Search

Several genetic mutations have been identified in human endometrial cancers, but the specific combinations of mutations required to form endometrial cancer cells remain unknown. In the present study, we established an in vitro model of endometrial carcinogenesis, in which defined genetic elements were introduced into endometrial epithelial cells to create transformed endometrial cells at different stages. Introduction of the human papillomavirus type 16 E6/E7 gene and the human telomerase reverse transcriptase (hTERT) gene into human primary endometrial epithelial cells was sufficient to generate immortalized cells. Introduction of hTERT in early passages stabilized telomeres and created immortalized cells with normal karyotype, whereas introduction of hTERT in later passages generated immortalized cells but with widespread chromosome abnormalities. However, neither of those two immortalized cell lines exhibited tumorigenic phenotypes. Tumorigenic endometrial epithelial cells with invasive capacity were created by introducing a mutant K-ras allele into immortalized cells, keeping their chromosomes intact. Inhibiting the PTEN gene and activating Akt pathways did not create tumorigenic phenotypes, although the latter conferred anchorage-independent growth capacity. These findings suggest that neoplastic transformation of human endometrial cells can occur in the absence of widespread chromosomal abnormality, and that the combination of Rb inactivation, telomerase activation and altered K-ras signaling is sufficient for in vitro neoplastic transformation. The present experimental model can help clarify the genetic requirements for endometrial carcinogenesis, and it is useful for testing and developing specific inhibitors of specific oncogenic pathways.Oncogene (2006) 25, 5673–5682. doi:10.1038/sj.onc.1209575; published online 24 April 2006 [ABSTRACT FROM AUTHOR]

Phthalate esters, commonly used as plasticizers, show anti-androgenic activity and cause male reproductive malformation in experimental animals. However, the effects of prenatal exposure to phthalate esters in humans have not been extensively studied. The purpose of this study was to examine the relationship between prenatal exposure to phthalate esters and the anogenital distance (AGD) as a reproductive endpoint in human male newborns. Spot urine samples were collected from 111 Japanese pregnant women after obtaining their informed consent. Seven urinary phthalate ester metabolites were determined by high performance liquid chromatography-tandem mass spectrometry. Urinary isoflavones concentrations were measured as possible covariates because their oestrogenicities and high exposure levels among Japanese have the potential to affect male genital development. Birth outcomes and AGD, the distance from the centre of the anus to external genitalia, were measured for their male newborns. In a multiple regression model, the log-transformed mono-2-ethylhexyl phthalate concentration (specific gravity-corrected) was negatively significant, and maternal smoking status was positively significant, in explaining anogenital index (AGI) when potential covariates were controlled for. Urinary isoflavones did not significantly contribute to AGI in any models. Our results suggest that prenatal exposure to di(2-ethylhexyl) phthalate affects reproductive development in human males. [ABSTRACT FROM AUTHOR]

Background: Although formalin has been widely used as an algesic substance in rodent studies, the unique biphasic effect seen in rats is not present in humans. Humans, like cats, have a monophasic behavioral response to formalin injection. Electrophysiologically, spinal dorsal horn neurons in cats also have what could be considered a monophasic response after the initial burst of activity following formalin injection. Although several studies of the effects of ketamine on formalin responses have been carried out in rodents, we are unaware of similar studies in cats. We hypothesize that such species differences may explain observed differences in preemptive analgesic effects. Therefore, we examined the effects of ketamine on activity of spinal wide dynamic range (WDR) neurons evoked by formalin injection in cats.Methods: We investigated in cats the effect of ketamine on the activity of WDR neurons in the spinal dorsal horn that was evoked by formalin. In addition, we studied the effects of pre- and post-administration of ketamine on the maintained phase of the formalin response. Each dose was a subanesthetic, anesthetic or high anesthetic dose (3.0 mg x kg(-1), 10 mg x kg(-1), and 30 mg x kg(-1)).Results: Intravenously administered ketamine produced a dose-dependent depression of evoked activity that was significantly greater when the drug was administered before formalin.Conclusion: In spite of the species differences in responses to formalin, there still appears to be a clear preemptive effect of ketamine in the cat. Species differences may not explain apparent differences between human and animal preemptive analgesia. [ABSTRACT FROM AUTHOR]

Background: Anastomotic leakage (AL) is one of the most troublesome complications in colorectal surgery. Recently, near-infrared fluorescence (NIRF) imaging has been used intraoperatively to detect sentinel lymph nodes and visualize the blood supply at the region of interest (ROI). The aim of this study was to evaluate the role of visualization and quantification of bowel perfusion around the anastomosis using NIRF system in predicting AL. Methods: A prospective study was conducted on patients who had laparoscopic surgery for colorectal cancer at our institution. Perfusion of the anastomosis was evaluated with NIRF imaging after intravenous injection of indocyanine green (ICG). The time course of fluorescence intensity was recorded by an imaging analyzer We measured the time from ICG injection to the beginning of fluorescence (T0), maximum intensity (Imax), time to reach Imax (Tmax), time to reach Imax 50% ( T max 1 / 2 ) and slope (S) after the anastomosis. Results: Tumor locations were as follows; cecum: 2, ascending colon: 2, transverse colon: 7, descending colon: 1, sigmoid colon: 2, rectosigmoid colon: 3 and rectum: 6 (one case with synchronous cancer). All operations were performed laparoscopically. Four patients were diagnosed with or suspected to have AL (2 patients with grade B anastomotic leakage after low anterior resection, 1 patient with minor leakage in transverse colon resection and 1 patient needing re-anastomosis intraoperatively in transverse colon resection). T0 was significantly longer in the AL group than in patients without AL (64.3 ± 27.6 and 18.2 ± 6.6 s, p = 2.2 × 10−3). Conclusions: Perfusion of the anastomosis could be successfully visualized and quantified using NIRF imaging with ICG. T0 might be a useful parameter for prediction of AL. [ABSTRACT FROM AUTHOR]

Background Defaecatory function is often poor after anterior resection. Denervation of the neorectum following high ligation of the inferior mesenteric artery ( IMA) is a possible cause of impaired defaecatory function. The purpose of this randomized clinical trial was to clarify whether the level of ligation of the IMA in patients with rectal cancer affects defaecatory function. Methods Between 2008 and 2011, patients who underwent anterior resection for rectal cancer were randomized to receive either high or low ligation of the IMA. The primary endpoint was to demonstrate the superiority of low ligation in terms of defaecatory function. Results One hundred patients were enrolled in the study; 51 were randomized to high ligation of the IMA and 49 to low ligation. There were no differences between the groups in terms of clinical data, except tumour stage, which was more advanced in the high-ligation group ( P = 0·046). Nor were there any differences in defaecatory function, self-assessment of defaecation, Faecal Incontinence Quality of Life scale or continence score between groups at 3 months and 1 year. The number of harvested lymph nodes was similar. The rate of symptomatic anastomotic leakage was 16 per cent in the high-ligation group and 10 per cent in the low-ligation group ( P = 0·415). Conclusion The level of ligation of the IMA in patients with rectal cancer did not affect defaecatory function or the incidence of postoperative complications. Registration number: NCT00701012 (). [ABSTRACT FROM AUTHOR]

Background:Recently developed detection system for circulating tumour cells (CTCs) using a telomerase-specific replicative adenovirus generated nonspecific green fluorescent protein (GFP) signals because of the co-presence of white blood cells (WBCs) nonspecifically infected by viruses. Here, we established a unique detection system for CTCs that completely excludes nonspecific signals.Methods:Blood obtained from the patients was subjected to haemolytic processes to eliminate red blood cells. The cell pellets were then infected with OBP-401, fixed, incubated with fluorescence-labelled anti-CD45 antibody to mark white blood WBCs, and examined on slides under a microscope.Results:Preparatory experiments with cancer cells artificially added to healthy donor samples confirmed that CD45 labelling could distinguish GFP-positive cancer cells from WBCs. In 53 patients with gynaecological cancers, CTCs were detected in 21 patients (39.6%) when CD45-positive cells were excluded as WBCs among GFP-positive cells. No CTCs were detected in samples from healthy volunteers. There was no significant correlation between CTC counts and known clinicopathological factors. The CTCs rapidly vanished after surgery or chemotherapy in most patients whose treatments were effective. In contrast, the persistence of CTCs even after treatments was tightly associated with poor response to the treatments (P<0.005).Conclusion:The presence of CTCs in our system may potentially be a novel therapeutic marker in gynaecological cancers. [ABSTRACT FROM AUTHOR]

Abstract: We have searched for very high energy (VHE) gamma rays from four blazars using the CANGAROO-III imaging atmospheric Cherenkov telescope. We report the results of the observations of H 2356-309, PKS 2155-304, PKS 0537-441, and 3C 279, performed from 2005 to 2009, applying a new analysis to suppress the effects of the position dependence of Cherenkov images in the field of view. No significant VHE gamma ray emission was detected from any of the four blazars. The GeV gamma-ray spectra of these objects were obtained by analyzing Fermi/LAT archival data. Wide range (radio to VHE gamma-ray bands) spectral energy distributions (SEDs) including CANGAROO-III upper limits, GeV gamma-ray spectra, and archival data, even though they are non-simultaneous, are discussed using a one-zone synchrotron self-Compton (SSC) model in combination with a external Compton (EC) radiation. The HBLs (H 2356-309 and PKS 2155-304) can be explained by a simple SSC model, and PKS 0537-441 and 3C 279 are well modeled by a combination of SSC and EC model. We find a consistency with the blazar sequence in terms of strength of magnetic field and component size. [Copyright &y& Elsevier]

Background:Epithelial cells of endometriotic tissues are difficult to propagate in vitro as experimental material is scarce owing to their limited life span. However, there is an increasing concern regarding their malignant transformation in ovaries. The present study sought to generate their stable culture system.Methods and results:Purified epithelial cells isolated from ovarian endometriomas using microscopic manipulation were successfully immortalised by combinatorial transfection of human cyclinD1, cdk4 and human telomerase reverse transcriptase (hTERT) genes, whereas the introduction of hTERT alone, or together with cdk4, was insufficient for immortalisation, leading to cellular senescence. We confirmed stable cytokeratin expression in the immortalised cells, proving their epithelial origin. These cells expressed progesterone receptor B and showed significant growth inhibition by various progestins. Oestrogen receptor (ER) expression was detected in these cells, albeit at low levels. Additional overexpression of ERα generated stable cells with oestrogen-dependent growth activation. Soft-agar colony formation assay and nude mice xenograft experiments demonstrated that these cells, even those with additional inactivation of p53, did not have transformed phenotypes.Conclusion:We for the first time generated immortalised epithelial cells from ovarian endometrioma that retained sex steroid responsiveness. These cells are invaluable tools not only for the consistent in vitro work but also for the study of molecular pathogenesis or carcinogenesis of endometriosis. [ABSTRACT FROM AUTHOR]

Background: Disabled phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase/extracellular signal-regulated kinase signalling is involved in endometrial carcinogenesis, and there is evidence that expression of epidermal growth factor receptor (EGFR) family members has a role in such intracellular signalling pathways. This study analysed the prognostic impact of EGFR family expression in endometrial cancer in relation to PI3K-AKT and MAPK-ERK signalling, as well as drug sensitivity.Methods and Results: Immunohistochemical analysis using 63 surgical specimens of endometrioid-type endometrial cancers revealed that EGFR, human epidermal growth factor receptor (HER)-2 and HER-4 were expressed in 25 (39.7%) of 63, 26 (41.3%) of 63 and 31 (49.2%) of 63 tumours, respectively. Gene amplification of HER-2 was observed in 2 of 26 patients with high HER-2 expression. Kaplan-Meier analysis revealed that high HER-2 expression was a factor that negatively influenced the progression-free and overall survival rate (P<0.05), and multivariate analysis showed high HER-2 expression to be an independent prognostic factor. Subsequently, we performed in vitro knockdown analysis to investigate the linkage between HER-2 expression and PI3K-AKT pathways. Short interfering RNA (siRNA)-based knockdown of HER-2 in endometrial cancer cells led to a significant reduction in phosphorylated AKT (p-AKT) expression, indicating the existence of a HER-2/PI3K-AKT axis. As the PI3K-AKT pathway is known to have crucial roles in anticancer drug sensitivity, we examined the involvement of HER-2 in sensitivity to paclitaxel. Short interfering RNA-based knockdown of HER-2 conferred increased sensitivity to paclitaxel in endometrial cancer cells, attenuating the induction of p-AKT on paclitaxel stimulation, which was cancelled by inactivating AKT by the introduction of a dominant-negative form.Conclusion: HER-2 is a significant prognostic factor of endometrioid-type endometrial cancer, as well as a key molecule that affects paclitaxel sensitivity by HER-2 interaction with the PI3K-AKT pathway. [ABSTRACT FROM AUTHOR]

Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01–100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1–10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1–10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5–1 μM, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1–10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg–1) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan–Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP. [ABSTRACT FROM AUTHOR]

Abstract: We have measured the lateral distributions of atmospheric C˘erenkov photons associated with extensive air showers to study the chemical composition of the primary cosmic rays in the energy range from 1014.5 to 1016 eV, so called knee region. The atmospheric C˘erenkov photon detectors were installed in the EAS array at Mt. Chacaltaya. The measured lateral distributions were fitted with an empirical formula with a parameter which is sensitive to mass numbers of primary cosmic rays. A three species model (proton, carbon, and iron nuclei) is used for the chemical composition study of the present experiment. To determine the mixing ratio of the three species, the distributions of the parameter for the observed events were examined to reproduce those for the simulated ones calculated with the CORSIKA code using the QGSJET hadronic interaction model. From the obtained mixing ratio of the three species, we determined the mean logarithmic mass numbers of primary cosmic rays, 〈ln A〉, in the knee region. The present result shows that the values of 〈ln A〉 are higher than the logarithmic mass number for carbon and the proton component is no more dominant at the knee. [Copyright &y& Elsevier]

Abstract: The amount of astronomical data is rapidly growing as the progress of telescope technology and the detection technique of recent years. As a result, the way of traditional analysis is becoming insufficient for utilizing the large amount of data efficiently. The SuprimeCam, which is one of the instruments equipped with the Subaru telescope, has been generating 7 TB of public data since its start of operation. It is almost impossible to transfer all the data to the local machine to analyze them. It is, therefore, desirable to have an environment where the data is analyzed where it is stored. In addition, it is not easy to use the Subaru data for an researcher who is not familiar with the Subaru data reduction. To overcome these difficulties, we developed the server side data analysis system and applied GRID technology to construct the system that carry out multiple jobs on multiple servers. Integrating this system to the Japanese Virtual Observatory, a user can easily utilize the GRID system through the web browser interface. [Copyright &y& Elsevier]

The article evaluates the feasibility and utility of performing ultrasound-guided culdotomy using a renal balloon dilator catheter for transvaginal ovarian cystectomies. The results indicate evidence that culdotomy assisted by ultrasound imaging and a dilator is a safe, reliable and effective method for removal of benign ovarian cysts via a vaginal approach.

Abstract: The Sun was intensely active from late October to the beginning of November 2003. A series of 11 X class solar flares occurred in NOAA regions 484, 486 and 488. Unique among this series of flares were those occurring on November 2 and 4 in which solar neutrons were observed by the ground based neutron monitors located at Mt. Chacaltaya, Bolivia and Haleakala, Hawaii, respectively. In these flares, intense emission of hard X-rays and γ-rays have been observed by the satellites. It seems that production of solar neutrons coincided with the production of the hard electromagnetic radiations of these two flares. [Copyright &y& Elsevier]

In this paper, we report solar neutron events detected in the solar cycle 23, especially three interesting events detected on November 23rd and 28th 1998 in Tibet and October 28th 2003 in Tsumeb. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with unresectable malignant gastroesophageal strictures often are troubled with reflux esophagitis after stent placement. METHODS: A self-expandable metallic stent (SEMS) without an antireflux mechanism was placed in seven patients with unresectable malignant gastroesophageal strictures (group A), and SEMS with an antireflux mechanism was placed in five patients (group B). After we obtained monitoring systems, two patients in group A and all the patients in group B underwent measurement of bilirubin and pH in the esophagus using a 24-h bilirubin and pH monitor. RESULTS: The mean percentage of total time less than 0.14 for use of the bilirubin absorbance unit was 12.4% in group B and 64.0% in group A. The mean percentage of total time for a pH less than 4 was 2.9% in group B and 37.8% in group A. CONCLUSION: The placement of SEMS with the antireflux mechanism can be effective not only for palliation of gastroesophageal stricture, but also for prevention of reflux. [ABSTRACT FROM AUTHOR]

The prompt γ-ray emission from γ-ray bursts (GRBs) should be detectable out to distances of z > 10 (ref. 1), and should therefore provide an excellent probe of the evolution of cosmic star formation, reionization of the intergalactic medium, and the metal enrichment history of the Universe. Hitherto, the highest measured redshift for a GRB has been z = 4.50 (ref. 5). Here we report the optical spectrum of the afterglow of GRB 050904 obtained 3.4 days after the burst; the spectrum shows a clear continuum at the long-wavelength end of the spectrum with a sharp cut-off at around 9,000 Å due to Lyman α absorption at z ≈ 6.3 (with a damping wing). A system of absorption lines of heavy elements at z = 6.295 ± 0.002 was also detected, yielding the precise measurement of the redshift. The Si ii fine-structure lines suggest a dense, metal-enriched environment around the progenitor of the GRB. [ABSTRACT FROM AUTHOR]

Evaluates self-expandable metallic stent (SEMS) with the anti-reflux mechanism by ambulatory 24-h bilirubin and pH monitoring of the esophagus. Treatment of patients with aphagia or dysphagia due to unresectable gastroesophageal junction; Medications known to affect gastrointestinal motility and gastric acid secretion.