score(p Conclusion: We successfully performed the quantitative IHC-PID for HER2, EGFR, HER3, Ki67, ER and PgR. And we propose using HER2 IHC-PID score as a predictive factor for trastuzumab and lapatinib containing neoadjuvant systemic therapy. This quantitative diagnostic method would be expected to contribute to the development of a molecular therapeutic strategy. Citation Format: Tada H, Miyashita M, Gonda K, Watanabe M, Suzuki A, Watanabe G, Harada N, Sato A, Hamanaka Y, Masuda N, Toi M, Ohno S, Bando H, Ishiguro H, Inoue K, Yamamoto N, Kuroi K, Ohuchi N, Ishida T. New quantitative diagnostic method by fluorescence nanoparticle for HER2 positive breast cancer treated with neoadjuvant lapatinib and trastuzumab: The Neo LaTH study (JBCRG-16TR) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-28.

Background/aim Little is known about the efficacy of neoadjuvant chemotherapy (NAC) with gemcitabine plus S-1 (GS) for patients with resectable pancreatic ductal adenocarcinoma (R-PDAC). The aim of this study was to investigate differences in the long-term outcome of patients with R-PDAC undergoing pancreatectomy with and without NAC-GS to clarify the clinical significance of NAC-GS. Patients and methods A total of 77 patients with R-PDAC who were scheduled for pancreatectomy between January 2012 and December 2017 were enrolled. Of these patients, 39 received NAC-GS (GS group) and 38 had upfront surgery (UFS group). Results Among the 77 patients, one patient in each group did not undergo pancreatectomy due to intraoperative non-curative factors. Median tumor size and the number of lymph nodes with metastasis were significantly lower in the GS group than in the UFS group (p=0.002 and p=0.017). However, the 5-year overall survival rate was similar in the two groups (26.1% versus 21.5%, p=0.930). Conclusion NAC-GS may not be recommended for patients with R-PDAC since it does not seem to offer any survival benefits.

SUMMARY A capacitive-coupled power extraction (CCPE) MHD generator was proposed to prevent electrode damages. In this study, we demonstrated the CCPE MHD generator driven by an inductively coupled plasma (ICP). The result shows that the electron temperature and the electron number density of the ICP are 69,600 K (6 eV) and 1016 1/m3, respectively. The output voltage of MHD generator using the ICP was followed the theory at DC MHD generation. To demonstrate the CCPE MHD generator, the alternating magnetic field was applied to the ICP. The output voltage from the CCPE MHD generator is observed at the load resistance. The output voltage evolution obtained by experimental results is similar to that estimated by the equivalent circuit model.

Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells. Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2'-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5' splice site of exon 1. Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5' splice site. Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5' splice site of exon 1 offers novel insight on 5' splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

Objective The objective of this study was to determine whether estrogen could be formed locally in the coronary arteries. Design Coronary arteries were examined from monkeys (Macaca fascicularis, one male and one female) and human subjects (one premenopausal woman, one postmenopausal woman, and one man) by immunocytochemistry, using purified antisera against human placental estrogen synthetase (aromatase) and ER alpha. The arteries were graded for the amount of atherosclerosis. Results There was clear immunopositivity for both aromatase and estrogen receptors in all arteries studied. Although all endothelial cells (CD31 positive) stained for both antigens, the staining in macrophages, fibroblasts, and smooth muscle cells was irregular. Conclusion The present results provide the first evidence for the local formation of estrogen in the coronary arteries. In addition to complementing the evidence of a cardioprotective effect of estrogen on the coronary circulation, our results highlight the potential importance of local regulation of estrogen formation and the role of available precursor androgens in maintaining the cardiovascular system.

Aromatase inhibitor (AI) resistance is a major obstacle in the treatment of estrogen receptor-positive breast cancer. Everolimus (EVE) ameliorates AI-resistant breast cancer and is therefore used in cancer treatment. However, some patients show resistance to EVE. Here, we used 30 clones of long-term estrogen-deprived (LTED) MCF-7 cells as a model of AI-resistant breast cancer. We examined changes in protein phosphatase type 2A (PP2A) and cancerous inhibitor of PP2A (CIP2A), a negative regulator of PP2A, in LTED cells treated with EVE. In LTED cells with high sensitivity to EVE, CIP2A expression decreased at low EVE concentrations; however, in LTED cells poorly sensitive to EVE, CIP2A and PP2A did not change upon exposure to EVE. Therefore, we hypothesized that there is a relation between expression of CIP2A and sensitivity to EVE. Knockdown of CIP2A increased the sensitivity to EVE in three clones poorly sensitive to EVE. Additionally, we found that treatment with FSK, which activates PP2A, increased the sensitivity of the cells to EVE. Our data point to CIP2A and PP2A as novel therapeutic targets for AI-resistant breast cancer.

Estrogens play a physiologically important role in the brain, but controversies exist regarding the association between Alzheimer’s disease (AD) and estrogens. Estrogen-related factors were comprehensively examined in frontal lobe tissues from autopsied AD patients, and compared with controls. Concentrations of estrogens, expression of estrogen receptors (ERs), and estrogen-metabolizing enzymes (EMEs) which are important for determining the peripheral estrogen concentrations, were examined using liquid chromatography tandem mass spectrometry, immunohistochemistry, and quantitative real-time PCR, respectively. Body mass index (BMI), known to correlate with the serum estrogen concentrations, was also taken into consideration. There were no significant differences in estrogen concentrations or each EME level between the two groups in both the cortex and white matter, whereas glial nuclear ER-β expression was significantly lower in white matter from the AD group than the control group (Allred score, 3.2 ± 0.3 and 6.5 ± 0.3, respectively. P

Aromatase inhibitors (AIs) are effective endocrine therapeutics for postmenopausal women with estrogen receptor (ER)α-positive breast cancer. However, the efficacy of the treatment is often limited by the onset of AI resistance, owing to the phosphorylation of ERα serine 167 (Ser167). Previous studies have indicated that hyperactivation of the phosphoinositide-3 kinase/RAC serine/threonine-protein kinase signaling pathway occurs in AI-resistant breast cancer models, which coincides with elevated levels of ERα phosphorylation at Ser167. The tumor suppressor serine/threonine-protein phosphatase 2A (PP2A) regulates the phosphatidylinositol 3-kinase/RAC serine/threonine-protein kinase signaling pathway. A previous study indicated that PP2A inhibition decreased ERα Ser167 phosphorylation and estradiol (E2)-independent cell growth. The present study investigated the potential relevance of PP2A in E2 deprivation-resistant MCF-7 cells. E2 depletion reduced the susceptibility of MCF-7 cells to inhibitors of mechanistic target of rapamycin (mTOR) and significantly increased ERα Ser167 phosphorylation and decreased expression of PP2A. Conversely, long-term E2-deprived (LTED) MCF-7 cells, a model of AI-resistant breast cancer, exhibited decreased ERα Ser167 phosphorylation and further upregulation of PP2A in E2-containing medium. The PP2A activator forskolin (FSK) significantly inhibited LTED cell proliferation by increasing the effect of everolimus (Eve), an mTOR inhibitor. In summary, the present study provides further evidence that PP2A represents a therapeutic target for AI-resistant breast cancer.

Obesity commonly occurs in postmenopausal women, increasing the risk of various diseases. Estrogen can prevent obesity by activating lipid metabolism and suppressing depressive behavior. However, the reasons for obesity in postmenopausal women are not clearly elucidated. To mimic the effect of estrogen decline in postmenopausal women, we analyzed the behavior and the lipid metabolism-related genes, PPARγ and CD36 in ovariectomized (OVX) mice. The OVX mice showed increased visceral fat mass and PPARγ and CD36 expression in the visceral fat. In contrast, they were not significantly affected in terms of physical activity and food intake. Further, subcutaneous supplementation of estrogen effectively suppressed the increase in subcutaneous and visceral fat mass in OVX mice. We conclude that obesity in postmenopausal women is unlikely to be caused by overeating and reduction in physical activity, and subcutaneous supplementation of estrogen is an effective strategy to prevent obesity in postmenopausal women., Highlights • We studied the effects of estrogen deficiency/supplementation on obesity in mice. • After ovariectomy, the study animals received transdermal injections of estrogen. • Exogenous 17β-estradiol appears to mediate the effects of menopause on obesity. • Obesity in the mice was caused solely by estrogen deficiency, not overeating. • Estrogen deficiency altered the mechanics of fat deposition in the mice.

Purpose To evaluate the efficiency of automated function imaging (AFI) on transthoracic echocardiogram (TTE) for detecting left ventricular (LV) wall motion (LVWM) abnormalities, we compared longitudinal peak systolic strain (LPSS) measurements using AFI with naked eye TTE evaluations by experienced cardiologists and non-experienced residents. Materials and methods A total of 352 segments of LV myocardium from 22 consecutive subjects with LVWM abnormalities based on American Heart Association classifications (11 male, mean age 58±14years) on previous TTE (Vivid-7, GE) were evaluated. LPSS was measured using stored AFI data. Naked eye evaluation of LVWM was performed by 2 experienced cardiologists and 2 non-experienced residents. Results AFI successfully tracked 342 (97%) of all segments (mean LPSS −14.8±8.1%). A significant strong negative correlation was observed between LV ejection fraction using method of disks and global LPSS (R=−0.8974). Temporary AFI criteria of LPSS were normal 2. Of 342 segments, 239, 87, and 16 segments were diagnosed as normal, hypokinesis, and akinesis, respectively. Level of agreement and kappa coefficients between qualitative evaluation of LVWM by AFI temporary criteria and qualitative evaluation of LVWM by experienced cardiologist 2 (0.784 and 0.479, respectively) were inferior to those comparing experienced cardiologists (0.845 and 0.595) but superior comparing experienced cardiologist with non-experienced resident (0.696 and 0.323), and between the 2 non-experienced-residents (0.682 and 0.347). Conclusion Qualitative evaluation of LVWM using temporary AFI criteria had a 97% success rate and agreed well with findings of an experienced cardiologist. AFI can be a useful tool for training residents.

Microorganisms in water were inactivated by irradiating with an atmospheric-pressure plasma generated by a dielectric barrier discharge. To understand the inactivation mechanism of microorganisms, the actions due to irradiation with plasma discharge, heating, and chemical reaction are studied. We compare the buffer gases helium and argon in generating the atmospheric-pressure plasma. The results indicate that the inactivation with the helium as buffer gas is higher than with argon. It is found that the inactivation ratio at different reactor volumes depends on the density of microorganisms in water. © 2013 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.

We examined the protective effect of Brazilian propolis against liver damage with cholestasis in rats treated withα-naphthylisothiocyanate (ANIT) in comparison with that of vitamin E (VE). Rats orally received Brazilian propolis ethanol extract (BPEE) (25, 50, or 100 mg/kg), VE (250 mg/kg) or vehicle at 12 h after intraperitoneal injection of ANIT (75 mg/kg) and were killed 24 h after the injection. Vehicle-treated rats showed liver cell damage and cholestasis, judging from the levels of serum marker enzymes and components. The vehicle group had increased serum total cholesterol, triglyceride, phospholipid, and lipid peroxide levels, increased hepatic lipid peroxide, reduced glutathione, and ascorbic acid levels and myeloperoxidase activity, and decreased hepatic superoxide dismutase activity. BPEE (50 mg/kg) administered to ANIT-treated rats prevented liver cell damage and cholestasis and attenuated these serum and hepatic biochemical changes except hepatic ascorbic acid, although administered BPEE (25 or 100 mg/kg) was less effective. VE administered to ANIT-treated rats prevented liver cell damage, but not cholestasis, and attenuated increased serum lipid peroxide level, increased hepatic lipid peroxide level and myeloperoxidase activity, and decreased hepatic superoxide dismutase activity. These results indicate that BPEE protects against ANIT-induced liver damage with cholestasis in rats more effectively than VE.

The purpose of this article is to investigate the effect of magnetic nozzle for disk Magnetohydrodynamics (MHD) accelerator using by Q1D (quasi-1-dimentional) numerical simulation. As results, as constant applied magnetic field of 2T is supplied to the MHD channel and 3, 6, 8 and 10T are supplied to the nozzle, acceleration performance for these cases could not observe the significant difference. However as applied magnetic field of 3, 6, 8 and 10T are supplied to downstream side of the MHD channel and the nozzle, gas velocity for case of 6T was accelerated to 3170m/s and 10T was accelerated to 3040m/s. Because of excessive applied magnetic field induced compression due to joule heating and friction loss.

This paper presents comparative performances of an linear and disk AC MHD power generation with an active power. The configuration of linear and disk consist of the top and bottom stators. the top stator bottom stator winding are connected with a power supply and an electrical load, respectively. The interaction between the metal fluid and traveling magnetic field can be explained by Maxwell’s equations and Ohm’s law based on the method of finite-elements. Power flow and electrical efficiency of an AC MHD power generation have been evaluated by various slip conditions. The optimal operating point of the generator was defined by adjusting slip values. The result confirms that disk AC MHD power generation has high active power more than linear AC MHD power generation at the same slip.

Neurosteroidal oestrogen has been proposed to play important roles in a variety of reproductive behaviours. Aromatase, a key enzyme in oestrogen synthesis, is localised in neural nuclei of specific brain regions and is developmentally regulated, with a transient expression peak at the perinatal period. The brain-specific promoter of the aromatase gene was analysed aiming to determine the transcriptional control mechanisms that could help explain the spatiotemporal expression. We previously reported that a 202-bp sequence, which is upstream from the transcriptional initiation site, is essential for the basal transcriptional activity. The 202-bp upstream region of brain-specific exon 1 comprises at least three types of cis-acting elements: aro-AI (Arom-Aα), aro-AII (Arom-Aβ) and aro-B (Arom-B). To identify the binding proteins for the cis-acting elements, a yeast one-hybrid screen was performed with these cis-element sequences using a mouse foetal cDNA library. Lhx2, a LIM-homeodomain protein, was identified as one of the aro-B binding proteins. The identification was further confirmed using the gel shift assay, which demonstrated binding competition of nuclear proteins to the aro-B element with a typical Lhx2-binding element. In addition, a chromatin immunoprecipitation assay with an anti-Lhx2 antibody demonstrated that Lhx2 bound to the aro-B site in vivo. A reporter assay of the brain-specific promoter demonstrated increased Lhx2-dependent promoter activity. Furthermore, the time-dependent increase in aromatase mRNA in primary cultured foetal neurones was suppressed by an small-interfering RNA-mediated knockdown of Lhx2 expression. These results show that Lhx2 is involved in the transcriptional regulation of aromatase in the rodent brain.

An effect of cross-section in electrode on the thrust efficiency has been studied by using an MHD accelerator which consists of a pulsed-power system and a model rocket engine. In order to estimate the thrust efficiency, temperature and velocity of combustion gas were measured by fitting the radiation temperature assuming blackbody and time-of-flight method. The results indicated that the thrust efficiency of the pulsed-MHD accelerator is improved when the cross-section of electrode is decreased. Because of the higher current density generates the stronger electromagnetic force for the smaller electrode.

Estrogens play an important role in the pathobiology of breast cancer. In postmenopausal women, peripheral synthesis of estrogens from adrenal/ovarian androgens, dehydroepiandrosterone (DHEA) or androstenedione (Adione), by estrogen-metabolizing enzymes is important. Besides estrone (E1) and estradiol (E2), androgen metabolites, such as androstene-3β, 17β-diol (Aenediol) or 5α-androstane-3β, 17β-diol (Aanediol), are known to have estrogenic functions, although they have been studied much less in breast cancer. To precisely elucidate steroid metabolism in breast cancer patients and to identify the pathobiological role of estrogenic androgen metabolites, concentrations of DHEA, Adione, Aenediol, Aanediol, E1, and E2 in pairs of serum and tumor tissue from patients with primary breast cancer were measured by liquid chromatography-tandem mass spectrometry. Cell proliferation assays using Aenediol were performed for four breast cancer cell lines. Serous E2 concentration was extremely low in postmenopausal women; however, a marked increase in tumor tissue was observed in hormone receptor-positive cases. E1 concentration, in contrast, was sustained at a higher level, even in postmenopausal serum, and did not increase in tumor tissue irrespective of the hormone receptor status. Dehydroepiandrosterone was most abundant in all samples, and exhibited a similar pattern as Adione and Aenediol. 5α-Androstane-3β, 17β-diol was undetectable in most samples. Androstene-3β, 17β-diol proliferated estrogen receptor-apositive breast cancer cells in the absence of E2. The intratumoral increase of E2, but not E1, in hormone receptor-positive postmenopausal breast cancer tissue, as well as the proliferative role of Aenediol, was elucidated.

Although the use of single-incision laparoscopic cholecystectomy (SILC) is spreading rapidly, this technique has disadvantages. It does not allow for sufficient surgical views to be obtained or for intraoperative radiographic cholangiography to be performed. Fluorescent cholangiography using a preoperative intravenous injection of indocyanine green (ICG) may be useful for identifying the biliary tract during both SILC and conventional laparoscopic cholecystectomy. For seven patients undergoing SILC, 1 ml of ICG (2.5 mg) was administered by intravenous injection before the surgery. The prototype fluorescent imaging system consisted of a xenon light source and a 30° laparoscope (diameter, 10 mm) equipped with a charge-coupled device camera capable of filtering out light with wavelengths shorter than 810 nm. The laparoscope was introduced through an umbilical trocar. Fluorescent cholangiography then was performed by changing the color images to fluorescent images using a foot switch during dissection of the triangle of Calot. Fluorescent cholangiography identified the confluence between the cystic duct and the common hepatic duct in all seven patients before and throughout the dissection of the triangle of Calot. The interval from the injection of ICG to the first obtained fluorescent cholangiography before dissection of the triangle of Calot ranged from 35 to 75 min. Fluorescent cholangiography enabled real-time identification of the extrahepatic bile ducts during SILC without necessitating catheterization of the bile duct. Such properties of fluorescent cholangiography are expected to be helpful for ensuring the safety of SILC and expanding the indications for the procedure.

This paper presents the possibility to generate the alternating current (AC) electrical power by using a linear MHD generator. The single-sided exciting winding of the generator is considered. Its structure consists of a channel, an insulator and stators. The channel type is a flat rectangular and the liquid flows along the channel as a conductor. The channel wall acted as an insulator separates the metal fluid and stator coil. The top stator winding of the generator is connected to polyphase systems. Under this condition, it can produce a magnetic field by means of time harmonics function in the same direction of the metal fluid. Energy in the channel is extracted by inductive coils at the bottom stator. An interaction between traveling wave and metal fluid is explained by finite element technique. The distributions of magnetic vector potential and magnetic field throughout channel are evidently shown in xy-plane. Power flow in an AC MHD generator is reported with magnetic Reynolds number and slip value. The optimized value of active power is suggested by small slip value as s < 0 and small magnetic Reynolds number.

This paper investigates the acceleration performance of a disk-shaped magnetohydrodynamics (MHD) accelerator. Quasi-1-dimensional (Q1D) numerical simulation employing the MacCormack scheme was developed. For the longer channel length of 0.9 m, thermal loss was estimated at over 60% and effective acceleration could not be achieved owing to large heat loss and large friction loss. For shorter channel lengths, thermal loss can be reduced below 20% owing to the smaller heat and the friction losses. However, with too short a channel length, accelerator performance was decreased by the MHD compression due to excessive Faraday current density. The effect of ratio of cross sectional area on performance was also studied. For a larger area ratio, the gas can be accelerated smoothly throughout the MHD channel. However, for the excessive expansion case of a sevenfold channel, gas velocity near the exit decreased due to transition to a “generator mode”. For the best acceleration performance, the design channel length should be as short as possible preventing compression at the channel inlet. The area ratio should be large enough to prevent the compression but not too large, to prevent transition to a “generator mode”.

Fluorescence imaging using indocyanine green (ICG) has recently been applied to laparoscopic surgery to identify cancerous tissues, lymph nodes, and vascular anatomy. Here we report the application of ICG-fluorescence imaging to visualize the boundary between the liver and subserosal tissues of the gallbladder during laparoscopic full-thickness cholecystectomy. A patient with a potentially malignant gallbladder lesion was administered 2.5-mg intravenous ICG just before laparoscopic full-thickness cholecystectomy. Intraoperative fluorescence imaging enabled the real-time delineation of both extrahepatic bile duct anatomy and hepatic parenchyma throughout the procedure, which resulted in complete removal of subserosal tissues between liver and gallbladder. Safe and feasible ICG-fluorescence imaging can be widely applied to laparoscopic hepatobiliary surgery by utilizing a biliary excretion property of ICG.

Aromatase, a key enzyme of estrogen biosynthesis, is transcriptionally regulated by many growth factors. IGF-I enhances aromatase activity in a variety of cells, but the mechanism of action has not been determined. We herein report our finding of a novel mechanism of action for IGF-I. IGF-I enhanced the dexamethasone (DEX)-induced aromatase activity by 30% in serum-starved THP-1 cells. The increase was associated with a corresponding increase in the level of aromatase protein but not with any change in the mRNA level. Metabolic labeling experiments revealed that IGF-I inhibited the degradation of aromatase. We identified pepstatin A as the most effective inhibitor of aromatase degradation by in vitro assay. Using a nontoxic concentration of pepstatin A, we examined IGF-I’s action on aromatase distribution in microsomes and lysosomes. In the presence of pepstatin A, DEX caused an increase in the amount of aromatase in both microsomes and lysosomes, and IGF-I attenuated the DEX-induced accumulation of aromatase in lysosomes and, conversely, enhanced its accumulation in the microsomes. The addition of serum abolished the IGF-I-induced changes. The transport from microsome to lysosome was fluorescently traced in cells using a recombinant aromatase. IGF-I selectively reduced the aromatase signal in the lysosomes. Finally, we observed that IGF-I enhanced the aromatase activity by 50% as early as 1 h after treatment; furthermore, rapamycin, an enhancer of autophagy, completely negated the effect of IGF-I on the enzyme. These results indicate that IGF-I enhances aromatase by the inhibition of autophagy.

Introduction: Laparoscopic hepatectomy has disadvantages in intraoperative diagnosis, because it offers limited visualization and palpability of the liver surface. Recently, we developed a novel fluorescent imaging technique using indocyanine green (ICG), which would enable identification of liver cancers during open hepatectomy. However, this technique has not yet been applied to laparoscopic hepatectomy. Materials and Surgical Technique: A patient with a hepatocellular carcinoma (HCC) located in Couinaud's segment II was administered ICG (0.5 mg per kg body weight) intravenous injection 5 d before surgery, as a routine liver function test. The prototype fluorescent imaging system was composed of a xenon light source and a laparoscope with a charge-coupled device camera that could filter out light with wavelengths below 810 nm. Intraoperatively, fluorescent imaging of the HCC was performed by changing color images to fluorescent images with a foot switch. Then, the fluorescing tumor was clearly identified on the visceral surface of segment II during mobilization of the left liver for resection of segments II and III. On the cut surface of the specimen, the tumor showed uniform fluorescence and was microscopically diagnosed as a well-differentiated HCC. Discussion: Laparoscopic fluorescent imaging using preoperative injection of ICG enabled real-time identification of HCC. This technique may be an easy and reliable tool to enhance the accuracy of intraoperative diagnosis during laparoscopic hepatectomy.

This paper studies physical phenomena, performance and optimal operating point of an AC MHD generator under the slip value by using a numerical simulation. The double-side exciting winding of the generator is considered. Its structure consists of a channel, an insulator and stators. Channel type is a flat rectangular and the liquid flows along the channel as a conductor. Channel wall acted as an insulator separates metal fluid and stator coils. The top and bottom stator winding of the generator is connected to polyphase system. Under this condition, it can produce a magnetic field by means of time harmonic function in the same direction of the metal fluid. An interaction between traveling wave and metal fluid is explained by finite element method under Maxwell's equation and Ohm law. The distribution of magnetic vector potential and magnetic flux density throughout channel is evidently shown in xy-plane. Power flow in AC MHD generator is evaluated by slip value. The optimal operating point of an AC MHD generator performance is reported by active power 0.99kW, reactive power 50kVAR, mechanical power 1.58kW, power dissipation 0.59kW and electrical efficiency 62.5%.

This paper presents the investigation of ablation plasma characteristics together with the flyer velocity for flyer acceleration when irradiating the 50-μm-Al target with a multi-pulsed ion beam. A one-dimensional hydrodynamic model is used in the calculations. The CIP method is used to describe the ablation plasma production and the acceleration mechanism by the repetition of ion beam irradiation. In the calculations, two shots of ion beam, which has a total energy density of 120 J/cm 2 , are used. The time intervals between the first pulse and the second pulse of 0 ns, 20 ns, 50 ns and 100 ns were used for the investigation of flyer (target) velocity. Results indicate that irradiating the second pulse for 20 ns, 50 ns and 100 ns after the first pulse increases the flyer velocity by approximately 16%, 32% and 40%, respectively.

In this study, the possible application of atmospheric pressure dielectric barrier discharge plasma for the annealing of metallic wire is examined and presented. The main purpose of the current study is to examine the surface cleaning effect for a cylindrical object by atmospheric pressure plasma. The experimental setup consists of a gas tank, plasma reactor, and power supply with control panel. The gas assists in the generation of plasma. Copper wire was used as an experimental cylindrical object. This copper wire was irradiated with the plasma, and the cleaning effect was confirmed. The result showed that it is possible to remove the tarnish which exists on the copper wire surface. The experiment reveals that atmospheric pressure plasma is usable for the surface cleaning of metal wire. However, it is necessary to examine the method for preventing oxidization of the copper wire.

SummarySex hormones are essential for neural circuit development and sex-specific behaviors. Male behaviors require both testosterone and estrogen, but it is unclear how the two hormonal pathways intersect. Circulating testosterone activates the androgen receptor (AR) and is also converted into estrogen in the brain via aromatase. We demonstrate extensive sexual dimorphism in the number and projections of aromatase-expressing neurons. The masculinization of these cells is independent of AR but can be induced in females by either testosterone or estrogen, indicating a role for aromatase in sexual differentiation of these neurons. We provide evidence suggesting that aromatase is also important in activating male-specific aggression and urine marking because these behaviors can be elicited by testosterone in males mutant for AR and in females subjected to neonatal estrogen exposure. Our results suggest that aromatization of testosterone into estrogen is important for the development and activation of neural circuits that control male territorial behaviors.

Domestic pigs have three CYP19 genes encoding functional paralogues of the enzyme aromatase cytochrome P450 (P450arom) that are expressed in the gonads, placenta, and preimplantation blastocyst. All catalyze estrogen synthesis, but the gonadal-type enzyme is unique in also synthesizing a nonaromatizable biopotent testosterone metabolite, 1OH-testosterone (1OH-T). P450arom is expressed in the vertebrate brain, is higher in males than females, but has not been investigated in pigs, to our knowledge. Therefore, these studies defined which of the porcine CYP19 genes was expressed, and at what level, in adult male and female hypothalamus. Regional expression was examined in mature boars, and regulation of P450arom expression in neonatal boars was investigated by inhibition of P450arom with letrozole, which is known to reprogram testicular expression. Pig hypothalami expressed the gonadal form of P450arom (redesignated the "gonadal/hypothalamic" porcine CYP19 gene and paralogue) based on functional analysis confirmed by cloning and sequencing transcripts. Hypothalamic tissue synthesized 1OH-T and was sensitive to the selective P450arom inhibitor etomidate. Levels were 4-fold higher in male than female hypothalami, with expression in the medial preoptic area and lateral borders of the ventromedial hypothalamus of boars. In vivo, letrozole-treated neonates had increased aromatase activity in hypothalami but decreased activity in testes. Therefore, although the same CYP19 gene is expressed in both tissues, expression is regulated differently in the hypothalamus than testis. These investigations, the first such studies in pig brain to our knowledge, demonstrate unusual aspects of P450arom expression and regulation in the hypothalamus, offering promise of gaining better insight into roles of P450arom in reproductive function.