Signal pathway of LH-induced expression of nuclear progestin receptor in vertebrate ovulation.

Nuclear progestin receptor (PGR), which is induced in the follicles destined to undergo ovulation, is believed to be obligatory for rupture of the follicles during ovulation in vertebrates. Studies in some mammals and teleost medaka have revealed the outline of the central signaling pathway that leads to the PGR expression in the preovulatory follicles at ovulation. In this review, we summarize the current knowledge on what signaling mediators are involved in the LH-induced follicular expression of PGR at ovulation in these animals. LH-inducibility of follicular PGR expression is conserved. In both group of animals, activation of the LH receptor on the granulosa cell surface with LH commonly results in the increase of intracellular cAMP levels, while the downstream signaling cascades activated by high level of cAMP are totally different between mice and medaka. PGR is currently presumed to be induced via PKA/CREB-mediated transactivation and ERK1/2-dependent signaling in mice, but the receptor is induced via EPAC/RAP and AKT/CREB pathways in the teleost medaka. The differences and similarities in the signaling pathways for PGR expression between them is discussed from comparative and evolutionary aspects. We also discussed questions concerning PGR expression and its regulation needed to be investigated in future.

Long-term and short-term outcomes of laparoscopic versus open resection following tube decompression for obstructive colorectal cancer: a single-center retrospective study.

PURPOSE: The benefits of laparoscopic surgery over open surgery are well documented; however, the suitability of laparoscopic surgery for obstructive colorectal cancer is still controversial. The aim of this retrospective study was to compare the clinical benefits of laparoscopic surgery vs. open surgery for obstructive colorectal cancer after tube decompression. METHODS: We analyzed the outcomes of patients who underwent laparoscopic surgery vs. open surgery for curative resection after tube decompression for obstructive colorectal cancer at our hospital between January, 2007 and March, 2018. RESULTS: This study comprised 67 patients: 29 patients who underwent open surgery and 38 patients who underwent laparoscopic surgery. The morbidity within 30 days after surgery was comparable between the groups. The 3-year overall survival rates of the open and laparoscopic groups were 83.3 and 79.4%, respectively (p = 0.6244), and the 3-year disease-free survival rates were 59.3 and 71.2%, respectively (p = 0.3200). Multivariate analysis showed that nodal stage (p = 0.021) was an independent prognostic factor for OS and sex (p = 0.010) and side-ness (p = 0.048) were independent prognostic factors for DFS. CONCLUSION: If adequate decompression is achieved, laparoscopic resection following tube decompression for obstructive colorectal cancer can be a safe alternative to open surgery.

Stimulatory effects of collagen production induced by coenzyme Q10 in cultured skin fibroblasts.

Coenzyme Q10 (CoQ10) is a well-known antioxidant and serves as an essential carrier for electron transport and proton translocation in the mitochondrial respiratory chain. CoQ10 has been widely commercially available in Japan as a dietary and health supple-ment since 2001 and it is used for the prevention of lifestyle-related diseases induced by aging. Recently, it was stated that for Japan, which is facing an aging society, CoQ10 has been used in many skincare products. However, the physiological actions of CoQ10 in skin fibroblasts are not fully understood. In this study, we examined the effect of CoQ10 on cultured human skin fibroblast. In this study, CoQ10 treatment increased intracellular CoQ10 level and promoted proliferation of fibroblasts. In addition, CoQ10 increased mRNA expression of type I, IV, VII collagen, elastin, and HSP47, whereas CoQ10 has little effect on mRNA of type II and VIII MMP. These results suggested that CoQ10 has the efficacy that it increases collagen production in skin, thereby there is possible of the anti-aging by CoQ10 in Japan which reached an aging society, so that it might be based on new physiological function by CoQ10.

A central role for cAMP/EPAC/RAP/PI3K/AKT/CREB signaling in LH-induced follicular Pgr expression at medaka ovulation†.

Nuclear progestin receptor (PGR) is a ligand-activated transcription factor that has been identified as a pivotal mediator of many processes associated with ovarian and uterine function, and aberrant control of PGR activity causes infertility and disease including cancer. The essential role of PGR in vertebrate ovulation is well recognized, but the mechanisms by which PGR is rapidly and transiently induced in preovulatory follicles after the ovulatory LH surge are not known in lower vertebrates. To address this issue, we utilized the small freshwater teleost medaka Oryzias latipes, which serves as a good model system for studying vertebrate ovulation. In the in vitro ovulation system using preovulatory follicles dissected from the fish ovaries, we found that inhibitors of EPAC (brefeldin A), RAP (GGTI298), PI3K (Wortmannin), AKT (AKT inhibitor IV), and CREB (KG-501) inhibited LH-induced follicle ovulation, while the PKA inhibitor H-89 had no effect on follicle ovulation. The inhibitors capable of inhibiting follicle ovulation also inhibited follicular expression of Pgr and matrix metalloproteinase-15 (Mmp15), the latter of which was previously shown to not only be a downstream effector of Pgr but also a proteolytic enzyme indispensable for follicle rupture in medaka ovulation. Further detailed analysis revealed for the first time that the cAMP/EPAC/RAP/PI3K/AKT/CREB signaling pathway mediates the LH signal to induce Pgr expression in preovulatory follicles. Our data also showed that phosphorylated Creb1 is a transcription factor essential for pgr expression and that Creb1 phosphorylated by Akt1, rather than PKA, may be preferably used to induce pgr expression.

Effects of dietary silkrose of Antheraea yamamai on gene expression profiling and disease resistance to Edwardsiella tarda in Japanese medaka (Oryzias latipes).

We previously identified a novel acidic polysaccharide, silkrose-AY, from the Japanese oak silkmoth (Antheraea yamamai), which can activate an innate immune response in mouse macrophage cells. However, innate immune responses stimulated by silkrose-AY in teleosts remain unclear. Here, we show the influence of dietary silkrose-AY in medaka (Oryzias latipes), a teleost model, in response to Edwardsiella tarda infection. Dietary silkrose-AY significantly improved the survival of fish and decreased the number of bacteria in their kidneys after the fish were artificially infected with E. tarda by immersion. We also performed a microarray analysis of the intestine, which serves as a primary barrier against microbial infection, to understand the profiles of differentially expressed genes (DEGs) evoked by silkrose-AY. The dietary silkrose-AY group showed differential expression of 2930 genes when compared with the control group prior to E. tarda infection. Gene ontology and pathway analysis of the DEGs highlighted several putative genes involved in pathogen attachment/recognition, the complement and coagulation cascade, antimicrobial peptides/enzymes, opsonization/phagocytosis, and epithelial junctional modification. Our findings thus provide fundamental information to help understand the molecular mechanism of bacterial protection offered by insect-derived immunostimulatory polysaccharides in teleosts.

Cost-effectiveness of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients with metastatic colorectal cancer.

BACKGROUND: TAS-102 plus bevacizumab is an anticipated combination regimen for patients who have metastatic colorectal cancer. However, evidence supporting its use for this indication is limited. We compared the cost-effectiveness of TAS-102 plus bevacizumab combination therapy with TAS-102 monotherapy for patients with chemorefractory metastatic colorectal cancer. METHOD: Markov decision modeling using treatment costs, disease-free survival, and overall survival was performed to examine the cost-effectiveness of TAS-102 plus bevacizumab combination therapy and TAS-102 monotherapy. The Japanese health care payer's perspective was adopted. The outcomes were modeled on the basis of published literature. The incremental cost-effectiveness ratio (ICER) between the two treatment regimens was the primary outcome. Sensitivity analysis was performed and the effect of uncertainty on the model parameters were investigated. RESULTS: TAS-102 plus bevacizumab had an ICER of $21,534 per quality-adjusted life-year (QALY) gained compared with TAS-102 monotherapy. Sensitivity analysis demonstrated that TAS-102 monotherapy was more cost-effective than TAS-102 and bevacizumab combination therapy at a willingness-to-pay of under $50,000 per QALY gained. CONCLUSIONS: TAS-102 and bevacizumab combination therapy is a cost-effective option for patients who have metastatic colorectal cancer in the Japanese health care system.

Roles of melatonin in the teleost ovary: A review of the current status.

Melatonin, the neurohormone mainly synthesized in and secreted from the pineal gland of vertebrates following a circadian rhythm, is an important factor regulating various physiological processes, including reproduction. Recent data indicate that melatonin is also synthesized in the ovary and that it acts directly at the level of the ovary to modulate ovarian physiology. In some teleosts, melatonin is reported to affect ovarian steroidogenesis. The direct action of melatonin on the ovary could be a possible factor promoting oocyte maturation in teleosts. A role for melatonin in follicle rupture during ovulation in the teleost medaka has recently emerged. In addition, melatonin is suggested to affect oocyte maturation by its antioxidant activity. However, the molecular mechanisms underlying these direct effects of melatonin are largely unknown.

Protective effects of coenzyme Q10 on cell damage induced by hydrogen peroxides in cultured skin fibroblasts.

Cellular senescence is an intricate and multifactorial phenomenon, which is characterized by an irreversible cellular growth arrest, it is caused in response to irretrievably DNA damage, telomere shorting, activation of oncogene, and oxidative stress. Human diploid fibroblasts are a well-established experimental model for premature senescence-related studies, and exposure of fibroblasts to H2O2 is widely used as a SIPS model. Recently, it has been reported many studies of CoQ10 as to anti-aging effects, however the effect of CoQ10 on H2O2-induced SIPS model of human skin fibroblasts has not been understood. So that, we investigated that human skin fibroblasts were used to investigate the prevention effect of CoQ10 against H2O2-induced SIPS model. We created SIPS model fibroblasts with treatment of 100 µM H2O2 for 2 h. In this study, CoQ10 also increased cell viability and mRNA levels of type I, IV collagen and protein level of type I collagen. Moreover, it is shown that CoQ10 suppressed oxidative stress, degradation of collagen by increasing MMP expression, and decreasing senescence-associated phenotypes (e.g. SA-ßgal positive staining and SASP) for preventing skin aging via H2O2-induced SIPS model. These results suggested that CoQ10 has possibility to be contributory for extension of healthy life expectancy in Japan.

Evaluation of safety and diagnostic performance for flexible hysteroscopy in 1591 outpatient cases.

BACKGROUND: To date, only few large studies are available concerning the safety and diagnostic concordance rates of outpatient flexible hysteroscopy. In our institution, outpatient hysteroscopy has been routinely and educationally applied Kosuke Tsuji to intrauterine lesions; thus, we retrospectively investigated the institution's outpatient flexible hysteroscopy cases. METHODS: A total of 1591 cases of outpatient flexible hysteroscopy conducted at our institution in 2012-2016 were retrospectively analyzed in terms of their clinical background, complications and diagnostic concordance rates. RESULTS: A total of 1591 cases included 546 cases of benign tumors (317 endometrial polyps, 168 myomas and 61 endometrial hyperplasia), 361 cases of atypical endometrial hyperplasia, 571 cases of endometrial cancers and 113 cases of other diagnoses. No major complications, including uterine perforation, occurred. However, one patient (0.06%) was diagnosed with septic shock caused by intrauterine infection that required prolonged immunosuppressive drug administration. Meanwhile, 335 patients diagnosed with benign tumors through outpatient flexible hysteroscopy underwent operation, and the diagnostic concordance rate was 74.6% (250 cases). However, this rate included 14 cases (4.2%) diagnosed with malignant tumors postoperatively. In preoperative endometrial cancer cases, the sensitivity and specificity for cervical invasion diagnosis were 39.4 and 90.8%, respectively. In addition, only one patient manifested positive ascites cytology intraoperatively, possibly caused by outpatient hysteroscopy. CONCLUSIONS: Outpatient flexible hysteroscopy is highly safe, with a slight negligible effect on ascites cytology. However, the diagnosis should be determined by multidisciplinary approaches, as hysteroscopy alone can miss malignancy.

Inhibition of medaka ovulation by gap junction blockers due to its disrupting effect on the transcriptional process of LH-induced Mmp15 expression.

Using medaka, we found that in vitro follicle ovulation, but not germinal vesicle breakdown, was inhibited by three gap junction blockers, carbenoxolone, mefloquine, and flufenamic acid. The blockers specifically inhibited follicular expression of matrix metalloproteinase-15 mRNA and the protein (mmp15/Mmp15), a protease indispensable for medaka ovulation, indicating that gap junctional communication may be required for successful ovulation and mmp15/Mmp15 expression. Further experiments using carbenoxolone as the representative of the gap junction blockers showed that expression of nuclear progestin receptor (Pgr), a transcription factor required for mmp15 expression, was not affected by carbenoxolone treatment, but the formation of phosphorylated Pgr was considerably suppressed. Carbenoxolone treatment caused a decrease in the Pgr binding to the promoter region of mmp15. mRNA expression of cyclin-dependent protein kinase-9 (cdk9) and cyclin I (ccni), whose translation products are demonstrated to be involved in Pgr phosphorylation in the medaka ovulating follicles, was suppressed by carbenoxolone treatment. Transcripts of connexin 34.5 (cx34.5) and connexin 35.4 (cx35.4) were dominantly expressed in the follicle cells of ovulating follicles. The results indicate that gap junctional communication plays an important role in medaka ovulation.

Follicle rupture during ovulation with an emphasis on recent progress in fish models.

Ovulation, which is induced by the ovulatory luteinizing hormone (LH) surge, is a dynamic process that results in a discharge of one or more fertilizable oocytes from the ovarian follicle into the ovarian cavity or into the abdominal cavity. Follicle rupture is a core event of the ovulatory process and has been the subject of intensive investigation. Many studies have been performed in various vertebrate animals that focused on proteolysis during ovulation. Despite much effort, the proteases responsible for follicle rupture in ovulation have not yet been identified for mammalian species. However, studies conducted using the teleost medaka have recently provided valuable information about the follicle rupture process. Follicle rupture during medaka ovulation is accomplished by a two-step extracellular matrix (ECM) hydrolysis mechanism involving two distinct protease systems, the urokinase-type plasminogen activator-1 /plasmin and the matrix metalloproteinase system. In the 24-h spawning cycle of the fish, the former protease system is activated first, and the latter subsequently becomes active. Proteolytic activities of these systems are regulated by their intrinsic inhibitors. The endocrine regulation of the rupture was examined by investigating the expression of matrix metalloproteinase 15 (Mmp15), which is the only LH-inducible protease among those involved in the rupture process. At least two transcription factors, classical nuclear progestin receptor and CCAAT/enhancer-binding protein ß, play critical roles in the expression of the protease transcript. This review also summarizes studies addressing follicle rupture during ovulation conducted using other teleost models to understand the current status of teleost ovulation studies.

Extracellular coenzyme Q10 (CoQ10) is reduced to ubiquinol-10 by intact Hep G2 cells independent of intracellular CoQ10 reduction.

Coenzyme Q10 (CoQ10) is an essential factor in the mitochondrial respiratory chain and is closely associated with ATP production in humans. It is known that orally administered CoQ10 in humans is rapidly reduced, and most is detected as a reduced form, ubiquinol-10 (CoQ10H2), in serum. However, the mechanism of exogenous CoQ10 reduction in vivo is unclear. Therefore, in order to clarify how CoQ10 is reduced to CoQ10H2, we conducted a study using human liver cancer cell line Hep G2 cells, which show strong intracellular CoQ10-reducing activity. When intact cells were incubated with CoQ10, the exogenously added CoQ10 was incorporated into the cells, time-, concentration-, and temperature-dependently, and 50-80% of that was detected as CoQ10H2. On the other hand, a part of the extracellular CoQ10 was also detected as CoQ10H2, and the amount was greater than that of the intracellular CoQ10H2. Furthermore, the CoQ10-loaded cells did not leak the intracellular CoQ10H2 (or CoQ10) to the outside of the cells, and modulation of the extracellular CoQ10H2 amount had little effect on the intracellular CoQ10 or CoQ10H2 contents, suggesting the existence of an individual mechanism of CoQ10 reduction inside and outside the cells. Moreover, intact cells could reduce CoQ10 in low-density lipoprotein to CoQ10H2. Therefore, we concluded that a novel CoQ10-reducing mechanism may exist in the plasma membrane, probably the outer surface, of Hep G2 cells, and it may work to reduce extracellular CoQ10 and/or maintain extracellular CoQ10H2.

Digital holographic particle volume reconstruction using a deep neural network.

This paper proposes a particle volume reconstruction directly from an in-line hologram using a deep neural network (DNN). Digital holographic volume reconstruction conventionally uses multiple diffraction calculations to obtain sectional reconstructed images from an in-line hologram, followed by detection of the lateral and axial positions, and the sizes of particles by using focus metrics. However, the axial resolution is limited by the numerical aperture of the optical system, and the processes are time consuming. The method proposed here can simultaneously detect the lateral and axial positions, and the particle sizes via a DNN. We numerically investigated the performance of the DNN in terms of the errors in the detected positions and sizes. The calculation time is faster than conventional diffracted-based approaches.

Warburg effect in Gynecologic cancers.

Mammalian cells produce energy by oxidative phosphorylation under aerobic conditions. However, in the 1920s, Otto Warburg reported the so-called "Warburg effect" in which cancer cells produce ATP that is biased toward glycolysis rather than mitochondrial oxidative phosphorylation not only in anaerobic environment but also in aerobic environment. Glucose is converted into lactate without going into mitochondria after being metabolized in glycolysis. Compared with oxidative phosphorylation, the glycolysis has a faster ATP production rate but it is very inefficient, resulting in cancer cells consuming a large amount of glucose. Increased glucose metabolism has become a biomarker for cancer cells and has led to the development of positron emission tomography with fluorodeoxyglucose. Till date, the Warburg effect has been an inefficient system for cancer cells with regard to efficient energy production, but since the consumption of oxygen can be suppressed as the tumor grows in mass, it is thought that the Warburg effect is advantageous in this situation wherein the tumor can increase despite the lack of vessels. In addition, an increased lactate by the glycolysis causes acidosis in the microenvironment of tissues, which is thought to damage the surrounding normal tissues and favor the invasion and metastasis of cancer. Thus, Warburg effect is one of the key mechanisms for cancer development and will be the next promising target. In this review, we introduce key players that can be targeted in the Warburg effect and outline the prospects of treatment, targeting the Warburg effect in gynecological cancer.

High incidence of BK virus-associated hemorrhagic cystitis in children after second or third allogeneic hematopoietic stem cell transplantation.

BKV-HC is a serious complication of allogeneic HSCT. To characterize the incidence, risk factors, and clinical outcomes of post-HSCT BKV-HC, we retrospectively analyzed 112 patients who underwent one or more allogeneic HSCTs at our hospital between 2001 and 2017. Twenty underwent second or third HSCT thereafter. Ten patients developed BKV-HC at a median of 30 days after HSCT. The 100-day cumulative incidences of grade 0-4 and grade 2-4 BKV-HC were 7.8% and 6.2%, respectively. HSCTs performed in 2011-2017 associated with significantly higher 100-day cumulative incidence of grade 2-4 BKV-HC (14.0%) than HSCTs performed in 2001-2010 (1.3%, P = 0.004). On multivariate analysis, second or third HSCT was the only independent significant risk factor for development of grade 2-4 BKV-HC (P = 0.015). Serial PCR monitoring of urine and blood BKV load did not predict BKV-HC. The recent increase in the incidence of BKV-HC may reflect recent innovations in transplant technologies that facilitate second or third HSCT, which are known to cause prolonged immune deficiency. If safe and effective treatment or prophylaxis becomes available, it could be used to target the high-risk patients for BKV-HC.

2,3-Dimethoxy-5-methyl-p-benzoquinone (Coenzyme Q0) Disrupts Carbohydrate Metabolism of HeLa Cells by Adduct Formation with Intracellular Free Sulfhydryl-Groups, and Induces ATP Depletion and Necrosis.

2,3-Dimethoxy-5-methyl-p-benzoquinone is a common chemical structure of coenzyme Q (CoQ) that conjugates different lengths of an isoprenoid side chain at the 6-position of the p-benzoquinone ring. In a series of studies to explore the cytotoxic mechanism of CoQ homologues with a short isoprenoid side chain, we found that a CoQ analogue without an isoprenoid side chain, CoQ0, showed marked toxicity against HeLa cells in comparison with cytotoxic homologues. Therefore, we examined the cytotoxic mechanism of CoQ0. Different from the cytotoxic CoQ homologues that induced apoptosis, 100 µM CoQ0 induced necrosis of HeLa cells. The CoQ0-induced cell death was accompanied by a decrease in endogenous non-protein and protein-associated sulfhydryl (SH)-groups, but this improved with the concomitant addition of compounds with SH-groups but not antioxidants without SH-groups. In addition, UV-spectrum analysis suggested that CoQ0 could rapidly form S-conjugated adducts with compounds with SH-groups by Michael addition. On the other hand, enzyme activities of both glyceraldehyde-3-phosphate dehydrogenase, which has a Cys residue in the active site, and α-ketoglutarate dehydrogenase complex, which requires cofactors with SH-groups, CoA and protein-bound α-lipoic acid, and CoA and ATP contents in the cells were significantly decreased by the addition of CoQ0 but not CoQ1. Furthermore, the decrease of an endogenous antioxidant, glutathione (GSH), by CoQ0 treatment was much greater than the predicted increase of endogenous GSH disulfide. These results suggest that CoQ0 rapidly forms S-conjugate adducts with these endogenous non-protein and protein-associated SH-groups of HeLa cells, which disrupts carbohydrate metabolism followed by intracellular ATP depletion and necrotic cell death.

Convolutional neural network-based data page classification for holographic memory.

We propose a deep-learning-based classification of data pages used in holographic memory. We numerically investigated the classification performance of a conventional multilayer perceptron (MLP) and a deep neural network, under the condition that reconstructed page data are contaminated by some noise and are randomly laterally shifted. When data pages are randomly laterally shifted, the MLP was found to have a classification accuracy of 93.02%, whereas the deep neural network was able to classify data pages at an accuracy of 99.98%. The accuracy of the deep neural network is 2 orders of magnitude better than the MLP.

Autoencoder-based holographic image restoration.

We propose a holographic image restoration method using an autoencoder, which is an artificial neural network. Because holographic reconstructed images are often contaminated by direct light, conjugate light, and speckle noise, the discrimination of reconstructed images may be difficult. In this paper, we demonstrate the restoration of reconstructed images from holograms that record page data in holographic memory and quick response codes by using the proposed method.

Holographic microinformation hiding.

We propose a holographic microinformation hiding scheme in which the embedding information to be embedded is small and imperceptible to the human eyes. This scheme converts the embedding information into a complex amplitude via scaled diffraction. The complex amplitude of the reduced embedding information is added to the complex amplitude of the host image, followed by conversion to a hologram. The reduced embedded information is inconspicuous from the hologram during the reconstruction process; however, the reduction leads to the degradation of the embedded image quality. Therefore, to improve the quality of the embedded image quality, we employ iterative optimization and the time averaging effect of multiple holograms.

A Dual Role for Melatonin in Medaka Ovulation: Ensuring Prostaglandin Synthesis and Actin Cytoskeleton Rearrangement in Follicular Cells.

Understanding the direct effects of melatonin on vertebrate ovulation remains a challenge. The present study provides the first characterization of the role of melatonin in ovulation using the teleost medaka. The melatonin receptor antagonist luzindole inhibited in vitro follicle ovulation. In the preovulatory follicles, arylalkylamine N-acetyltransferase 1a and hydroxyindole-O-methyltransferase 2, the enzymes responsible for melatonin synthesis, were expressed in the granulosa cells throughout the 24 h spawning cycle. The granulosa cells of the follicle also expressed the melatonin receptor 1a-a. An in vitro characterization study using medaka OLHNI-2 cells revealed that melatonin and luzindole act as an agonist and an antagonist, respectively, of the melatonin receptor. The intracellular cAMP levels in these cells were reduced after melatonin treatment. The expression of cytosolic phospholipase A2 group 4a (Pla2g4a), the enzyme producing arachidonic acid (cyclooxygenase-2 substrate), was inhibited in the granulosa cells in luzindole-treated follicles. Follicular prostaglandin E2 levels and in vitro follicle ovulation were suppressed in follicles isolated at 12 h prior to ovulation and incubated with the Pla2g4a inhibitor AACOCF3. The G-actin:F-actin ratios in follicular cells increased with approaching ovulation, but this increase was suppressed after luzindole treatment. The phosphorylation of moesin, an ezrin-radixin-moesin protein, was inhibited in the follicular cells in luzindole-treated follicles. These results indicate a dual role for melatonin in medaka ovulation: melatonin ensures prostaglandin E2 synthesis throughout the spawning cycle and induces actin cytoskeleton rearrangement in the follicular cells at ovulation.