Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens

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Puxeddu, Efisio [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Zhao Guisheng [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Stringer, James R. [Department of Molecular Genetics, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Medvedovic, Mario [Center for Biostatistic Service, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States); Moretti, Sonia [Dipartimento di Medicina Interna, Universita degli Studi di Perugia, Via E. dal Pozzo, Perugia 06126, (Italy); Fagin, James A. [Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, PO Box 670547, Cincinnati, OH 45267-0547 (United States)]. E-mail: james.fagin@uc.edu

2005-02-15

The two main forms of RET rearrangement in papillary thyroid carcinomas (PTC) arise from intrachromosomal inversions fusing the tyrosine kinase domain of RET with either the H4 (RET/PTC1) or the ELE1/RFG genes (RET/PTC3). PTEN codes for a dual-specificity phosphatase and maps to chromosome 10q22-23. Germline mutations confer susceptibility to Cowden syndrome whereas somatic mutations or deletions are common in several sporadic human tumors. Decreased PTEN expression has been implicated in thyroid cancer development. We report the characterization of a new chromosome 10 rearrangement involving H4 and PTEN. The initial H4/PTEN rearrangement was discovered as a non-specific product of RT-PCR for RET/PTC1 in irradiated thyroid cell lines. Sequencing revealed a transcript consisting of exon 1 and 2 of H4 fused with exons 3-6 of PTEN. Nested RT-PCR with specific primers bracketing the breakpoints confirmed the H4/PTEN rearrangements in irradiated KAT-1 and KAT-50 cells. Additional H4/PTEN variants, generated by recombination of either exon 1 or exon 2 of H4 with exon 6 of PTEN, were found in non-irradiated KAK-1, KAT-50, ARO and NPA cells. Their origin through chromosomal recombination was confirmed by detection of the reciprocal PTEN/H4 product. H4/PTEN recombination was not a clonal event in any of the cell lines, as Southern blots with appropriate probes failed to demonstrate aberrant bands, and multicolor FISH of KAK1 cells with BAC probes for H4 and PTEN did not show a signal overlap in all cells. Based on PCR of serially diluted samples, the minimal frequency of spontaneous recombination between these loci was estimated to be approximately 1/10{sup 6} cells. H4/PTEN products were found by nested RT-PCR in 4/14 normal thyroid tissues (28%) and 14/18 PTC (78%) (P < 0.01). H4/PTEN is another example of recombination involving the H4 locus, and points to the high susceptibility of thyroid cells to intrachromosomal gene rearrangements. As this also represents a

A role for Pten in paediatric intestinal dysmotility disorders.

LENUS (Irish Health Repository)

O'Donnell, Anne-Marie

2012-02-01

PURPOSE: The enteric nervous system (ENS) is a network of neurons and glia that lies within the gut wall. It is responsible for the normal regulation of gut motility and secretory activities. Hirschsprung\\'s disease (HD) is a congenital defect of the ENS, characterised by an absence of ganglia in the distal colon. Intestinal neuronal dysplasia (IND) is a condition that clinically resembles HD, characterised by hyperganglionosis, giant and ectopic ganglia, resulting in intestinal dysmotility. Intestinal ganglioneuromatosis is characterised by hyperplasia and hypertrophy of enteric neuronal cells and causes chronic intestinal pseudo-obstruction (CIPO). Phosphatase and tensin homolog deleted on chromosome 10 (Pten) is a phosphatase that is critical for controlling cell growth, proliferation and cell death. A recent study of Pten knockout mice showed evidence of ganglioneuromatosis in the ENS suggesting a role for this protein in ENS development. Ganglioneuromatosis patients have also been shown to have a decreased level of Pten expression in the colon. The aim of our study was to investigate Pten expression in the ENS of HD and IND patients compared to normal controls. METHODS: Resected tissue from 10 HD and 10 IND type B patients was fixed and embedded in paraffin wax. Normal control colon tissue was obtained from ten patients who underwent a colostomy closure for imperforate anus. Sections were cut and immunohistochemistry was carried out using a Pten antibody. Results were analysed by light microscopy. RESULTS: Staining showed that Pten was strongly expressed in ganglia of both the submucosal and myenteric plexus of normal and HD specimens from the ganglionic colon. Pten expression was significantly reduced in the giant ganglia in IND patients in both the myenteric and submucosal plexuses compared to the normal controls. Specimens from the aganglionic region of HD did not show Pten expression. CONCLUSION: To the best of our knowledge, this is the first study

Adenovirus mediated homozygous endometrial epithelial Pten deletion results in aggressive endometrial carcinoma

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Joshi, Ayesha; Ellenson, Lora Hedrick, E-mail: lora.ellenson@med.cornell.edu

2011-07-01

Pten is the most frequently mutated gene in uterine endometriod carcinoma (UEC) and its precursor complex atypical hyperplasia (CAH). Because the mutation frequency is similar in CAH and UEC, Pten mutations are thought to occur relatively early in endometrial tumorigenesis. Previous work from our laboratory using the Pten{sup +/-} mouse model has demonstrated somatic inactivation of the wild type allele of Pten in both CAH and UEC. In the present study, we injected adenoviruses expressing Cre into the uterine lumen of adult Pten floxed mice in an attempt to somatically delete both alleles of Pten specifically in the endometrium. Our results demonstrate that biallelic inactivation of Pten results in an increased incidence of carcinoma as compared to the Pten{sup +/-} mouse model. In addition, the carcinomas were more aggressive with extension beyond the uterus into adjacent tissues and were associated with decreased expression of nuclear ER{alpha} as compared to associated CAH. Primary cultures of epithelial and stromal cells were prepared from uteri of Pten floxed mice and Pten was deleted in vitro using Cre expressing adenovirus. Pten deletion was evident in both the epithelial and stromal cells and the treatment of the primary cultures with estrogen had different effects on Akt activation as well as Cyclin D3 expression in the two purified components. This study demonstrates that somatic biallelic inactivation of Pten in endometrial epithelium in vivo results in an increased incidence and aggressiveness of endometrial carcinoma compared to mice carrying a germline deletion of one allele and provides an important in vivo and in vitro model system for understanding the genetic underpinnings of endometrial carcinoma.

Adenovirus mediated homozygous endometrial epithelial Pten deletion results in aggressive endometrial carcinoma

International Nuclear Information System (INIS)

Joshi, Ayesha; Ellenson, Lora Hedrick

2011-01-01

Pten is the most frequently mutated gene in uterine endometriod carcinoma (UEC) and its precursor complex atypical hyperplasia (CAH). Because the mutation frequency is similar in CAH and UEC, Pten mutations are thought to occur relatively early in endometrial tumorigenesis. Previous work from our laboratory using the Pten +/- mouse model has demonstrated somatic inactivation of the wild type allele of Pten in both CAH and UEC. In the present study, we injected adenoviruses expressing Cre into the uterine lumen of adult Pten floxed mice in an attempt to somatically delete both alleles of Pten specifically in the endometrium. Our results demonstrate that biallelic inactivation of Pten results in an increased incidence of carcinoma as compared to the Pten +/- mouse model. In addition, the carcinomas were more aggressive with extension beyond the uterus into adjacent tissues and were associated with decreased expression of nuclear ERα as compared to associated CAH. Primary cultures of epithelial and stromal cells were prepared from uteri of Pten floxed mice and Pten was deleted in vitro using Cre expressing adenovirus. Pten deletion was evident in both the epithelial and stromal cells and the treatment of the primary cultures with estrogen had different effects on Akt activation as well as Cyclin D3 expression in the two purified components. This study demonstrates that somatic biallelic inactivation of Pten in endometrial epithelium in vivo results in an increased incidence and aggressiveness of endometrial carcinoma compared to mice carrying a germline deletion of one allele and provides an important in vivo and in vitro model system for understanding the genetic underpinnings of endometrial carcinoma.

DNA methylation of PTEN gene promoter region is not correlated ...

African Journals Online (AJOL)

Tumor suppressor gene PTEN plays an important role in cell cycle. Disorder of PTEN protein can cause cell growth and division in an uncontrolled way, which can lead to the formation of tumors. It has been proven that epigenetic mechanisms, such as promoter hypermethylation, may account for inactivation of PTEN in a ...

The PTEN/NRF2 Axis Promotes Human Carcinogenesis

DEFF Research Database (Denmark)

Rojo, Ana I; Rada, Patricia; Mendiola, Marta

2014-01-01

and tumorigenic advantage. Tissue microarrays from endometrioid carcinomas showed that 80% of PTEN-negative tumors expressed high levels of NRF2 or its target heme oxygenase-1 (HO-1). INNOVATION: These results uncover a new mechanism of oncogenic activation of NRF2 by loss of its negative regulation by PTEN/GSK-3....../β-TrCP that may be relevant to a large number of tumors, including endometrioid carcinomas. CONCLUSION: Increased activity of NRF2 due to loss of PTEN is instrumental in human carcinogenesis and represents a novel therapeutic target. Antioxid. Redox Signal. 21, 2498-2514....

BMP suppresses PTEN expression via RAS/ERK signaling.

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Beck, Stayce E; Carethers, John M

2007-08-01

Bone morphogenetic protein (BMP), a member of the transforming growth factor beta family, classically utilizes the SMAD signaling pathway for its growth suppressive effects,and loss of this signaling cascade may accelerate cell growth. In the colon cancer predisposition syndrome Juvenile Polyposis, as well as in the late progression stages of nonsyndromic colorectal cancers, SMAD4 function is typically abrogated. Here, we utilized the SMAD4-null SW480 colon cancer cell line to examine BMPs effect on a potential target gene, PTEN, and how its expression might be regulated. Initial treatment of the SMAD4-null cells with BMP resulted in mild growth suppression, but with prolonged exposure to BMP, the cells become growth stimulatory, which coincided with observed decreases in transcription and translation of PTEN, and with corresponding increases in phospho-AKT protein levels. BMP-induced PTEN suppression was mediated via the RAS/ERK pathway, as pharmacologic inhibition of RAS/ERK, or interference with protein function in the cytosol by DN-RAS prevented BMP-induced growth promotion and changes in PTEN levels, as did treatment with noggin, a BMP ligand inhibitor. Thus, BMP downregulates PTEN via RAS/ERK in a SMAD4-null environment that contributes to cell growth, and constitutes a SMAD4-independent but BMP-responsive signaling pathway.

Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene

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Ohtoshi Akihira

2008-10-01

Full Text Available Abstract To investigate the roles of Pten and β-Catenin in the midbrain, either the Pten gene or the β-catenin gene was conditionally ablated, using Dmbx1 (diencephalon/mesencephalon-expressed brain homeobox gene 1-Cre mice. Homozygous disruption of the Pten or β-catenin gene in Dmbx1-expressing cells caused severe hydrocephalus and mortality during the postnatal period. Conditional deletion of Pten resulted in enlargement of midbrain structures. β-catenin conditional mutant mice showed malformation of the superior and inferior colliculi and stenosis of the midbrain aqueduct. These results demonstrate that both Pten and β-Catenin are essential for proper midbrain development, and provide the direct evidence that mutations of both Pten and β-catenin lead to hydrocephalus.

PTEN drives Th17 cell differentiation by preventing IL-2 production.

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Kim, Hyeong Su; Jang, Sung Woong; Lee, Wonyong; Kim, Kiwan; Sohn, Hyogon; Hwang, Soo Seok; Lee, Gap Ryol

2017-11-06

T helper 17 (Th17) cells are a CD4 + T cell subset that produces IL-17A to mediate inflammation and autoimmunity. IL-2 inhibits Th17 cell differentiation. However, the mechanism by which IL-2 is suppressed during Th17 cell differentiation remains unclear. Here, we show that phosphatase and tensin homologue (PTEN) is a key factor that regulates Th17 cell differentiation by suppressing IL-2 production. Th17-specific Pten deletion ( Pten fl/fl Il17a cre ) impairs Th17 cell differentiation in vitro and ameliorated symptoms of experimental autoimmune encephalomyelitis (EAE), a model of Th17-mediated autoimmune disease. Mechanistically, Pten deficiency up-regulates IL-2 and phosphorylation of STAT5, but reduces STAT3 phosphorylation, thereby inhibiting Th17 cell differentiation. PTEN inhibitors block Th17 cell differentiation in vitro and in the EAE model. Thus, PTEN plays a key role in Th17 cell differentiation by blocking IL-2 expression. © 2017 Kim et al.

Expression patterns and role of PTEN in rat peripheral nerve development and injury.

Science.gov (United States)

Chen, Hui; Xiang, Jianping; Wu, Junxia; He, Bo; Lin, Tao; Zhu, Qingtang; Liu, Xiaolin; Zheng, Canbin

2018-05-29

Studies have suggested that phosphatase and tensin homolog (PTEN) plays an important role in neuroprotection and neuronal regeneration. To better understand the potential role of PTEN with respect to peripheral nerve development and injury, we investigated the expression pattern of PTEN at different stages of rat peripheral nerve development and injury and subsequently assessed the effect of pharmacological inhibition of PTEN using bpV(pic) on axonal regeneration in a rat sciatic nerve crush injury model. During the early stages of development, PTEN exhibits low expression in neuronal cell bodies and axons. From embryonic day (E) 18.5 and postnatal day (P)5 to adult, PTEN protein becomes more detectable, with high expression in the dorsal root ganglia (DRG) and axons. PTEN expression is inhibited in peripheral nerves, preceding myelination during neuronal development and remyelination after acute nerve injury. Low PTEN expression after nerve injury promotes Akt/mammalian target of rapamycin (mTOR) signaling pathway activity. In vivo pharmacological inhibition of PTEN using bpV(pic) promoted axonal regrowth, increased the number of myelinated nerve fibers, improved locomotive recovery and enhanced the amplitude response and nerve conduction velocity following stimulation in a rat sciatic nerve crush injury model. Thus, we suggest that PTEN may play potential roles in peripheral nerve development and regeneration and that inhibition of PTEN expression is beneficial for nerve regeneration and functional recovery after peripheral nerve injury. Copyright © 2018 Elsevier B.V. All rights reserved.

Cell-type specific roles for PTEN in establishing a functional retinal architecture.

Directory of Open Access Journals (Sweden)

Robert Cantrup

Full Text Available The retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture.In the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam.We conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and

Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

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Meng, Zhen [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn [Central Laboratory, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China); Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081 (China)

2015-05-01

Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocation and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.

RNA interference mediated pten knock-down inhibit the formation of polycystic ovary.

Science.gov (United States)

Ouyang, Jie-Xiu; Luo, Tao; Sun, Hui-Yun; Huang, Jian; Tang, Dan-Feng; Wu, Lei; Zheng, Yue-Hui; Zheng, Li-Ping

2013-08-01

Pten (phosphatase and tensin homolog deleted on chromosome 10), a kind of tumor suppressor gene, plays important roles in female reproductive system. But its expression and roles in the formation of polycystic ovaries are yet to be known. In this study, we constructed a rat model of PCOS using norethindrone and HCG injections and found the expressions of pten mRNA and PTEN protein increased significantly in the polycystic ovary tissue by immunohistochemistry, RT-PCR, and western blot. Furthermore, the results showed that in vivo ovaries could be effectively transfected by lentiviral vectors through the ovarian microinjection method and indicated that pten shRNA may inhibit the formation of polycystic ovaries by pten down-regulation. Our study provides new information regarding the role of PTEN in female reproductive disorders, such as polycystic ovary syndrome.

Hyperactivity of newborn Pten knock-out neurons results from increased excitatory synaptic drive.

Science.gov (United States)

Williams, Michael R; DeSpenza, Tyrone; Li, Meijie; Gulledge, Allan T; Luikart, Bryan W

2015-01-21

Developing neurons must regulate morphology, intrinsic excitability, and synaptogenesis to form neural circuits. When these processes go awry, disorders, including autism spectrum disorder (ASD) or epilepsy, may result. The phosphatase Pten is mutated in some patients having ASD and seizures, suggesting that its mutation disrupts neurological function in part through increasing neuronal activity. Supporting this idea, neuronal knock-out of Pten in mice can cause macrocephaly, behavioral changes similar to ASD, and seizures. However, the mechanisms through which excitability is enhanced following Pten depletion are unclear. Previous studies have separately shown that Pten-depleted neurons can drive seizures, receive elevated excitatory synaptic input, and have abnormal dendrites. We therefore tested the hypothesis that developing Pten-depleted neurons are hyperactive due to increased excitatory synaptogenesis using electrophysiology, calcium imaging, morphological analyses, and modeling. This was accomplished by coinjecting retroviruses to either "birthdate" or birthdate and knock-out Pten in granule neurons of the murine neonatal dentate gyrus. We found that Pten knock-out neurons, despite a rapid onset of hypertrophy, were more active in vivo. Pten knock-out neurons fired at more hyperpolarized membrane potentials, displayed greater peak spike rates, and were more sensitive to depolarizing synaptic input. The increased sensitivity of Pten knock-out neurons was due, in part, to a higher density of synapses located more proximal to the soma. We determined that increased synaptic drive was sufficient to drive hypertrophic Pten knock-out neurons beyond their altered action potential threshold. Thus, our work contributes a developmental mechanism for the increased activity of Pten-depleted neurons. Copyright © 2015 the authors 0270-6474/15/350943-17$15.00/0.

PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival

International Nuclear Information System (INIS)

Atreya, Chloe E; Sangale, Zaina; Xu, Nafei; Matli, Mary R; Tikishvili, Eliso; Welbourn, William; Stone, Steven; Shokat, Kevan M; Warren, Robert S

2013-01-01

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates the phosphoinositide-3-kinase (PI3K) signaling pathway. In colorectal cancer (CRC), observed frequencies of loss of PTEN expression, concordant expression in primary tumors and metastases, and the association of PTEN status with outcome vary markedly by detection method. We determined the degree to which PTEN expression is consistent in 70 matched human CRC primaries and liver metastases using a validated immunohistochemistry assay. We found loss of PTEN expression in 12.3% of assessable CRC primaries and 10.3% of assessable liver metastases. PTEN expression (positive or negative) was concordant in 98% of matched colorectal primaries and liver metastases. Next we related PTEN status to mutations in RAS and PI3K pathway genes (KRAS, NRAS, BRAF, and PIK3CA) and to overall survival (OS). PTEN expression was not significantly associated with the presence or absence of mutations in RAS or PI3K pathway genes. The median OS of patients whose tumors did not express PTEN was 9 months, compared to 49 months for patients whose tumors did express PTEN (HR = 6.25, 95% confidence intervals (CI) (1.98, 15.42), P = 0.0017). The association of absent PTEN expression with increased risk of death remained significant in multivariate analysis (HR = 6.31, 95% CI (2.03, 17.93), P = 0.0023). In summary, PTEN expression was consistent in matched CRC primaries and in liver metastases. Therefore, future investigations of PTEN in metastatic CRC can use primary tumor tissue. In patients with liver-only metastases, loss of PTEN expression predicted poor OS. We observed concordant PTEN expression in 98% of colorectal cancer (CRC) primary and liver metastasis pairs using a validated immunohistochemistry assay. Consistent PTEN expression at both disease sites is significant because tumor tissue is usually available from CRC primaries but not metastases. Loss of PTEN expression associated with poor survival of

Endogenous S-sulfhydration of PTEN helps protect against modification by nitric oxide

International Nuclear Information System (INIS)

Ohno, Kazuki; Okuda, Kosaku; Uehara, Takashi

2015-01-01

Highlights: • PTEN is S-sulfhydrated endogenously in SH-SY5Y human neuroblastoma cells. • Preventing this modification by knocking down CBS renders PTEN sensitive to NO. • pAkt levels are increased significantly in CBS siRNA-transfected cells. • H 2 S functions as an endogenous regulator of PTEN in neuronal cells. - Abstract: Hydrogen sulfide (H 2 S) is a gaseous regulatory factor produced by several enzymes, and plays a pivotal role in processes such as proliferation or vasodilation. Recent reports demonstrated the physiological and pathophysiological functions of H 2 S in neurons. PTEN is a target of nitric oxide (NO) or hydrogen peroxide, and the oxidative modification of cysteine (Cys) residue(s) attenuates its enzymatic activity. In the present study, we assessed the effect of H 2 S on the direct modification of PTEN and the resulting downstream signaling. A modified biotin switch assay in SH-SY5Y human neuroblastoma cells revealed that PTEN is S-sulfhydrated endogenously. Subsequently, site-directed mutagenesis demonstrated that both Cys71 and Cys124 in PTEN are targets for S-sulfhydration. Further, the knockdown of cystathionine β-synthetase (CBS) using siRNA decreased this modification in a manner that was correlated to amount of H 2 S. PTEN was more sensitive to NO under these conditions. These results suggest that the endogenous S-sulfhydration of PTEN via CBS/H 2 S plays a role in preventing the S-nitrosylation that would inhibition its enzymatic activity under physiological conditions

Endogenous S-sulfhydration of PTEN helps protect against modification by nitric oxide

Energy Technology Data Exchange (ETDEWEB)

Ohno, Kazuki; Okuda, Kosaku; Uehara, Takashi, E-mail: uehara@pharm.okayama-u.ac.jp

2015-01-02

Highlights: • PTEN is S-sulfhydrated endogenously in SH-SY5Y human neuroblastoma cells. • Preventing this modification by knocking down CBS renders PTEN sensitive to NO. • pAkt levels are increased significantly in CBS siRNA-transfected cells. • H{sub 2}S functions as an endogenous regulator of PTEN in neuronal cells. - Abstract: Hydrogen sulfide (H{sub 2}S) is a gaseous regulatory factor produced by several enzymes, and plays a pivotal role in processes such as proliferation or vasodilation. Recent reports demonstrated the physiological and pathophysiological functions of H{sub 2}S in neurons. PTEN is a target of nitric oxide (NO) or hydrogen peroxide, and the oxidative modification of cysteine (Cys) residue(s) attenuates its enzymatic activity. In the present study, we assessed the effect of H{sub 2}S on the direct modification of PTEN and the resulting downstream signaling. A modified biotin switch assay in SH-SY5Y human neuroblastoma cells revealed that PTEN is S-sulfhydrated endogenously. Subsequently, site-directed mutagenesis demonstrated that both Cys71 and Cys124 in PTEN are targets for S-sulfhydration. Further, the knockdown of cystathionine β-synthetase (CBS) using siRNA decreased this modification in a manner that was correlated to amount of H{sub 2}S. PTEN was more sensitive to NO under these conditions. These results suggest that the endogenous S-sulfhydration of PTEN via CBS/H{sub 2}S plays a role in preventing the S-nitrosylation that would inhibition its enzymatic activity under physiological conditions.

A Chimeric Protein PTEN-L-p53 Enters U251 Cells to Repress Proliferation and Invasion.

Science.gov (United States)

Xiao, Man; An, Yang; Wang, Fengling; Yao, Chao; Zhang, Chu; Xin, Junfang; Duan, Yongjian; Zhao, Xiaofang; Fang, Na; Ji, Shaoping

2018-05-23

PTEN, a well-known tumor suppressor, dephosphorylates PIP3 and inhibits AKT activity. A translational variant of PTEN has been identified and termed PTEN-Long (PTEN-L). The additional 173 amino acids (PTEN-L leader) at the N-terminal constitute a potential signal peptide. Differing from canonical PTEN, PTEN-L is secreted into the extracellular fluid and re-enters recipient cells, playing the similar roles as PTEN in vivo and in vitro. This character confers the PTEN-L a therapeutic ability via directly protein delivering instead of traditional DNA and RNA vector options. In the present study, we employed PTEN-L leader to assemble a fusion protein, PTEN-L-p53, inosculated with the transcriptional regulator TP53, which is another powerful tumor suppressor. We overexpressed PTEN-L-p53 in HEK293T cells and detected it in both the cytoplasm and nucleus. Subsequently, we found that PTEN-L-p53 was secreted outside of the cells and detected in the culture media by immunoblotting. Furthermore, we demonstrated that PTEN-L-p53 freely entered the cells and suppressed the viability of U251cells (p53 R273H , a cell line with p53 R273H-mutation). PTEN-L-p53 is composed of endogenous protein/peptide bearing low immunogenicity, and only the junction region between PTEN-L leader and p53 can act as a new immune epitope. Accordingly, this fusion protein can potentially be used as a therapeutic option for TP53-abnormality cancers. Copyright © 2018. Published by Elsevier Inc.

Intermittent fasting uncovers and rescues cognitive phenotypes in PTEN neuronal haploinsufficient mice.

Science.gov (United States)

Cabral-Costa, J V; Andreotti, D Z; Mello, N P; Scavone, C; Camandola, S; Kawamoto, E M

2018-06-05

Phosphatase and tensin homolog (PTEN) is an important protein with key modulatory functions in cell growth and survival. PTEN is crucial during embryogenesis and plays a key role in the central nervous system (CNS), where it directly modulates neuronal development and synaptic plasticity. Loss of PTEN signaling function is associated with cognitive deficits and synaptic plasticity impairment. Accordingly, Pten mutations have a strong link with autism spectrum disorder. In this study, neuronal Pten haploinsufficient male mice were subjected to a long-term environmental intervention - intermittent fasting (IF) - and then evaluated for alterations in exploratory, anxiety and learning and memory behaviors. Although no significant effects on spatial memory were observed, mutant mice showed impaired contextual fear memory in the passive avoidance test - an outcome that was effectively rescued by IF. In this study, we demonstrated that IF modulation, in addition to its rescue of the memory deficit, was also required to uncover behavioral phenotypes otherwise hidden in this neuronal Pten haploinsufficiency model.

Metformin inhibits inflammatory response via AMPK–PTEN pathway in vascular smooth muscle cells

International Nuclear Information System (INIS)

Kim, Sun Ae; Choi, Hyoung Chul

2012-01-01

Highlights: ► PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. ► Metformin suppressed TNF-α-induced COX-2 and iNOS mRNA expression. ► Compound C and bpv (pic) increased iNOS and COX-2 protein expression. ► NF-κB activation was restored by inhibiting AMPK and PTEN. ► AMPK and PTEN regulated TNF-α-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK–PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 μM) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-α) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-κB. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-κB activation decreased in response to metformin and was restored by inhibiting AMPK and PTEN. Inhibiting AMPK and PTEN restored ROS levels stimulated with TNF-α. Taken together, PTEN could be a possible downstream regulator of AMPK, and the

Molecular Analysis of AFP and HSA Interactions with PTEN Protein

Directory of Open Access Journals (Sweden)

Mingyue Zhu

2015-01-01

Full Text Available Human cytoplasmic alpha-fetoprotein (AFP has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA, but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K/protein kinase B (AKT pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP, and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog, demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN. In silicon substitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.

PTEN Signaling in the Postnatal Perivascular Progenitor Niche Drives Medulloblastoma Formation.

Science.gov (United States)

Zhu, Guo; Rankin, Sherri L; Larson, Jon D; Zhu, Xiaoyan; Chow, Lionel M L; Qu, Chunxu; Zhang, Jinghui; Ellison, David W; Baker, Suzanne J

2017-01-01

Loss of the tumor suppressor gene PTEN exerts diverse outcomes on cancer in different developmental contexts. To gain insight into the effect of its loss on outcomes in the brain, we conditionally inactivated the murine Pten gene in neonatal neural stem/progenitor cells. Pten inactivation created an abnormal perivascular proliferative niche in the cerebellum that persisted in adult animals but did not progress to malignancy. Proliferating cells showed undifferentiated morphology and expressed the progenitor marker Nestin but not Math1, a marker of committed granule neuron progenitors. Codeletion of Pten and Trp53 resulted in fully penetrant medulloblastoma originating from the perivascular niche, which exhibited abnormal blood vessel networks and advanced neuronal differentiation of tumor cells. EdU pulse-chase experiments demonstrated a perivascular cancer stem cell population in Pten/Trp53 double mutant medulloblastomas. Genetic analyses revealed recurrent somatic inactivations of the tumor suppressor gene Ptch1 and a recapitulation of the sonic hedgehog subgroup of human medulloblastomas. Overall, our results showed that PTEN acts to prevent the proliferation of a progenitor niche in postnatal cerebellum predisposed to oncogenic induction of medulloblastoma. Cancer Res; 77(1); 123-33. ©2016 AACR. ©2016 American Association for Cancer Research.

Interaction of IGF2 and PTEN in ( M alignant Breast T issues

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Preetha J Shetty

2012-07-01

Full Text Available Background: Breast Cancer (BC is one of the leading malignancies affecting women worldwide. Epigenetic mechanisms regulate gene expression playing an important role in the pathophysiology of cancer. In the present study IGF2 and PTEN genes in AKT pathway were selected for evaluation. Objective: To investigate the role of methylation and interaction of IGF2 and PTEN and in the pathoetiology of BC. Methods: Paraffin embedded archival breast tumor and adjacent normal tissue samples were used for carrying out PCR based methylation assay, genomic PCR, immunohistochemistry and qRT PCR. Results: In-Silico study indicated the absence of hormone responsive elements in the promoters of the selected genes. Methylation results indicated significant loss of methylation in IGF2 exon 9 CpG cluster and significant gain of PTEN promoter methylation in tumors. Immunohistochemistry revealed enhanced cytoplasmic expression o f IGF2 protein (p< 0.0001 and decreased nuclear localization of PTEN protein (p=0.0069 in the breast tumors. RT-PCR results indicated an increased IGF2 (p=0.024 and decreased PTEN transcripts (p<0.0001 in the tumors. Conclusion: Increased IGF2 in normal tissues increases PTEN which acts as a negative regulator of AKT pathway in the cytoplasm controlling excessive proliferation while in tumors this regulation is lost. PTEN acts as a negative regulator of MAPK pathway in the nucleus, plays an important role in cell cycle arrest in normal breast tissue. Reduction of PTEN in tumor tissue affects this pathway leading to cell survival. IGF2 and PTEN have a role in breast cancer and these molecular factors can be used for targeting therapy in future.

Inhibition of PTEN and activation of Akt by menadione.

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Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

2007-04-01

Menadione (vitamin K(3)) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an intact cell system, menadione inhibited the effect of transfected PTEN on Akt. Thus, one mechanism of its action was considered the accelerated activation of Akt through inhibition of PTEN. This was not the sole mechanism responsible for the EGFR-independent activation of Akt, because menadione attenuated the rate of Akt dephosphorylation even in PTEN-null PC3 cells. The decelerated inactivation of Akt, probably through inhibition of some tyrosine phosphatases, was considered another mechanism of its action.

PTEN overexpression improves cisplatin-resistance of human ovarian cancer cells through upregulating KRT10 expression

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Wu, Huijuan; Wang, Ke; Liu, Wenxin; Hao, Quan

2014-01-01

Highlights: • Overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin. • KRT10 is a downstream molecule of PTEN involved in the resistance-reversing effect. • Overexpression of KRT10 enhanced the chemosensitivity of C13K cells to cisplatin. - Abstract: Multi-drug resistance (MDR) is a common cause of the failure of chemotherapy in ovarian cancer. PTEN, a tumor suppressor gene, has been demonstrated to be able to reverse cisplatin-resistance in ovarian cancer cell line C13K. However, the downstream molecules of PTEN involved in the resistance-reversing effect have not been completely clarified. Therefore, we screened the downstream molecules of PTEN and studied their interactions in C13K ovarian cancer cells using a 3D culture model. Firstly, we constructed an ovarian cancer cell line stably expressing PTEN, C13K/PTEN. MTT assay showed that overexpression of PTEN enhanced the sensitivity of C13K cells to cisplatin, but not to paclitaxel. Then we examined the differently expressed proteins that interacted with PTEN in C13K/PTEN cells with or without cisplatin treatment by co-immunoprecipitation. KRT10 was identified as a differently expressed protein in cisplatin-treated C13K/PTEN cells. Further study confirmed that cisplatin could induce upregulation of KRT10 mRNA and protein in C13K/PTEN cells and there was a directly interaction between KRT10 and PTEN. Forced expression of KRT10 in C13K cells also enhanced cisplatin-induced proliferation inhibition and apoptosis of C13K cells. In addition, KRT10 siRNA blocked cisplatin-induced proliferation inhibition of C13K/PTEN cells. In conclusion, our data demonstrate that KRT10 is a downstream molecule of PTEN which improves cisplatin-resistance of ovarian cancer and forced KRT10 overexpression may also act as a therapeutic method for overcoming MDR in ovarian cancer

Redox Regulation of the Tumor Suppressor PTEN by Hydrogen Peroxide and Tert-Butyl Hydroperoxide

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Ying Zhang

2017-05-01

Full Text Available Organic peroxides and hydroperoxides are skin tumor promoters. Free radical derivatives from these compounds are presumed to be the prominent mediators of tumor promotion. However, the molecular targets of these species are unknown. Phosphatase and tensin homologs deleted on chromosome 10 (PTEN are tumor suppressors that play important roles in cell growth, proliferation, and cell survival by negative regulation of phosphoinositol-3-kinase/protein kinase B signaling. PTEN is reversibly oxidized in various cells by exogenous and endogenous hydrogen peroxide. Oxidized PTEN is converted back to the reduced form by cellular reducing agents, predominantly by the thioredoxin (Trx system. Here, the role of tert-butyl hydroperoxide (t-BHP in redox regulation of PTEN was analyzed by using cell-based and in vitro assays. Exposure to t-BHP led to oxidation of recombinant PTEN. In contrast to H2O2, PTEN oxidation by t-BHP was irreversible in HeLa cells. However, oxidized PTEN was reduced by exogenous Trx system. Taken together, these results indicate that t-BHP induces PTEN oxidation and inhibits Trx system, which results in irreversible PTEN oxidation in HeLa cells. Collectively, these results suggest a novel mechanism of t-BHP in the promotion of tumorigenesis.

RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells.

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Chow, Jimmy Y C; Quach, Khai T; Cabrera, Betty L; Cabral, Jennifer A; Beck, Stayce E; Carethers, John M

2007-11-01

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-beta might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFbeta and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFbeta surface receptors. Cells were treated with TGFbeta1 and separated into cytosolic/nuclear fractions for western blotting with phospho-SMAD2, SMAD 2, 4 phospho-ATP-dependent tyrosine kinases (Akt), Akt and PTEN antibodies. PTEN mRNA levels were assessed by reverse transcriptase-polymerase chain reaction. The MEK1 inhibitor, PD98059, was used to block the downstream action of oncogenic K-RAS/ERK, as was a dominant-negative (DN) K-RAS construct. TGFbeta increased phospho-SMAD2 in both cytosolic and nuclear fractions. PD98059 treatment further increased phospho-SMAD2 in the nucleus of both pancreatic cell lines, and DN-K-RAS further improved SMAD translocation in K-RAS mutant CAPAN cells. TGFbeta treatment significantly suppressed PTEN protein levels concomitant with activation of Akt by 48 h through transcriptional reduction of PTEN mRNA that was evident by 6 h. TGFbeta-induced PTEN suppression was reversed by PD98059 and DN-K-RAS compared with treatments without TGFbeta. TGFbeta-induced PTEN expression was inversely related to cellular proliferation. Thus, oncogenic K-RAS/ERK in pancreatic adenocarcinoma facilitates TGFbeta-induced transcriptional down-regulation of the tumor suppressor PTEN in a SMAD4-independent manner and could constitute a signaling switch mechanism from growth suppression to growth promotion in pancreatic cancers.

Regulation of T Cell Homeostasis and Responses by Pten

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Ryan H. Newton

2012-06-01

Full Text Available The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, costimulatory, cytokine and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K reaction, directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages of T cell development.

Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

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Kim, Sun Ae [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

2012-09-07

Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production.

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Tilot, Amanda K; Gaugler, Mary K; Yu, Qi; Romigh, Todd; Yu, Wanfeng; Miller, Robert H; Frazier, Thomas W; Eng, Charis

2014-06-15

PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Genomic Deletion at 10q23 in Prostate Cancer: More Than PTEN Loss?

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Raghavendra Tejo Karthik Poluri

2018-06-01

Full Text Available The PTEN gene encodes for the phosphatase and tensin homolog; it is a tumor suppressor gene that is among the most frequently inactivated genes throughout the human cancer spectrum. The most recent sequencing approaches have allowed the identification of PTEN genomic alterations, including deletion, mutation, or rearrangement in about 50% of prostate cancer (PCa cases. It appears that mechanisms leading to PTEN inactivation are cancer-specific, comprising gene mutations, small insertions/deletions, copy number alterations (CNAs, promoter hypermethylation, and RNA interference. The examination of publicly available results from deep-sequencing studies of various cancers showed that PCa appears to be the only cancer in which PTEN is lost mostly through CNA. Instead of inactivating mutations, which are seen in other cancers, deletion of the 10q23 locus is the most common form of PTEN inactivation in PCa. By investigating the minimal deleted region at 10q23, several other genes appear to be lost simultaneously with PTEN. Expression data indicate that, like PTEN, these genes are also downregulated upon loss of 10q23. These analyses raise the possibility that 10q23 is lost upon selective pressure not only to inactivate PTEN but also to impair the expression of surrounding genes. As such, several genes from this deleted region, which represents about 500 kb, may also act as tumor suppressors in PCa, requiring further studies on their respective functions in that context.

A unified nomenclature and amino acid numbering for human PTEN

NARCIS (Netherlands)

Pulido, Rafael; Baker, Suzanne J; Barata, Joao T; Carracedo, Arkaitz; Cid, Victor J; Chin-Sang, Ian D; Davé, Vrushank; den Hertog, Jeroen; Devreotes, Peter; Eickholt, Britta J; Eng, Charis; Furnari, Frank B; Georgescu, Maria-Magdalena; Gericke, Arne; Hopkins, Benjamin; Jiang, Xeujun; Lee, Seung-Rock; Lösche, Mathias; Malaney, Prerna; Matias-Guiu, Xavier; Molina, María; Pandolfi, Pier Paolo; Parsons, Ramon; Pinton, Paolo; Rivas, Carmen; Rocha, Rafael M; Rodríguez, Manuel S; Ross, Alonzo H; Serrano, Manuel; Stambolic, Vuk; Stiles, Bangyan; Suzuki, Akira; Tan, Seong-Seng; Tonks, Nicholas K; Trotman, Lloyd C; Wolff, Nicolas; Woscholski, Rudiger; Wu, Hong; Leslie, Nicholas R

2014-01-01

The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line

Region-specific role for Pten in maintenance of epithelial phenotype and integrity

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Flodby, Per; Sunohara, Mitsuhiro; Castillo, Dan R.; McConnell, Alicia M.; Krishnaveni, Manda S.; Banfalvi, Agnes; Li, Min; Stripp, Barry; Zhou, Beiyun; Crandall, Edward D.; Minoo, Parviz

2017-01-01

Previous studies have demonstrated resistance to naphthalene-induced injury in proximal airways of mice with lung epithelial-specific deletion of the tumor-suppressor gene Pten, attributed to increased proliferation of airway progenitors. We tested effects of Pten loss following bleomycin injury, a model typically used to study distal lung epithelial injury, in conditional PtenSFTPC-cre knockout mice. Pten-deficient airway epithelium exhibited marked hyperplasia, particularly in small bronchioles and at bronchoalveolar duct junctions, with reduced E-cadherin and β-catenin expression between cells toward the luminal aspect of the hyperplastic epithelium. Bronchiolar epithelial and alveolar epithelial type II (AT2) cells in PtenSFTPC-cre mice showed decreased expression of epithelial markers and increased expression of mesenchymal markers, suggesting at least partial epithelial-mesenchymal transition at baseline. Surprisingly, and in contrast to previous studies, mutant mice were exquisitely sensitive to bleomycin, manifesting rapid weight loss, respiratory distress, increased early mortality (by day 5), and reduced dynamic lung compliance. This was accompanied by sloughing of the hyperplastic airway epithelium with occlusion of small bronchioles by cellular debris, without evidence of increased parenchymal lung injury. Increased airway epithelial cell apoptosis due to loss of antioxidant defenses, reflected by decreased expression of superoxide dismutase 3, in combination with deficient intercellular adhesion, likely predisposed to airway sloughing in knockout mice. These findings demonstrate an important role for Pten in maintenance of airway epithelial phenotype integrity and indicate that responses to Pten deletion in respiratory epithelium following acute lung injury are highly context-dependent and region-specific. PMID:27864284

The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia

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Zuurbier, Linda; Petricoin, Emanuel F.; Vuerhard, Maartje J.; Calvert, Valerie; Kooi, Clarissa; Buijs-Gladdines, Jessica G.C.A.M.; Smits, Willem K.; Sonneveld, Edwin; Veerman, Anjo J.P.; Kamps, Willem A.; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

2012-01-01

Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. Design and Methods The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKT mutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1-activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors. PMID:22491738

Pten Regulates Retinal Amacrine Cell Number by Modulating Akt, Tgfβ, and Erk Signaling.

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Tachibana, Nobuhiko; Cantrup, Robert; Dixit, Rajiv; Touahri, Yacine; Kaushik, Gaurav; Zinyk, Dawn; Daftarian, Narsis; Biernaskie, Jeff; McFarlane, Sarah; Schuurmans, Carol

2016-09-07

All tissues are genetically programmed to acquire an optimal size that is defined by total cell number and individual cellular dimensions. The retina contains stereotyped proportions of one glial and six neuronal cell types that are generated in overlapping waves. How multipotent retinal progenitors know when to switch from making one cell type to the next so that appropriate numbers of each cell type are generated is poorly understood. Pten is a phosphatase that controls progenitor cell proliferation and differentiation in several lineages. Here, using a conditional loss-of-function strategy, we found that Pten regulates retinal cell division and is required to produce the full complement of rod photoreceptors and amacrine cells in mouse. We focused on amacrine cell number control, identifying three downstream Pten effector pathways. First, phosphoinositide 3-kinase/Akt signaling is hyperactivated in Pten conditional knock-out (cKO) retinas, and misexpression of constitutively active Akt (Akt-CA) in retinal explants phenocopies the reduction in amacrine cell production observed in Pten cKOs. Second, Akt-CA activates Tgfβ signaling in retinal explants, which is a negative feedback pathway for amacrine cell production. Accordingly, Tgfβ signaling is elevated in Pten cKO retinas, and epistatic analyses placed Pten downstream of TgfβRII in amacrine cell number control. Finally, Pten regulates Raf/Mek/Erk signaling levels to promote the differentiation of all amacrine cell subtypes, which are each reduced in number in Pten cKOs. Pten is thus a positive regulator of amacrine cell production, acting via multiple downstream pathways, highlighting its diverse actions as a mediator of cell number control. Despite the importance of size for optimal organ function, how individual cell types are generated in correct proportions is poorly understood. There are several ways to control cell number, including readouts of organ function (e.g., secreted hormones reach functional

Loss of CDH1 and Pten accelerates cellular invasiveness and angiogenesis in the mouse uterus.

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Lindberg, Mallory E; Stodden, Genna R; King, Mandy L; MacLean, James A; Mann, Jordan L; DeMayo, Francesco J; Lydon, John P; Hayashi, Kanako

2013-07-01

E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1(d/d) Pten(d/d)) in the mouse uterus. We observed that Cdh1(d/d) Pten(d/d) mice died at Postnatal Days 15-19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1(d/d) Pten(d/d) mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1(d/d) Pten(d/d) mice. However, complex hyperplasia was not found in the uteri of Cdh1(d/d) Pten(d/d) mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death.

Selective neuronal PTEN deletion: can we take the brakes off of growth without losing control?

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Erin A Gutilla

2016-01-01

Full Text Available The limited ability for injured adult axons to regenerate is a major cause for limited functional recovery after injury to the nervous system, motivating numerous efforts to uncover mechanisms capable of enhancing regeneration potential. One promising strategy involves deletion or knockdown of the phosphatase and tensin (PTEN gene. Conditional genetic deletion of PTEN before, immediately following, or several months after spinal cord injury enables neurons of the corticospinal tract (CST to regenerate their axons across the lesion, which is accompanied by enhanced recovery of skilled voluntary motor functions mediated by the CST. Although conditional genetic deletion or knockdown ofPTEN in neurons enables axon regeneration, PTEN is a well-known tumor suppressor and mutations of the PTEN gene disrupt brain development leading to neurological abnormalities including macrocephaly, seizures, and early mortality. The long-term consequences of manipulating PTEN in the adult nervous system, as would be done for therapeutic intervention after injury, are only now being explored. Here, we summarize evidence indicating that long-term deletion of PTEN in mature neurons does not cause evident pathology; indeed, cortical neurons that have lived without PTEN for over 1 year appear robust and healthy. Studies to date provide only a first look at potential negative consequences of PTEN deletion or knockdown, but the absence of any detectable neuropathology supports guarded optimism that interventions to enable axon regeneration after injury are achievable.

PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism.

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Liang, Hui; He, Shiming; Yang, Jingyi; Jia, Xinying; Wang, Pan; Chen, Xi; Zhang, Zhong; Zou, Xiajuan; McNutt, Michael A; Shen, Wen Hong; Yin, Yuxin

2014-05-06

PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTENα, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation, which requires a CUG-centered palindromic motif. We show that PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. PTENα interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes. Copyright © 2014 Elsevier Inc. All rights reserved.

Loss of PTEN causes SHP2 activation, making lung cancer cells unresponsive to IFN-γ

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Chen, Chia-Ling [Translational Research Center, Taipei Medical University, Taipei 110, Taiwan (China); Chiang, Tzu-Hui; Tseng, Po-Chun [Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan (China); Wang, Yu-Chih [Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China); Lin, Chiou-Feng, E-mail: cflin2014@tmu.edu.tw [Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China); Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan (China)

2015-10-23

Src homology-2 domain-containing phosphatase (SHP) 2, an oncogenic phosphatase, inhibits type II immune interferon (IFN)-γ signaling by subverting signal transducers and activators of transcription 1 tyrosine phosphorylation and activation. For cancer immunoediting, this study aimed to investigate the decrease of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor protein, leading to cellular impairment of IFN-γ signaling. In comparison with human lung adenocarcinoma A549 cells, the natural PTEN loss in another human lung adenocarcinoma line, PC14PE6/AS2 cells, presents reduced responsiveness in IFN-γ-induced IFN regulatory factor 1 activation and CD54 expression. Artificially silencing PTEN expression in A549 cells also caused cells to be unresponsive to IFN-γ without affecting IFN-γ receptor expression. IFN-γ-induced inhibition of cell proliferation and cytotoxicity were demonstrated in A549 cells but were defective in PC14PE6/AS2 cells and in PTEN-deficient A549 cells. Aberrant activation of SHP2 by ROS was specifically shown in PC14PE6/AS2 cells and PTEN-deficient A549 cells. Inhibiting ROS and SHP2 rescued cellular responses to IFN-γ-induced cytotoxicity and inhibition of cell proliferation in PC14PE6/AS2 cells. These results demonstrate that a decrease in PTEN facilitates ROS/SHP2 signaling, causing lung cancer cells to become unresponsive to IFN-γ. - Highlights: • This study demonstrates that PTEN decrease causes cellular unresponsive to IFN-γ. • Lung cancer cells with PTEN deficiency show unresponsive to IFN-γ signaling. • PTEN decrease inhibits IFN-γ-induced CD54, cell proliferation inhibition, and cytotoxicity. • ROS-mediated SHP2 activation makes PTEN-deficient cells unresponsive to IFN-γ.

ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin.

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Li, Ke; Yan, Huaying; Guo, Wenhao; Tang, Mei; Zhao, Xinyu; Tong, Aiping; Peng, Yong; Li, Qintong; Yuan, Zhu

2018-05-01

PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer

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2017-10-01

AWARD NUMBER: W81XWH-16-1-0737 TITLE: Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer PRINCIPAL...AND SUBTITLE 5a. CONTRACT NUMBER Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer 5b. GRANT NUMBER W81XWH...that there exist distinctive molecular correlates of PTEN loss in the context of ETS-negative versus ETS-positive human prostate cancers and that

Regulation of the activity of the tumor suppressor PTEN by thioredoxin in Drosophila melanogaster

International Nuclear Information System (INIS)

Song, Zuohe; Saghafi, Negin; Gokhale, Vijay; Brabant, Marc; Meuillet, Emmanuelle J.

2007-01-01

Human Thioredoxin-1 (hTrx-1) is a small redox protein with a molecular weight of 12 kDa that contains two cysteine residues found in its catalytic site. HTrx-1 plays an important role in cell growth, apoptosis, and cancer patient prognosis. Recently, we have demonstrated that hTrx-1 binds to the C2 domain of the human tumor suppressor, PTEN, in a redox dependent manner. This binding leads to the inhibition of PTEN lipid phosphatase activity in mammalian tissue culture systems. In this study, we show that over-expression of hTrx-1 in Drosophila melanogaster promotes cell growth and proliferation during eye development as measured by eye size and ommatidia size. Furthermore, hTrx-1 rescues the small eye phenotype induced by the over-expression of PTEN. We demonstrate that this rescue of the PTEN-induced eye size phenotype requires cysteine-218 in the C2 domain of PTEN. We also show that hTrx-1 over-expression results in increased Akt phosphorylation in fly head extracts supporting our observations that the hTrx-1-induced eye size increase results from the inhibition of PTEN activity. Our study confirms the redox regulation of PTEN through disulfide bond formation with the hTrx-1 in Drosophila and suggests conserved mechanisms for thioredoxins and their interactions with the phosphatidylinositol-3-kinase signaling pathway in humans and fruit flies

A study of the dynamics of PTEN proteins in living cells using in vivo fluorescence correlation spectroscopy

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Du, Zhixue; Dong, Chaoqing; Ren, Jicun

2017-06-01

PTEN (phosphatase and tensin homolog on chromosome 10) is one of the most important tumor-suppressor proteins, which plays a key role in negative regulation of the PI3K/AKT pathway, and governs many cellular processes including growth, proliferation, survival and migration. The dynamics of PTEN proteins in single living cells is as yet unclear owing to a shortage of suitable in vivo approaches. Here, we report a single-molecule method for in vivo study of the dynamics of PTEN proteins in living cells using fluorescence correlation spectroscopy (FCS). First, we established a monoclonal H1299 stable cell line expressing enhanced green fluorescent protein (EGFP) and PTEN (EGFP-PTEN) fusion proteins; we then developed an in vivo FCS method to study the dynamics of EGFP-PTEN both in the nucleus and the cytoplasm. We investigated the diffusion behaviors of EGFP and EGFP-PTEN in solution, nucleus and cytosol, and observed that the motion of PTEN in living cells was restricted compared with EGFP. Finally, we investigated the protein dynamics in living cells under oxidative stress stimulation and a cellular ATP depletion treatment. Under oxidative stress stimulation, the EGFP-PTEN concentration increased in the nucleus, but slightly decreased in the cytoplasm. The diffusion coefficient and alpha value of EGFP-PTEN reduced significantly both in the nucleus and cytoplasm; the significantly decreased alpha parameter indicates a more restricted Brownian diffusion behavior. Under the cellular ATP depletion treatment, the concentration of EGFP-PTEN remained unchanged in the nucleus and decreased significantly in cytosol. The diffusion coefficient of EGFP-PTEN decreased significantly in cytosol, but showed no significant change in the nucleus; the alpha value decreased significantly in both the nucleus and cytoplasm. These results suggest that the concentration and mobility of PTEN in the nucleus and cytoplasm can be regulated by stimulation methods. Our approach provides a unique

Posttranslational regulation of phosphatase and tensin homolog (PTEN and its functional impact on cancer behaviors

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Xu WT

2014-10-01

Full Text Available Wenting Xu,1 Zhen Yang,1 Shu-Feng Zhou,2 Nonghua Lu1 1Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA Abstract: The incidence of cancer is increasing worldwide, but the biochemical mechanisms for the occurrence of cancer is not fully understood, and there is no cure for advanced tumors. Defects of posttranslational modifications of proteins are linked to a number of important diseases, such as cancer. This review will update our knowledge on the critical role of posttranscriptional regulation of phosphatase and tensin homolog (PTEN and its activities and the functional impact on cancer behaviors. PTEN is a tumor suppressor gene that occupies a key position in regulating cell growth, proliferation, apoptosis, mobility, signal transduction, and other crucial cellular processes. The activity and function of PTEN are regulated by coordinated epigenetic, transcriptional, posttranscriptional, and posttranslational modifications. In particular, PTEN is subject to phosphorylation, ubiquitylation, somoylation, acetylation, and active site oxidation. Posttranslational modifications of PTEN can dynamically change its activity and function. Deficiency in the posttranslational regulation of PTEN leads to abnormal cell proliferation, apoptosis, migration, and adhesion, which are associated with cancer initiation, progression, and metastasis. With increasing information on how PTEN is regulated by multiple mechanisms and networked proteins, its exact role in cancer initiation, growth, and metastasis will be revealed. PTEN and its functionally related proteins may represent useful targets for the discovery of new anticancer drugs, and gene therapy and the therapeutic potentials should be fully explored. Keywords: phosphorylation, ubiquitination, acetylation, oxidation

An inducible knockout mouse to model the cell-autonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasias

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Mirantes, Cristina; Eritja, Núria; Dosil, Maria Alba; Santacana, Maria; Pallares, Judit; Gatius, Sónia; Bergadà, Laura; Maiques, Oscar; Matias-Guiu, Xavier; Dolcet, Xavier

2013-01-01

SUMMARY PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. The role of PTEN in carcinogenesis has been validated by knockout mouse models. PTEN heterozygous mice develop neoplasms in multiple organs. Unfortunately, the embryonic lethality of biallelic excision of PTEN has inhibited the study of complete PTEN deletion in the development and progression of cancer. By crossing PTEN conditional knockout mice with transgenic mice expressing a tamoxifen-inducible Cre-ERT under the control of a chicken actin promoter, we have generated a tamoxifen-inducible mouse model that allows temporal control of PTEN deletion. Interestingly, administration of a single dose of tamoxifen resulted in PTEN deletion mainly in epithelial cells, but not in stromal, mesenchymal or hematopoietic cells. Using the mT/mG double-fluorescent Cre reporter mice, we demonstrate that epithelial-specific PTEN excision was caused by differential Cre activity among tissues and cells types. Tamoxifen-induced deletion of PTEN resulted in extremely rapid and consistent formation of endometrial in situ adenocarcinoma, prostate intraepithelial neoplasia and thyroid hyperplasia. We also analyzed the role of PTEN ablation in other epithelial cells, such as the tubular cells of the kidney, hepatocytes, colonic epithelial cells or bronchiolar epithelium, but those tissues did not exhibit neoplastic growth. Finally, to validate this model as a tool to assay the efficacy of anti-tumor drugs in PTEN deficiency, we administered the mTOR inhibitor everolimus to mice with induced PTEN deletion. Everolimus dramatically reduced the progression of endometrial proliferations and significantly reduced thyroid hyperplasia. This model could be a valuable tool to study the cell-autonomous mechanisms involved in PTEN-loss-induced carcinogenesis and provides a good platform to study the effect of anti-neoplastic drugs on PTEN-negative tumors. PMID:23471917

A Critical Role of the PTEN/PDGF Signaling Network for the Regulation of Radiosensitivity in Adenocarcinoma of the Prostate

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Christensen, Michael, E-mail: mechristense@uwalumni.com [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Najy, Abdo J. [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Snyder, Michael; Movilla, Lisa S. [Department of Radiation Oncology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States); Kim, Hyeong-Reh Choi [Department of Pathology, Wayne State University School of Medicine, Barbara Ann Karmanos Cancer Center, Detroit, Michigan (United States)

2014-01-01

Purpose: Loss or mutation of the phosphate and tensin homologue (PTEN) is a common genetic abnormality in prostate cancer (PCa) and induces platelet-derived growth factor D (PDGF D) signaling. We examined the role of the PTEN/PDGF axis on radioresponse using a murine PTEN null prostate epithelial cell model. Methods and Materials: PTEN wild-type (PTEN{sup +/+}) and PTEN knockout (PTEN{sup −/−}) murine prostate epithelial cell lines were used to examine the relationship between the PTEN status and radiosensitivity and also to modulate the PDGF D expression levels. PTEN{sup −/−} cells were transduced with a small hairpin RNA (shRNA) lentiviral vector containing either scrambled nucleotides (SCRM) or sequences targeted to PDGF D (shPDGF D). Tumorigenesis and morphogenesis of these cell lines were evaluated in vivo via subcutaneous injection of male nude mice and in vitro using Matrigel 3-dimensional (3D) culture. Effects of irradiation on clonogenic survival, cell migration, and invasion were measured with respect to the PTEN status and the PDGF D expression level. In addition, apoptosis and cell cycle redistribution were examined as potential mechanisms for differences seen. Results: PTEN{sup −/−} cells were highly tumorigenic in animals and effectively formed foci in 3D culture. Importantly, loss of PDGF D in these cell lines drastically diminished these phenotypes. Furthermore, PTEN{sup −/−} cells demonstrated increased clonogenic survival in vitro compared to PTEN{sup +/+}, and attenuation of PDGF D significantly reversed this radioresistant phenotype. PTEN{sup −/−} cells displayed greater migratory and invasive potential at baseline as well as after irradiation. Both the basal and radiation-induced migratory and invasive phenotypes in PTEN{sup −/−} cells required PDGF D expression. Interestingly, these differences were independent of apoptosis and cell cycle redistribution, as they showed no significant difference. Conclusions: We propose

Differential role of PTEN in transforming growth factor β (TGF-β) effects on proliferation and migration in prostate cancer cells.

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Kimbrough-Allah, Mawiyah N; Millena, Ana C; Khan, Shafiq A

2018-04-01

Transforming growth factor-β (TGF-β) acts as a tumor suppressor in normal epithelial cells but as a tumor promoter in advanced prostate cancer cells. PI3-kinase pathway mediates TGF-β effects on prostate cancer cell migration and invasion. PTEN inhibits PI3-kinase pathway and is frequently mutated in prostate cancers. We investigated possible role(s) of PTEN in TGF-β effects on proliferation and migration in prostate cancer cells. Expression of PTEN mRNA and proteins were determined using RT-PCR and Western blotting in RWPE1 and DU145 cells. We also studied the role of PTEN in TGF-β effects on cell proliferation and migration in DU145 cells after transient silencing of endogenous PTEN. Conversely, we determined the role of PTEN in cell proliferation and migration after over-expression of PTEN in PC3 cells which lack endogenous PTEN. TGF-β1 and TGF-β3 had no effect on PTEN mRNA levels but both isoforms increased PTEN protein levels in DU145 and RWPE1 cells indicating that PTEN may mediate TGF-β effects on cell proliferation. Knockdown of PTEN in DU145 cells resulted in significant increase in cell proliferation which was not affected by TGF-β isoforms. PTEN overexpression in PC3 cells inhibited cell proliferation. Knockdown of endogenous PTEN enhanced cell migration in DU145 cells, whereas PTEN overexpression reduced migration in PC3 cells and reduced phosphorylation of AKT in response to TGF-β. We conclude that PTEN plays a role in inhibitory effects of TGF-β on cell proliferation whereas its absence may enhance TGF-β effects on activation of PI3-kinase pathway and cell migration. © 2018 Wiley Periodicals, Inc.

Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance

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Singh, Mohan; Chaudhry, Parvesh; Fabi, Francois; Asselin, Eric

2013-01-01

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells

Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance.

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Singh, Mohan; Chaudhry, Parvesh; Fabi, Francois; Asselin, Eric

2013-05-10

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. Cells were treated with 10μM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells.

A common variation of the PTEN gene is associated with peripheral insulin resistance

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Grinder-Hansen, L; Ribel-Madsen, R; Wojtaszewski, Jørgen

2016-01-01

. RESULTS: The minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single...... nucleotide polymorphism was not associated with either PI3K or Akt activities. CONCLUSION: A common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling......AIM: Phosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated...

PTEN phosphatase-independent maintenance of glandular morphology in a predictive colorectal cancer model system.

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Jagan, Ishaan C; Deevi, Ravi K; Fatehullah, Aliya; Topley, Rebecca; Eves, Joshua; Stevenson, Michael; Loughrey, Maurice; Arthur, Kenneth; Campbell, Frederick Charles

2013-11-01

Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na(+)/H(+) exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

PTEN Phosphatase-Independent Maintenance of Glandular Morphology in a Predictive Colorectal Cancer Model System

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Ishaan C. Jagan

2013-11-01

Full Text Available Organotypic models may provide mechanistic insight into colorectal cancer (CRC morphology. Three-dimensional (3D colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN coupling of cell division cycle 42 (cdc42 to atypical protein kinase C (aPKC. This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3 were ineffective. The isolated PTEN C2 domain (C2 accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na+/H+ exchanger regulatory factor-1 (NHERF-1 in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice.

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Xu, X; Ehdaie, B; Ohara, N; Yoshino, T; Deng, C-X

2010-02-04

Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.

PTEN-induction in U251 glioma cells decreases the expression of insulin-like growth factor binding protein-2

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Levitt, Randy J.; Georgescu, Maria-Magdalena; Pollak, Michael

2005-01-01

PTEN is a tumor suppressor gene whose loss of function is observed in ∼40-50% of human cancers. Although insulin-like growth factor binding protein-2 (IGFBP-2) was classically described as a growth inhibitor, multiple recent reports have shown an association of overexpression and/or high serum levels of IGFBP-2 with poor prognosis of several malignancies, including gliomas. Using an inducible PTEN expression system in the PTEN-null glioma cell line U251, we demonstrate that PTEN-induction is associated with reduced proliferation, increased apoptosis, and a substantial reduction of the high levels of IGFBP-2 expression. The PTEN-induced decrease in IGFBP-2 expression could be mimicked with the PI3-kinase inhibitor LY294002, indicating that the lipid phosphatase activity of PTEN is responsible for the observed effect. However, the rapamycin analog CCI-779 did not affect IGFBP-2 expression, suggesting that the PTEN-induced decrease in IGFBP-2 expression is not attributable to decreased mTOR signalling. Recombinant human IGFBP-2 was unable to rescue U251-PTEN cells from the antiproliferative effects of PTEN, and IGFBP-2 siRNA did not affect the IGF-dependent or -independent growth of this cell line. These results suggest that the clinical data linking IGFBP-2 expression to poor prognosis may arise, at least in part, because high levels of IGFBP-2 expression correlate with loss of function of PTEN, which is well known to lead to aggressive behavior of gliomas. Our results motivate translational research regarding the relationship between IGFBP-2 expression and loss of function of PTEN

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib.

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Zhai, Yang; Zhang, Yanjun; Nan, Kejun; Liang, Xuan

2017-05-01

The clinical resistance of non-small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been linked to EGFR T790M resistance mutations or MET amplifications. Additional mechanisms underlying EGFR-TKI drug resistance remain unclear. The present study demonstrated that icotinib significantly inhibited the proliferation and increased the apoptosis rate of HCC827 cells; the cellular mRNA and protein expression levels of phosphatase and tensin homolog (PTEN) were also significantly downregulated. To investigate the effect of PTEN expression levels on the sensitivity of HCC827 cells to icotinib, PTEN expression was silenced using a PTEN-specific small interfering RNA. The current study identified that the downregulation of PTEN expression levels may promote cellular proliferation in addition to decreasing the apoptosis of HCC827 cells, and may reduce the sensitivity of HCC827 cells to icotinib. These results suggested that reduced PTEN expression levels were associated with the decreased sensitivity of HCC827 cells to icotinib. Furthermore, PTEN expression levels may be a useful marker for predicting icotinib resistance and elucidating the resistance mechanisms underlying EGFR-mutated NSCLC.

PTEN gene and phosphorylation of Akt protein expression in the LPS-induced lung fibroblast

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Mao-lin HUANG

2014-09-01

Full Text Available Objective: To investigate PTEN gene expression and the Akt phosphorylation of protein expression in the LPS-induced lung fibroblast, to initially reveal the relation between PTEN gene and the Akt phosphorylated proteins to LPS-induced lung fibroblast proliferation mechanism. Methods: BrdU experiments was performed to evaluate the LPS-induced lung fibroblast proliferation,  RT-PCR and Western Blot analysis were used to analyze the PTEN gene expression and Western blot was performed to analyze Akt phosphorylated protein expression. Results: PTEN mRNA level of the experimental group were significantly lower than the control group (P<0.05 with LPS simulation for 24h and 72h , and there were no significant difference between the experimental group and control group the experimental group and control group (P>0.05 . PTEN protein expression levels of the experimental group were significantly lower than the control group (P<0.05 , at 72h, and PTEN mRNA levels had no significant differences between these of the experimental and control group at 6h,12h and 24h(p>0.05. Phosphorylation Akt protein level (relative to total Akt protein was significantly higer than the control group (P<0.05 at 24h and 72h, and phosphorylation Akt protein levels had no significant differences between these of the experimental and control group at 6h and 12h (P>0.05 .Conclusion: PTEN gene and phosphorylation Akt protein involve in LPS-induced lung fibroblast proliferation signal transduction pathway.

Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.

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Bansagi, Boglarka; Phan, Vietxuan; Baker, Mark R; O'Sullivan, Julia; Jennings, Matthew J; Whittaker, Roger G; Müller, Juliane S; Duff, Jennifer; Griffin, Helen; Miller, James A L; Gorman, Grainne S; Lochmüller, Hanns; Chinnery, Patrick F; Roos, Andreas; Swan, Laura E; Horvath, Rita

2018-05-22

To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog ( PTEN ), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity

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Choucair Khalil

2012-11-01

Full Text Available Abstract Background Prostate cancer (PCa, a leading cause of cancer death in North American men, displays a broad range of clinical outcome from relatively indolent to lethal metastatic disease. Several genomic alterations have been identified in PCa which may serve as predictors of progression. PTEN, (10q23.3, is a negative regulator of the phosphatidylinositol 3-kinase (PIK3/AKT survival pathway and a tumor suppressor frequently deleted in PCa. The androgen receptor (AR signalling pathway is known to play an important role in PCa and its blockade constitutes a commonly used treatment modality. In this study, we assessed the deletion status of PTEN along with AR expression levels in 43 primary PCa specimens with clinical follow-up. Methods Fluorescence In Situ Hybridization (FISH was done on formalin fixed paraffin embedded (FFPE PCa samples to examine the deletion status of PTEN. AR expression levels were determined using immunohistochemistry (IHC. Results Using FISH, we found 18 cases of PTEN deletion. Kaplan-Meier analysis showed an association with disease recurrence (P=0.03. Concurrently, IHC staining for AR found significantly lower levels of AR expression within those tumors deleted for PTEN (PPTEN deleted. We confirmed the predictive value of PTEN deletion in disease recurrence (P=0.03. PTEN deletion was also linked to diminished expression of PTEN (PP=0.02. Furthermore, gene set enrichment analysis revealed a diminished expression of genes downstream of AR signalling in PTEN deleted tumors. Conclusions Altogether, our data suggest that PTEN deleted tumors expressing low levels of AR may represent a worse prognostic subset of PCa establishing a challenge for therapeutic management.

Interaction of E-cadherin and PTEN regulates morphogenesis and growth arrest in human mammary epithelial cells

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Fournier, Marcia V.; Fata, Jimmie E.; Martin, Katherine J.; Yaswen, Paul; Bissell, Mina J.

2009-06-03

PTEN is a dual function phosphatase with tumor suppressor function compromised in a wide spectrum of cancers. Because tissue polarity and architecture are crucial modulators of normal and malignant behavior, we postulated that PTEN may play a role in maintenance of tissue integrity. We used two non-malignant human mammary epithelial cell lines (HMECs) that form polarized, growth-arrested structures (acini) when cultured in 3-dimensional laminin-rich extracellular matrix gels (3D lrECM). As acini begin to form, PTEN accumulates in both the cytoplasm, and at cell-cell contacts where it colocalizes with E-cadherin/{beta}-catenin complex. Reduction of PTEN levels by shRNA in lrECM prevents formation of organized breast acini and disrupts growth arrest. Importantly, disruption of acinar polarity and cell-cell contact by E-cadherin function-blocking antibodies reduces endogenous PTEN protein levels and inhibits its accumulation at cell-cell contacts. Conversely, in SKBR3 breast cancer cells lacking endogenous E-cadherin expression, exogenous introduction of E-cadherin gene causes induction of PTEN expression and its accumulation at sites of cell interactions. These studies provide evidence that E-cadherin regulates both the PTEN protein levels and its recruitment to cell-cell junctions in 3D lrECM indicating a dynamic reciprocity between architectural integrity and the levels and localization of PTEN. This interaction thus appears to be a critical integrator of proliferative and morphogenetic signaling in breast epithelial cells.

Study on construction of pEgr-hPTEN expression vector induced by irradiation and its anti-tumor effect in vitro

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Tian Mei; Jin Guanghui; Piao Chunji; Li Xiuyi; Liu Linlin

2003-01-01

Objective: To clone the cDNA of human tumor suppressor gene-PTEN, construct pEgr-hPTEN expression vector induced by irradiation and study its inhibitory effect on proliferation of malignant glioma cell line SHG-44 transfected steadily with pEgr-hPTEN after different doses of X-ray irradiation. Methods: A DNA fragment about 1200 bp, PTEN, was amplified from human placenta tissues by using RT-nested PCR and was cloned into pUCm-T vector after automatic sequencing, then the fragment was inserted into a vector pcD-NA3.1-Egr to construct an expression vector pEgr-hPTEN. pEgr-hPTEN was transfected into SHG-44 cells in vitro. Stably transfected cell line SHG-44-sPTEN was selected through G418. The inhibitor effect on SHG-44-sPTEN was observed after different doses of X-ray irradiation in vitro. Results: The PTEN cDNA has been cloned correctly and its expression vector pEgr-hPTEN was also constructed. Growth of SHG-44 cells was inhibited significantly by stable pEgr-hPTEN transfection combined with X-ray irradiation. With the increase of dose, the inhibitory effect was enhanced within 5 Gy. Conclusion: Human tumor suppressor gene-PTEN cDNA has been cloned and its expression vector has been constructed. The tumor was inhibited significantly by gene-radiotherapy in vitro. The result provides the theoretical and experimental basis for improvement of clinical radiotherapeutic effect on tumors

PLZF mediates the PTEN/AKT/FOXO3a signaling in suppression of prostate tumorigenesis.

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JingPing Cao

Full Text Available Promyelocytic leukemia zinc finger (PLZF protein expression is closely related to the progression of human cancers, including prostate cancer (PCa. However, the according context of a signaling pathway for PLZF to suppress prostate tumorigenesis remains greatly unknown. Here we report that PLZF is a downstream mediator of the PTEN signaling pathway in PCa. We found that PLZF expression is closely correlated with PTEN expression in a cohort of prostate cancer specimens. Interestingly, both PTEN rescue and phosphoinositide 3-kinase (PI3K inhibitor LY294002 treatment increase the PLZF expression in prostate cancer cell lines. Further, luciferase reporter assay and chromatin immunoprecipitation assay demonstrate that FOXO3a, a transcriptional factor phosphorylated by PI3K/AKT, could directly bind to the promoter of PLZF gene. These results indicate that PTEN regulates PLZF expression by AKT/FOXO3a. Moreover, our animal experiments also demonstrate that PLZF is capable of inhibiting prostate tumorigenesis in vivo. Taken together, our study defines a PTEN/PLZF pathway and would shed new lights for developing therapeutic strategy of prostate cancer.

miR-367 promotes proliferation and invasion of hepatocellular carcinoma cells by negatively regulating PTEN

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Meng, Xiangrui, E-mail: mengxiangruibb2008@163.com [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Lu, Peng [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Fan, Qingxia [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China)

2016-01-29

MicroRNAs play important roles in the carcinogenesis of many types of cancers by inhibiting gene expression at posttranscriptional level. However, the roles of microRNAs in hepatocellular carcinoma, are still unclear. Here, we identified that miR-367 promotes hepatocellular carcinoma (HCC) cell proliferation by negatively regulates its target gene PTEN. The expression of miR-367 and PTEN are significantly inverse correlated in 35 HCC patients. In HCC cell line, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-367, while miR-367 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-367 mimics significantly promoted the migration and invasion of HCC cells, whereas miR-367 inhibitors significantly reduced cell migration and invasion. Luciferase assays confirmed that miR-367 directly bound to the 3'untranslated region of PTEN, and western blotting showed that miR-367 suppressed the expression of PTEN at the protein levels. This study indicated that miR-367 negatively regulates PTEN and promotes proliferation and invasion of HCC cells. Thus, miR-367 may represent a potential therapeutic target for HCC intervention. - Highlights: • miR-367 mimics promote the proliferation and invasion of HCC cells. • miR-367 inhibitors inhibit the proliferation and invasion of HCC cells. • miR-367 targets 3′UTR of PTEN in HCC cells. • miR-367 negatively regulates PTEN in HCC cells.

Effects of PTEN transfer on cell cycle progression and expression of P27kipl followed by X-ray irradiation

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Tian Mei; Wu Congmei; Liu Linlin; Piao Chunji; Li Xiuyi

2007-01-01

Objective: To investigate the effect of pEgr-hPTEN stable transfer combined with irradiation on the cell cycle progression and the expression of cell cycle kinase inhibitor P27 kipl protein of SHG-44 human glioma cells. Methods: pEgr-hPTEN vector containing the exogenous wild type PTEN gene was transfected into SHG-44 cells under mediation of lipofectamine in vitro, the positive cell clones were selected and amplified by using G418. Western blotting was used to measure the expression of PTEN protein. Transmission electron microscope was adopted to detect the cell ultrastructural changes and flow cytometry was adopted to analysis the changes of cell cycle progression and the expression of P27 kipl in SHG-44-sPTEN cells followed by different doses of X-ray irradiation. Results: Egr-1 promoter could be induced and activated by irradiation and then enhanced the expression of downstream PTEN gene within 5 Gy. The ultrastructure of SHG-44-sPTEN cells had many degenerative changes and many early apoptotic changes including the chromosome condensate around the nuclear envelope. pEgr-hPTEN stable transfer combined with X-ray irradiation could significantly induce G 1 arrest. The expression of P27 kipl proteins increased in SHG-44-sPTEN stable transfected cells. Conclusion: PTEN stable transfer combined with irradiation can significantly induce G 1 arrest. The molecular basis may be correlated with the enhanced expression of PTEN induced by irradiation and increased expression of cell cycle kinase inhibitor P27 kipl . (authors)

A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

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Pradella, Laura Maria; Gasparre, Giuseppe; Turchetti, Daniela; Evangelisti, Cecilia; Ligorio, Claudia; Ceccarelli, Claudio; Neri, Iria; Zuntini, Roberta; Amato, Laura Benedetta; Ferrari, Simona; Martelli, Alberto Maria

2014-01-01

An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted. We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one. This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN

Kaempferol Promotes Apoptosis in Human Bladder Cancer Cells by Inducing the Tumor Suppressor, PTEN

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Liqun Zhou

2013-10-01

Full Text Available Kaempferol (Kae, a natural flavonoid, is widely distributed in fruits and vegetables. Previous studies have identified Kae as a possible cancer preventive and therapeutic agent. We found Kae to exhibit potent antiproliferation and anti-migration effects in human bladder cancer EJ cells. Kaempferol robustly induced apoptosis in EJ cells in a dose-dependent manner, as evidenced by increased cleavage of caspase-3. Furthermore, we found Kae-induced apoptosis in EJ cells to be associated with phosphatase and the tensin homolog deleted on the chromosome 10 (PTEN/PI3K/Akt pathway. Kae significantly increased PTEN and decreased Akt phosphorylation. Kae-induced apoptosis was partially attenuated in PTEN-knockdown cells. Our findings indicate that Kae could be an alternative medicine for bladder cancer, based on a PTEN activation mechanism.

The PTEN protein: cellular localization and post-translational regulation.

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Leslie, Nick R; Kriplani, Nisha; Hermida, Miguel A; Alvarez-Garcia, Virginia; Wise, Helen M

2016-02-01

The phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase dephosphorylates PIP3, the lipid product of the class I PI 3-kinases, and suppresses the growth and proliferation of many cell types. It has been heavily studied, in large part due to its status as a tumour suppressor, the loss of function of which is observed through diverse mechanisms in many tumour types. Here we present a concise review of our understanding of the PTEN protein and highlight recent advances, particularly in our understanding of its localization and regulation by ubiquitination and SUMOylation. © 2016 Authors; published by Portland Press Limited.

MicroRNA-221 and -222 Regulate Radiation Sensitivity by Targeting the PTEN Pathway

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Zhang Chunzhi; Kang Chunsheng; Wang Ping; Cao Yongzhen; Lv Zhonghong; Yu Shizhu; Wang Guangxiu; Zhang Anling; Jia Zhifan; Han Lei; Yang Chunying; Ishiyama, Hiromichi; Teh, Bin S.; Xu Bo; Pu Peiyu

2011-01-01

Purpose: MicroRNAs (miRNAs) are noncoding RNAs inhibiting expression of numerous target genes by posttranscriptional regulation. miRNA-221 and miRNA-222 (miRNA-221/-222) expression is elevated in radioresistant tumor cell lines; however, it is not known whether and how miRNAs control cellular responses to ionizing irradiation. Methods and Materials: We used bioinformatic analyses, luciferase reporter assay, and genetic knockdown and biochemical assays to characterize the regulation pathways of miRNA-221/-222 in response to radiation treatment. Results: We identified the PTEN gene as a target of miRNA-221/-222. Furthermore, we found that knocking down miRNA-221/-222 by antisense oligonucleotides upregulated PTEN expression. Upregulated PTEN expression suppressed AKT activity and increased radiation-induced apoptosis, resulting in enhancement of radiosensitivity in tumor cells. Conclusions: miRNA-221/-222 control radiation sensitivity by regulating the PTEN/AKT pathway and can be explored as novel targets for radiosensitization.

Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity.

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Riquelme, Sebastián A; Hopkins, Benjamin D; Wolfe, Andrew L; DiMango, Emily; Kitur, Kipyegon; Parsons, Ramon; Prince, Alice

2017-12-19

The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti-inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl -/- mice, which lack the NH 2 -amino terminal splice variant of PTEN, were unable to eradicate Pseudomonas aeruginosa from the airways and could not generate sufficient anti-inflammatory PI3K activity, similar to what is observed in CF. PTEN and the CF transmembrane conductance regulator (CFTR) interacted directly and this interaction was necessary to position PTEN at the membrane. CF patients under corrector-potentiator therapy, which enhances CFTR transport to the membrane, have increased PTEN amounts. These findings suggest that improved CFTR trafficking could enhance P. aeruginosa clearance from the CF airway by activating PTEN-mediated anti-bacterial responses and might represent a therapeutic strategy. Published by Elsevier Inc.

A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.

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Schwerd, Tobias; Khaled, Andrea V; Schürmann, Manfred; Chen, Hannah; Händel, Norman; Reis, André; Gillessen-Kaesbach, Gabriele; Uhlig, Holm H; Abou Jamra, Rami

2016-06-01

PTEN hamartoma tumour syndrome (PHTS) is caused by heterozygous variants in PTEN and is characterised by tumour predisposition, macrocephaly, and cognition impairment. Bi-allelic loss of PTEN activity has not been reported so far and animal models suggest that bi-allelic loss of PTEN activity is embryonically lethal. Here, we report the identification of a novel homozygous variant in PTEN, NM_000314.4; c.545T>C; p.Leu182Ser, in two adolescent siblings with severe macrocephaly and mild intellectual disability. The variant is predicted to be damaging and is associated with significantly increased phospho-S6 downstream of PTEN. The absence of tumours in the two homozygous siblings as well as lack of symptoms of PHTS in the heterozygous carriers of the family suggest that this particular variant is functionally hypomorphic rather than deleterious.

The microbiome in PTEN hamartoma tumor syndrome.

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Byrd, Victoria; Getz, Ted; Padmanabhan, Roshan; Arora, Hans; Eng, Charis

2018-03-01

Germline PTEN mutations defining PTEN hamartoma tumor syndrome (PHTS) confer heritable predisposition to breast, endometrial, thyroid and other cancers with known age-related risks, but it remains impossible to predict if any individual will develop cancer. In the general population, gut microbial dysbiosis has been linked to cancer, yet is unclear whether these are associated in PHTS patients. In this pilot study, we aimed to characterize microbial composition of stool, urine, and oral wash from 32 PTEN mutation-positive individuals using 16S rRNA gene sequencing. PCoA revealed clustering of the fecal microbiome by cancer history ( P  = 0.03, R 2  = 0.04). Fecal samples from PHTS cancer patients had relatively more abundant operational taxonomic units (OTUs) from family Rikenellaceae and unclassified members of Clostridia compared to those from non-cancer patients, whereas families Peptostreptococcaceae, Enterobacteriaceae, and Bifidobacteriaceae represented relatively more abundant OTUs among fecal samples from PHTS non-cancer patients. Functional metagenomic prediction revealed enrichment of the folate biosynthesis, genetic information processing and cell growth and death pathways among fecal samples from PHTS cancer patients compared to non-cancer patients. We found no major shifts in overall diversity and no clustering by cancer history among oral wash or urine samples. Our observations suggest the utility of an expanded study to interrogate gut dysbiosis as a potential cancer risk modifier in PHTS patients. © 2018 The authors.

Association of promoter methylation and 32-bp deletion of the PTEN gene with susceptibility to metabolic syndrome.

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Hashemi, Mohammad; Rezaei, Hamzeh; Eskandari-Nasab, Ebrahim; Kaykhaei, Mahmoud-Ali; Taheri, Mohsen

2013-01-01

Metabolic syndrome (MeS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for type II diabetes (T2D) and cardiovascular disease. Genetic and epigenetic alteration of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) has been associated with components of MeS. The aim of the present study was to investigate the possible association of a 32-bp deletion polymorphism and promoter methylation of the PTEN gene with MeS. DNA was extracted from the peripheral blood of 151 subjects with and 149 subjects without MeS. The 32-bp deletion variant of PTEN was detected by polymerase chain reaction (PCR) and PTEN promoter methylation was defined by a nested methylation‑specific PCR (MSP) method. No significant differences were found in the allelic and genotypic frequencies of the 32-bp deletion variant of PTEN between the groups [odds ratio (OR), 0.77; 95% confidence interval (CI), 0.41-1.45; P=0.431]. However, patients with MeS were identified to have lower levels of PTEN promoter hypermethylation than subjects without MeS. Promoter methylation may be a protective factor against susceptibility to MeS (OR, 0.52; 95% CI, 0.29-0.92; P=0.029). Our findings suggest that PTEN promoter methylation may be a mechanism for PTEN downregulation or silencing in MeS, which remains to be fully clarified.

Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors

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Naguib, Adam; Arends, Mark J; Cooke, James C; Happerfield, Lisa; Kerr, Lucy; Gay, Laura J; Luben, Robert N; Ball, Richard Y; Mitrou, Panagiota N; McTaggart, Alison

2011-01-01

The PTEN tumour suppressor gene and PIK3CA proto-oncogene encode proteins which contribute to regulation and propagation of signal transduction through the PI3K/AKT signalling pathway. This study investigates the prevalence of loss of PTEN expression and mutations in both PTEN and PIK3CA in colorectal cancers (CRC) and their associations with tumour clinicopathological features, lifestyle factors and dietary consumptions. 186 adenocarcinomas and 16 adenomas from the EPIC Norfolk study were tested for PTEN and PIK3CA mutations by DNA sequencing and PTEN expression changes by immunohistochemistry. Dietary and lifestyle data were collected prospectively using seven day food diaries and lifestyle questionnaires. Mutations in exons 7 and 8 of PTEN were observed in 2.2% of CRC and PTEN loss of expression was identified in 34.9% CRC. Negative PTEN expression was associated with lower blood low-density lipoprotein concentrations (p = 0.05). PIK3CA mutations were observed in 7% of cancers and were more frequent in CRCs in females (p = 0.04). Analysis of dietary intakes demonstrated no link between PTEN expression status and any specific dietary factor. PTEN expression negative, proximal CRC were of more advanced Dukes' stage (p = 0.02) and poor differentiation (p < 0.01). Testing of the prevalence of PIK3CA mutations and loss of PTEN expression demonstrated that these two events were independent (p = 0.55). These data demonstrated the frequent occurrence (34.9%) of PTEN loss of expression in colorectal cancers, for which gene mutations do not appear to be the main cause. Furthermore, dietary factors are not associated with loss of PTEN expression. PTEN expression negative CRC were not homogenous, as proximal cancers were associated with a more advanced Dukes' stage and poor differentiation, whereas distal cancers were associated with earlier Dukes' stage

The Involvement of Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN in the Regulation of Inflammation Following Coronary Microembolization

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Jiangyou Wang

2014-06-01

Full Text Available Background/Aims: Growing evidence shows that phosphatase and tensin homolog deleted on chromosome ten (PTEN is involved in regulating inflammation in different pathological conditions. Therefore, we hypothesized that the upregulation of PTEN correlates with the impairment of cardiac function in swine following coronary microembolization (CME. Methods: To possibly disclose an anti-inflammatory effect of PTEN, we induced swine CME by injecting inertia plastic microspheres (42 μm in diameter into the left anterior descending coronary artery and analyzed the myocardial tissue by immunochemistry, qRT-PCR and western blot analyses. In addition, we downregulated PTEN using siRNA. Results: Following CME, PTEN mRNA and protein levels were elevated as early as 3 h, peaked at 12 h, and then continuously decreased at 24 h and 48 h but remained elevated. Through linear correlation analysis, the PTEN protein level positively correlated with cTnI and TNF-α but was negatively correlated with LVEF. Furthermore, PTEN siRNA reduced the microinfarct volume, improved cardiac function (LVEF, reduced the release of cTnI, and suppressed PTEN and TNF-α protein expression. Conclusion: This study demonstrated, for the first time, that PTEN is involved in CME-induced inflammatory injury. The data generated from this study provide a rationale for the development of PTEN-based anti-inflammatory strategies.

PTEN deletion from adult-generated dentate granule cells disrupts granule cell mossy fiber axon structure.

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LaSarge, Candi L; Santos, Victor R; Danzer, Steve C

2015-03-01

Dysregulation of the mTOR-signaling pathway is implicated in the development of temporal lobe epilepsy. In mice, deletion of PTEN from hippocampal dentate granule cells leads to mTOR hyperactivation and promotes the rapid onset of spontaneous seizures. The mechanism by which these abnormal cells initiate epileptogenesis, however, is unclear. PTEN-knockout granule cells develop abnormally, exhibiting morphological features indicative of increased excitatory input. If these cells are directly responsible for seizure genesis, it follows that they should also possess increased output. To test this prediction, dentate granule cell axon morphology was quantified in control and PTEN-knockout mice. Unexpectedly, PTEN deletion increased giant mossy fiber bouton spacing along the axon length, suggesting reduced innervation of CA3. Increased width of the mossy fiber axon pathway in stratum lucidum, however, which likely reflects an unusual increase in mossy fiber axon collateralization in this region, offsets the reduction in boutons per axon length. These morphological changes predict a net increase in granule cell innervation of CA3. Increased diameter of axons from PTEN-knockout cells would further enhance granule cell communication with CA3. Altogether, these findings suggest that amplified information flow through the hippocampal circuit contributes to seizure occurrence in the PTEN-knockout mouse model of temporal lobe epilepsy. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of PTEN inhibition on the regulation of Tau phosphorylation in rat cortical neuronal injury after oxygen and glucose deprivation.

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Zhao, Jing; Chen, Yurong; Xu, Yuxia; Pi, Guanghuan

2016-01-01

This report investigated the involvement of the PTEN pathway in the regulation of Tau phosphorylation using an oxygen and glucose deprivation (OGD) model with rat cortical neurons. Primary cortical neurons were used to establish the oxygen and glucose deprivation (OGD) model in vitro. These were randomly divided into control, OGD, bpV+OGD, As+OGD, Se+OGD and Mock treatment groups. The neuron viability was assessed by MTT, the cell apoptosis was detected using TUNEL staining. The expression of Phospho-PTEN/PTEN, Phospho-Tau/Tau, Phospho-Akt/Akt and Phospho-GSK-3β/GSK-3β were detected by Western blotting. OGD induced Tau phosphorylation through PTEN and glycogen synthase kinase-3β (GSK-3β) activation, together with a decrease in AKT activity. Pre-treatment with bpv, a potent PTEN inhibitor, and PTEN antisense nucleotides decreased PTEN and GSK-3β activity and caused alterations in Tau phosphorylation. Neuronal apoptosis was also reduced. The PTEN/Akt/GSK-3β/Tau pathway is involved in the regulation of neuronal injury, providing a novel route for protecting neurons following neonatal HI.

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

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Beg, Shaham; Siraj, Abdul K; Prabhakaran, Sarita; Jehan, Zeenath; Ajarim, Dahish; Al-Dayel, Fouad; Tulbah, Asma; Al-Kuraya, Khawla S

2015-06-01

PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.

Recombinant adenovirus-mediated overexpression of PTEN and KRT10 improves cisplatin resistance of ovarian cancer in vitro and in vivo.

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Wu, H; Wang, K; Liu, W; Hao, Q

2015-06-18

Drug resistance is a major cause of treatment failure in ovarian cancer patients, and novel therapeutic strategies are urgently needed. Overexpression of phosphatase and tensin homolog (PTEN) has been shown to preserve the cisplatin-resistance of ovarian cancer cells, while cisplatin-induced keratin 10 (KRT10) overexpression mediates the resistance-reversing effect of PTEN. However, whether overexpression of PTEN or KRT10 can improve the cisplatin resistance of ovarian cancer in vivo has not been investigated. Therefore, we investigated the effects of adenovirus-mediated PTEN or KRT10 overexpression on the cisplatin resistance of ovarian cancer in vivo. Recombinant adenoviruses carrying the gene for PTEN or KRT10 were constructed. The effects of overexpression of PTEN and KRT10 on cisplatin resistance of ovarian cancer cells were examined using the 3(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) and TdT-mediated dUTP nick-end labeling (TUNEL) assays in vitro. Subcutaneously transplanted nude mice, as a model of human ovarian cancer, were used to test the effects of PTEN and KRT10 on cisplatin resistance of ovarian cancer in vivo. The MTT assay showed that recombinant adenovirus-mediated overexpression of KRT10 and PTEN enhanced the proliferation inhibition effect of cisplatin on C13K cells. Recombinant adenovirus-mediated overexpression of KRT10 and PTEN also increased the cisplatin-induced apoptosis rate of C13K cells. Furthermore, recombinant adenovirus-mediated overexpression of KRT10 and PTEN enhanced the inhibitory effect of cisplatin on C13K xenograft tumor growth. Thus, recombinant adenovirus-mediated overexpression of KRT10 and PTEN may improve the cisplatin resistance of ovarian cancer in vitro and in vivo.

PTEN and DMBT1 homozygous deletion and expression in medulloblastomas and supratentorial primitive neuroectodermal tumors.

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Inda, María Mar; Mercapide, Javier; Muñoz, Jorge; Coullin, Philippe; Danglot, Giséle; Tuñon, Teresa; Martínez-Peñuela, José María; Rivera, José María; Burgos, Juan J; Bernheim, Alain; Castresana, Javier S

2004-12-01

Medulloblastoma, which accounts for 20-25% of all childhood brain tumors, is defined as a primitive neuroectodermal tumor (PNET) located in the cerebellum. Supratentorial PNET are less frequent than medulloblastoma. But their clinical outcome is worse than in medulloblastomas. Chromosome 10q contains at least 2 tumor suppressor genes that might play a role in brain tumor development: PTEN and DMBT1. The aim of this study was to compare the status of homozygous deletion and expression of PTEN and DMBT1 genes in PNET primary tumor samples and cell lines. Homozygous deletions of PTEN and DMBT1 were studied in 32 paraffin-embedded PNET samples (23 medulloblastomas and 9 supratentorial PNET) and in 7 PNET cell lines, by differential PCR and by FISH. PTEN homozygous losses were demonstrated in 7 medulloblastomas (32%) and in no supratentorial PNET, while homozygous deletions of DMBT1 appeared in 1 supratentorial PNET (20%) and in 7 medulloblastomas (33%). No homozygous deletion of PTEN or DMBT1 was detected in any of the PNET cell lines either by differential PCR or by FISH. Expression study of the 2 genes was performed in the 7 PNET cell lines by RT-PCR. One PNET cell line lacked PTEN and DMBT1 expression, while 2 medulloblastoma cell lines did not express DMBT1. Our results add some positive data to the hypothesis that supratentorial PNETs and medulloblastomas might be genetically different.

Hesperitin derivative-11 suppress hepatic stellate cell activation and proliferation by targeting PTEN/AKT pathway

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Li, Wan-xia; Chen, Xin; Yang, Yang; Huang, Hui-min; Li, Hai-di; Huang, Cheng; Meng, Xiao-ming; Li, Jun

2017-01-01

Hesperitin derivative (HD-11) is a monomeric compound derived from Hesperidin, which is a naturally occurring flavanone glycoside that exerts extensive clinical effects such as anti-inflammatory, anti-oxidant and anti-angiogenic. However, the role and fundamental mechanism of HD-11 in hepatic fibrosis are still unrevealed. In this study, HD-11 not only alleviates ECM deposition in rats with liver fibrosis, but also reduces the expression of α-SMA and col1a1 in TGF-β1-induced HSC-T6 cells. Moreover, it was demonstrated that HD-11 significantly promoted the expression of PTEN in vivo and in vitro. In order to evaluate the involvement of HD-11 in TGF-β1-induced HSC-T6 activation, a specific blocking agent of PTEN (bpv) and PTEN small interfering (si)-RNA-mediated silencing were used. Interestingly, HD-11 treatment couldn’t inhibit α-SMA and col1a1 expression on the basis of PTEN knockdown. On the contrary, over-expression of PTEN had an opposite effect on the expression of α-SMA and col1a1 in TGF-β1-induced HSC-T6 cells after treatment of HD-11. In addition, HD-11 remarkably inhibited the expression of p-AKT in vivo and in vitro. Taken together, all the above results indicate that HD-11 may play the part of an effective modulator of PTEN/AKT signaling pathway.

PTEN expression as a predictor for the response to trastuzumab-based therapy in Her-2 overexpressing metastatic breast cancer.

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Daphne Gschwantler-Kaulich

Full Text Available Even though trastuzumab is an effective therapy in early stage Her-2+ breast cancer, 40-50% of advanced Her-2+ breast cancer patients develop trastuzumab resistance. A potential resistance mechanism is aberrant downstream signal transmission due to loss of phosphatase and tensin homologue (PTEN. This study investigated the relationship between the expression of PTEN and trastuzumab response in Her-2 overexpressing metastatic breast cancer patients.Between 2000 and 2007, 164 patients with Her-2+ metastatic breast cancer received trastuzumab-based therapy in our institution. We analyzed PTEN status by immunohistochemistry of 115 available tumor tissues and analyzed associations with other histopathological parameters, response rate, progression free survival (PFS and overall survival (OS with a median follow-up of 60 months.Eighty patients were PTEN positive (69.6% and 35 patients PTEN negative (30.4%. We found a significant association of the expression of PTEN and p53 (p = 0.041, while there was no association with grading, hormone receptor status, IGFR or MIB. We found significantly more cases with progressive disease under trastuzumab-based therapy in patients with PTEN positive breast cancers (p = 0.018, while there was no significant correlation with PFS or OS.In Her-2-positive metastatic breast cancers, PTEN positivity was significantly associated with progressive disease, but not with PFS or OS.

PTEN Sequence Analysis in Endometrial Hyperplasia and Endometrial Carcinoma in Slovak Women

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H. Gbelcová

2015-01-01

Full Text Available Phosphatase and tensin homolog (PTEN is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa. ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3, complex hyperplasia (5, atypical complex hyperplasia (7, endometrioid carcinomas G1 (20 and G3 (5, and serous carcinoma (5 were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

Pten regulates spindle pole movement through Dlg1-mediated recruitment of Eg5 to centrosomes

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Ree, J.H. van; Nam, H.J.; Jeganathan, K.B.; Kanakkanthara, A.; Deursen, J.M.A. van

2016-01-01

Phosphatase and tensin homologue (Pten) suppresses neoplastic growth by negatively regulating PI(3)K signalling through its phosphatase activity. To gain insight into the actions of non-catalytic Pten domains in normal physiological processes and tumorigenesis, we engineered mice lacking the

High-incidence of PTEN mutations in Chinese patients with primary small cell carcinoma of the esophagus

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Zhang, Zhimin; Wang, Ge; Xiao, Hualiang; Xie, Fei; Zhang, Hui; Chen, Chuan; Xiao, He; Yang, Zhenzhou; Wang, Dong; Li, Zengpeng

2014-01-01

Primary small cell carcinoma of the esophagus (PSCCE) is a rare and aggressive tumor with poor prognosis. The aim of this study was to investigate the existence of EGFR, KRAS, PIK3CA and PTEN mutations in PSCCE. Clinical–pathological data and paraffin-embedded specimens were collected from 38 patients. Exons 18 to 21 of EGFR, KRAS and PIK3CA status were analyzed by real-time PCR based on ARMS and Scorpion technology in all patients, and the PTEN gene was also screened using real-time PCR and high-resolution melting curve analysis (HRMA). Only 1 (2.63%) out of 38 patients had EGFR mutations in L858R missense, and KRAS and PIK3CA were not found in the mutational spot in all patients. However, PTEN mutations presented in 14 (36.84%) out of 38 patients, including exon 5 coding for PTEN missense mutation (n =4, 10.53%), exon 6 (n =7, 18.42%), concurrent exon 5 and exon 6 (n =2, 5.26%), and exon 8 (n =1, 2.63%). Concurrent mutations of these genes were not detected in all samples. No statistically significant associations were found between the clinicopathological features and the mutation status of PTEN. The incidence of PTEN mutations in Chinese patients with PSCCE was higher than that of previous reports in other histological subtypes of esophageal cancer

miR-1297 mediates PTEN expression and contributes to cell progression in LSCC

International Nuclear Information System (INIS)

Li, Xin; Wang, Hong-liang; Peng, Xin; Zhou, Hui-fang; Wang, Xin

2012-01-01

Highlights: ► miR-1297 was found to be overexpressed in LSCC and contribute to the cell progression. ► PTEN was confirmed to be a target gene of miR-1297. ► Downregulation of PTEN can rescue the proliferation and invasion ability of miR-1297 downregulated Hep-2 cells. ► Downregulation of miR-1297 inhibits tumor growth in vivo. -- Abstract: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression after transcription, and are involved in cancer development. Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant neoplasms with increasing incidence in recent years. In this paper, we report the overexpression of miR-1297 in LSCC and Hep-2 cells. In addition, PTEN was identified to be directly regulated by miR-1297 through western blot and luciferase activity assay. Furthermore, downregulation of miR-1297 in Hep-2 cells was shown to inhibit cancer cell proliferation, migration, and tumor genesis. Our results document a new epigenetic mechanism for PTEN regulation in LSCC, which is crucial for the development of these tumors.

The melatonin-MT1 receptor axis modulates tumor growth in PTEN-mutated gliomas.

Science.gov (United States)

Ma, Huihui; Wang, Zhen; Hu, Lei; Zhang, Shangrong; Zhao, Chenggang; Yang, Haoran; Wang, Hongzhi; Fang, Zhiyou; Wu, Lijun; Chen, Xueran

2018-02-19

More than 40% of glioma patients have tumors that harbor PTEN (phosphatase and tensin homologue deleted on chromosome ten) mutations; this disease is associated with poor therapeutic resistance and outcome. Such mutations are linked to increased cell survival and growth, decreased apoptosis, and drug resistance; thus, new therapeutic strategies focusing on inhibiting glioma tumorigenesis and progression are urgently needed. Melatonin, an indolamine produced and secreted predominantly by the pineal gland, mediates a variety of physiological functions and possesses antioxidant and antitumor properties. Here, we analyzed the relationship between PTEN and the inhibitory effect of melatonin in primary human glioma cells and cultured glioma cell lines. The results showed that melatonin can inhibit glioma cell growth both in culture and in vivo. This inhibition was associated with PTEN levels, which significantly correlated with the expression level of MT1 in patients. In fact, c-fos-mediated MT1 was shown to be a key modulator of the effect of melatonin on gliomas that harbor wild type PTEN. Taken together, these data suggest that melatonin-MT1 receptor complexes represent a potential target for the treatment of glioma. Copyright © 2018 Elsevier Inc. All rights reserved.

MicroRNA-103 Promotes Colorectal Cancer by Targeting Tumor Suppressor DICER and PTEN

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Li Geng

2014-05-01

Full Text Available MicroRNAs (miRNAs are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms for miRNAs in colorectal cancer remain largely unknown. Here, we found that miR-103 is up-regulated in colorectal cancer and its overexpression is closely associated with tumor proliferation and migration. In addition, repressing the expression of miR-103 apparently inhibits colorectal cancer cell proliferation and migration in vitro and HCT-116 xenograft tumor growth in vivo. Subsequent software analysis and dual-luciferase reporter assay identified two tumor suppressor genes DICER and PTEN as direct targets of miR-103, and up-regulation of DICER and PTEN obtained similar results to that occurred in the silencing of miR-103. In addition, restoration of DICER and PTEN can inhibit miR-103-induced colorectal cancer cell proliferation and migration. Our data collectively demonstrate that miR-103 is an oncogene miRNA that promotes colorectal cancer proliferation and migration through down-regulation of the tumor suppressor genes DICER and PTEN. Thus, miR-103 may represent a new potential diagnostic and therapeutic target for colorectal cancer treatment.

Age-related clinical and biological features of PTEN abnormalities in T-cell acute lymphoblastic leukaemia.

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Tesio, M; Trinquand, A; Ballerini, P; Hypolite, G; Lhermitte, L; Petit, A; Ifrah, N; Baruchel, A; Dombret, H; Macintyre, E; Asnafi, V

2017-12-01

The tumour suppressor gene PTEN is commonly altered in T-cell acute lymphoblastic leukaemia but its prognostic impact is still debated. We screened a cohort of 573 fully characterised adult and paediatric T-cell acute lymphoblastic leukaemia (T-ALL) patients for genomic PTEN abnormalities. PTEN-inactivating mutations and/or deletions were identified in 91 cases (16%), including 18% of paediatric (49/277) and 14% of adult cases (42/296). Thirty-four patients harboured only mutations, 12 cases demonstrated only large deletions and 9 only microdeletions. About 36 patients had combined alterations. Different mechanisms of PTEN inactivation predicted differences in the clinical outcome for both adult and paediatric patients treated according to the GRAALL03/05 and FRALLE2000 protocols. Whereas large deletions predicted lower 5-year overall survival (P=0.0053 in adults, P=0.001 in children) and disease-free survival (P=0.0009 in adults, P=0.0002 in children), mutations were not associated with a worse prognosis. The prognostic impact of PTEN loss is therefore linked to the underlying type of genomic abnormality, both in adult and paediatric T-ALLs, demonstrating that detailed analysis of the type of abnormality type would be useful to refine risk stratification.

Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits.

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He, Xin; Thacker, Stetson; Romigh, Todd; Yu, Qi; Frazier, Thomas W; Eng, Charis

2015-01-01

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines of evidence support genetic factors as a predominant cause of ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified as predisposing to Cowden heritable cancer syndrome, was found to be mutated in a subset of ASD patients with extreme macrocephaly. However, the ASD-relevant molecular mechanism mediating the effect of PTEN mutations remains elusive. We developed a Pten knock-in murine model to study the effects of Pten germline mutations, specifically altering subcellular localization, in ASD. Proteins were isolated from the hemispheres of the male littermates, and Western blots were performed to determine protein expression levels of tyrosine hydroxylase (TH). Immunohistochemical stains were carried out to validate the localization of TH and dopamine D2 receptors (D2R). PC12 cells ectopically expressing either wild-type or missense mutant PTEN were then compared for the differences in TH expression. Mice carrying Pten mutations have high TH and D2R in the striatum and prefrontal cortex. They also have increased phosphorylation of cAMP response element-binding protein (CREB) and TH. Mechanistically, PTEN downregulates TH production in PC12 cells via inhibiting the phosphoinositide 3-kinase (PI3K)/CREB signaling pathway, while PTEN reduces TH phosphorylation via suppressing MAPK pathway. Unlike wild-type PTEN but similar to the mouse knock-in mutant Pten, three naturally occurring missense mutations of PTEN that we previously identified in ASD patients, H93R, F241S, and D252G, were not able to suppress TH when overexpressed in PC12 cells. In addition, two other PTEN missense mutations, C124S (pan phosphatase dead) and G129E (lipid phosphatase dead), failed to suppress TH when ectopically expressed in PC12 cells

Broad spectrum of neuropsychiatric phenotypes associated with white matter disease in PTEN hamartoma tumor syndrome.

Science.gov (United States)

Balci, Tugce B; Davila, Jorge; Lewis, Denice; Boafo, Addo; Sell, Erick; Richer, Julie; Nikkel, Sarah M; Armour, Christine M; Tomiak, Eva; Lines, Matthew A; Sawyer, Sarah L

2018-01-01

White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals. © 2017 Wiley Periodicals, Inc.

The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis

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Cheng, Yahui; Tian, Yuanyao; Xia, Jialu; Wu, Xiaoqin; Yang, Yang; Li, Xiaofeng; Huang, Cheng; Meng, Xiaoming; Ma, Taotao; Li, Jun, E-mail: lj@ahmu.edu.cn

2017-02-15

Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl{sub 4}-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl{sub 4}-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. - Highlights: • CCl{sub 4} treatment triggered a mixed M1/M2 macrophage phenotype in fibrosis. • Lower expression of PTEN in murine M2 macrophages in vivo and vitro. • PTEN modulates M2 macrophages activation via PI3K/Akt/STAT6 signaling. • Provide a new cellular target modulate macrophage mediated hepatic fibrosis.

Studies of variability in the PTEN gene among Danish caucasian patients with Type II diabetes mellitus

DEFF Research Database (Denmark)

Hansen, L; Jensen, J N; Ekstrøm, C T

2001-01-01

Phosphatase and tensin homologue deleted from chromosome ten (PTEN) has recently been characterized as a novel member in the expanding network of proteins regulating the intracellular effects of insulin. By dephosphorylation of phosphatidyl-inositol-(3, 4, 5)-trisphosphate (PIP3) the PTEN protein...... regulates the insulin-dependent phosphoinositide 3-kinase (PI3K) signalling cassette and accordingly might function as a regulator of insulin sensitivity in skeletal muscle and adipose tissue. In this study we tested PTEN as a candidate gene for insulin resistance and late-onset Type II (non...

Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells

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Kim, Sung-Young; Hong, Chansik; Wie, Jinhong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Kim, Euiyong [Department of Physiology, College of Medicine, Inje University, Busan 614-735 (Korea, Republic of); Kim, Byung Joo [Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870 (Korea, Republic of); Ha, Kotdaji [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Cho, Nam-Hyuk; Kim, In-Gyu [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Jeon, Ju-Hong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); So, Insuk, E-mail: insuk@snu.ac.kr [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)

2014-04-25

Highlights: • TRPV6 interacts with tumor suppressor proteins. • Numb has a selective effect on TRPV6, depending on the prostate cancer cell line. • PTEN is a novel regulator of TRPV6–Numb complex. - Abstract: Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB–TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6–NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB–TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex.

Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice.

Science.gov (United States)

Lan, Zi-Jian; Krause, M S; Redding, S D; Li, X; Wu, G Z; Zhou, H X; Bohler, H C; Ko, C; Cooney, A J; Zhou, Junmei; Lei, Z M

2017-03-15

Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Heterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling.

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Shah, Rajal B; Bentley, James; Jeffery, Zach; DeMarzo, Angelo M

2015-05-01

ERG and PTEN biomarkers are increasingly being analyzed on prostate core biopsies (NBXs); ERG as a marker of clonality and number of separately arising tumor foci and PTEN for prognostic information. Yet, in patients with multiple biopsy cores positive for cancer (PCa), there is no standardized approach for interrogation of these biomarkers in terms of the number of positive cores to evaluate. A total of 194 NBX cases containing more than one positive core with cancer were evaluated for ERG overexpression and PTEN loss by immunostaining (immunohistochemistry) of all positive cores. ERG overexpression or PTEN loss in at least one cancer core was present in 111 (57%) and 69 (36%) cases respectively. ERG overexpression was significantly associated with PTEN loss (P < .0001), and PTEN loss was associated with a high Gleason score (P < .0001). Inter- and intra-tumor core staining heterogeneity for ERG overexpression occurred in 42% and 5% cases and for PTEN loss both intra- and inter-tumor core heterogeneity was 68%. PTEN staining was highly discordant between PCa sites regardless of laterality. When the Gleason score was non-uniform across PCa sites, the combination of cores showing the highest Gleason score and largest tumor volume provided the best representation of ERG overexpression (92%) and PTEN loss (98%). When grades were uniform across cancer sites, the highest tumor volume core was generally representative of ERG overexpression (90%) but was less representative for PTEN loss (76%). Our results suggest that knowledge of this heterogeneity is critical for developing optimal yet cost-effective strategies to identify these underlying molecular abnormalities. Copyright © 2015 Elsevier Inc. All rights reserved.

RAS/ERK modulates TGFβ-regulated PTEN expression in human pancreatic adenocarcinoma cells

OpenAIRE

Chow, Jimmy Y.C.; Quach, Khai T.; Cabrera, Betty L.; Cabral, Jennifer A.; Beck, Stayce E.; Carethers, John M.

2007-01-01

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is rarely mutated in pancreatic cancers, but its regulation by transforming growth factor (TGF)-β might mediate growth suppression and other oncogenic actions. Here, we examined the role of TGFβ and the effects of oncogenic K-RAS/ERK upon PTEN expression in the absence of SMAD4. We utilized two SMAD4-null pancreatic cell lines, CAPAN-1 (K-RAS mutant) and BxPc-3 (WT-K-RAS), both of which express TGFβ surface receptors. Cells were t...

Role of PTEN in the Tumor Microenvironment

Science.gov (United States)

2009-06-01

themselves, as well as the matrix that holds these cells together. Because the entire system is so complex, we plan to study how the Pten gene behaves as...Rev. 17, 501-519 8. Gould HJ, Sutton BJ. (2008). IgE in allergy and asthma today. Nat. Rev. Immunol. 8, 205-217. 9. Granucci F, Petralia F, Urbano M

Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.

Science.gov (United States)

Xu, Xiaoling; Kobayashi, Shogo; Qiao, Wenhui; Li, Cuiling; Xiao, Cuiying; Radaeva, Svetlana; Stiles, Bangyan; Wang, Rui-Hong; Ohara, Nobuya; Yoshino, Tadashi; LeRoith, Derek; Torbenson, Michael S; Gores, Gregory J; Wu, Hong; Gao, Bin; Deng, Chu-Xia

2006-07-01

Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.

Failure of the PTEN/aPKC/Lgl Axis Primes Formation of Adult Brain Tumours in Drosophila

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Simona Paglia

2017-01-01

Full Text Available Different regions in the mammalian adult brain contain immature precursors, reinforcing the concept that brain cancers, such as glioblastoma multiforme (GBM, may originate from cells endowed with stem-like properties. Alterations of the tumour suppressor gene PTEN are very common in primary GBMs. Very recently, PTEN loss was shown to undermine a specific molecular axis, whose failure is associated with the maintenance of the GBM stem cells in mammals. This axis is composed of PTEN, aPKC, and the polarity determinant Lethal giant larvae (Lgl: PTEN loss promotes aPKC activation through the PI3K pathway, which in turn leads to Lgl inhibition, ultimately preventing stem cell differentiation. To find the neural precursors responding to perturbations of this molecular axis, we targeted different neurogenic regions of the Drosophila brain. Here we show that PTEN mutation impacts aPKC and Lgl protein levels also in Drosophila. Moreover, we demonstrate that PI3K activation is not sufficient to trigger tumourigenesis, while aPKC promotes hyperplastic growth of the neuroepithelium and a noticeable expansion of the type II neuroblasts. Finally, we show that these neuroblasts form invasive tumours that persist and keep growing in the adult, leading the affected animals to untimely death, thus displaying frankly malignant behaviours.

An integrative genomic and proteomic analysis of PIK3CA, PTEN and AKT mutations in breast cancer

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Stemke-Hale, Katherine; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Neve, Richard M.; Kuo, Wen-Lin; Davies, Michael; Carey, Mark; Hu, Zhi; Guan, Yinghui; Sahin, Aysegul; Symmans, W. Fraser; Pusztai, Lajos; Nolden, Laura K.; Horlings, Hugo; Berns, Katrien; Hung, Mien-Chie; van de Vijver, Marc J.; Valero, Vicente; Gray, Joe W.; Bernards, Rene; Mills, Gordon B.; Hennessy, Bryan T.

2008-05-06

Phosphatidylinositol-3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT and PTEN mutations, and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in-vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor positive (33.8%) and HER2-positive (24.6%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers with PTEN protein levels also being significantly lower in hormone receptor-positive cancers. Unlike AKT1 mutations, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant impact on outcome in 166 hormone receptor-positive breast cancer patients after adjuvant tamoxifen. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and indeed inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines, and PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss but not PIK3CA mutations rendered cells sensitive to growth inhibition by the PI3K inhibitor LY294002. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

Four MicroRNAs Promote Prostate Cell Proliferation with Regulation of PTEN and Its Downstream Signals In Vitro

Science.gov (United States)

Xue, Jing-lun; Chen, Jin-zhong

2013-01-01

Background Phosphatase and tensin homologue (PTEN), as a tumor suppressor, plays vital roles in tumorigenesis and progression of prostate cancer. However, the mechanisms of PTEN regulation still need further investigation. We here report that a combination of four microRNAs (miR-19b, miR-23b, miR-26a and miR-92a) promotes prostate cell proliferation by regulating PTEN and its downstream signals in vitro. Methodology/Principal Findings We found that the four microRNAs (miRNAs) could effectively suppress PTEN expression by directly interacting with its 3’ UTR in prostate epithelial and cancer cells. Under-expression of the four miRNAs by antisense neutralization up-regulates PTEN expression, while overexpression of the four miRNAs accelerates epithelial and prostate cancer cell proliferation. Furthermore, the expression of the four miRNAs could, singly or jointly, alter the expression of the key components in the phosphoinositide 3-kinase (PI3K)/Akt pathway, including PIK3CA, PIK3CD, PIK3R1 and Akt, along with their downstream signal, cyclin D1. Conclusions These results suggested that the four miRNAs could promote prostate cancer cell proliferation by co-regulating the expression of PTEN, PI3K/Akt pathway and cyclin D1 in vitro. These findings increase understanding of the molecular mechanisms of prostate carcinogenesis and progression, even provide valuable insights into the diagnosis, prognosis, and rational design of novel therapeutics for prostate cancer. PMID:24098737

PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

Science.gov (United States)

Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

2018-01-01

Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

Atorvastatin Inhibits Myocardial Apoptosis in a Swine Model of Coronary Microembolization by Regulating PTEN/PI3K/Akt Signaling Pathway

Directory of Open Access Journals (Sweden)

Jiangyou Wang

2016-01-01

Full Text Available Background/Aims: Phosphatase and tensin homolog deleted on chromosome ten (PTEN has been recognized as a promoter of apoptosis in various tissues, and revealed to be up-regulated in circumstances of coronary microembolization (CME. However, whether this functional protein could be modified by pretreatment of atorvastatin in models of CME has not been disclosed yet. Methods: Swine CME was induced by intra-coronary injection of inertia plastic microspheres (diameter 42 μm into left anterior descending coronary, with or without pretreatment of atorvastatin or PTEN siRNA. Echocardiologic measurements, pathologic examination, TUNEL staining and western blotting were applied to assess their functional, morphological and molecular effects in CME. Results: PTEN were aberrantly up-regulated in cardiomyocytes following CME, with both the mRNA and protein levels increased after CME modeling. Pretreatment with atorvastatin could attenuate the induction of PTEN. Furthermore, down-regulation of PTEN in vivo via siRNA was associated with an improved cardiac function, attenuated myocardial apoptosis, and concomitantly inhibited expressions of key proapoptotic proteins such as Bax, cleaved-caspase-3. Interestingly, atorvastatin could markedly attenuate PTEN expression and therefore partially reverse cardiac dysfunction and attenuate the apoptosis of the myocardium following CME. Conclusion: Modulation of PTEN was probably as a potential mechanism involved in the beneficial effects of pretreatment of atorvastatin to cardiac function and apoptosis in large animal models of CME.

PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

International Nuclear Information System (INIS)

Singh, Alok R.; Peirce, Susan K.; Joshi, Shweta; Durden, Donald L.

2014-01-01

Pattern recognition receptors (PRRs), e.g. toll receptors (TLRs) that bind ligands within the microbiome have been implicated in the pathogenesis of cancer. LPS is a ligand for two TLR family members, TLR4 and RP105 which mediate LPS signaling in B cell proliferation and migration. Although LPS/TLR/RP105 signaling is well-studied; our understanding of the underlying molecular mechanisms controlling these PRR signaling pathways remains incomplete. Previous studies have demonstrated a role for PTEN/PI-3K signaling in B cell selection and survival, however a role for PTEN/PI-3K in TLR4/RP105/LPS signaling in the B cell compartment has not been reported. Herein, we crossed a CD19cre and PTEN fl/fl mouse to generate a conditional PTEN knockout mouse in the CD19+ B cell compartment. These mice were further crossed with an IL-14α transgenic mouse to study the combined effect of PTEN deletion, PI-3K inhibition and expression of IL-14α (a cytokine originally identified as a B cell growth factor) in CD19+ B cell lymphoproliferation and response to LPS stimulation. Targeted deletion of PTEN and directed expression of IL-14α in the CD19+ B cell compartment (IL-14+PTEN-/-) lead to marked splenomegaly and altered spleen morphology at baseline due to expansion of marginal zone B cells, a phenotype that was exaggerated by treatment with the B cell mitogen and TLR4/RP105 ligand, LPS. Moreover, LPS stimulation of CD19+ cells isolated from these mice display increased proliferation, augmented AKT and NFκB activation as well as increased expression of c-myc and cyclinD1. Interestingly, treatment of LPS treated IL-14+PTEN-/- mice with a pan PI-3K inhibitor, SF1126, reduced splenomegaly, cell proliferation, c-myc and cyclin D1 expression in the CD19+ B cell compartment and normalized the splenic histopathologic architecture. These findings provide the direct evidence that PTEN and PI-3K inhibitors control TLR4/RP105/LPS signaling in the CD19+ B cell compartment and that pan PI-3

PTEN and PI-3 kinase inhibitors control LPS signaling and the lymphoproliferative response in the CD19+ B cell compartment

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Singh, Alok R. [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Peirce, Susan K. [Department of Pediatrics, Emory University School of Medicine, Atlanta, GA (United States); Joshi, Shweta [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Durden, Donald L., E-mail: ddurden@ucsd.edu [UCSD Department of Pediatrics, Moores UCSD Cancer Center, University of California School of Medicine, San Diego, CA 92093 (United States); Division of Pediatric Hematology-Oncology, UCSD Rady Children' s Hospital, La Jolla, CA (United States)

2014-09-10

Pattern recognition receptors (PRRs), e.g. toll receptors (TLRs) that bind ligands within the microbiome have been implicated in the pathogenesis of cancer. LPS is a ligand for two TLR family members, TLR4 and RP105 which mediate LPS signaling in B cell proliferation and migration. Although LPS/TLR/RP105 signaling is well-studied; our understanding of the underlying molecular mechanisms controlling these PRR signaling pathways remains incomplete. Previous studies have demonstrated a role for PTEN/PI-3K signaling in B cell selection and survival, however a role for PTEN/PI-3K in TLR4/RP105/LPS signaling in the B cell compartment has not been reported. Herein, we crossed a CD19cre and PTEN{sup fl/fl} mouse to generate a conditional PTEN knockout mouse in the CD19+ B cell compartment. These mice were further crossed with an IL-14α transgenic mouse to study the combined effect of PTEN deletion, PI-3K inhibition and expression of IL-14α (a cytokine originally identified as a B cell growth factor) in CD19+ B cell lymphoproliferation and response to LPS stimulation. Targeted deletion of PTEN and directed expression of IL-14α in the CD19+ B cell compartment (IL-14+PTEN-/-) lead to marked splenomegaly and altered spleen morphology at baseline due to expansion of marginal zone B cells, a phenotype that was exaggerated by treatment with the B cell mitogen and TLR4/RP105 ligand, LPS. Moreover, LPS stimulation of CD19+ cells isolated from these mice display increased proliferation, augmented AKT and NFκB activation as well as increased expression of c-myc and cyclinD1. Interestingly, treatment of LPS treated IL-14+PTEN-/- mice with a pan PI-3K inhibitor, SF1126, reduced splenomegaly, cell proliferation, c-myc and cyclin D1 expression in the CD19+ B cell compartment and normalized the splenic histopathologic architecture. These findings provide the direct evidence that PTEN and PI-3K inhibitors control TLR4/RP105/LPS signaling in the CD19+ B cell compartment and that pan PI

Exosomes promote cetuximab resistance via the PTEN/Akt pathway in colon cancer cells.

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Zhang, S; Zhang, Y; Qu, J; Che, X; Fan, Y; Hou, K; Guo, T; Deng, G; Song, N; Li, C; Wan, X; Qu, X; Liu, Y

2017-11-13

Cetuximab is widely used in patients with metastatic colon cancer expressing wildtype KRAS. However, acquired drug resistance limits its clinical efficacy. Exosomes are nanosized vesicles secreted by various cell types. Tumor cell-derived exosomes participate in many biological processes, including tumor invasion, metastasis, and drug resistance. In this study, exosomes derived from cetuximab-resistant RKO colon cancer cells induced cetuximab resistance in cetuximab-sensitive Caco-2 cells. Meanwhile, exosomes from RKO and Caco-2 cells showed different levels of phosphatase and tensin homolog (PTEN) and phosphor-Akt. Furthermore, reduced PTEN and increased phosphorylated Akt levels were found in Caco-2 cells after exposure to RKO cell-derived exosomes. Moreover, an Akt inhibitor prevented RKO cell-derived exosome-induced drug resistance in Caco-2 cells. These findings provide novel evidence that exosomes derived from cetuximab-resistant cells could induce cetuximab resistance in cetuximab-sensitive cells, by downregulating PTEN and increasing phosphorylated Akt levels.

MicroRNA-22 promotes cell survival upon UV radiation by repressing PTEN

International Nuclear Information System (INIS)

Tan, Guangyun; Shi, Yuling; Wu, Zhao-Hui

2012-01-01

Highlights: ► miR-22 is induced in cells treated with UV radiation. ► ATM is required for miR-22 induction in response to UV. ► miR-22 targets 3′-UTR of PTEN to repress its expression in UV-treated cells. ► Upregulated miR-22 inhibits apoptosis in cells exposed to UV. -- Abstract: DNA damage response upon UV radiation involves a complex network of cellular events required for maintaining the homeostasis and restoring genomic stability of the cells. As a new class of players involved in DNA damage response, the regulation and function of microRNAs in response to UV remain poorly understood. Here we show that UV radiation induces a significant increase of miR-22 expression, which appears to be dependent on the activation of DNA damage responding kinase ATM (ataxia telangiectasia mutated). Increased miR-22 expression may result from enhanced miR-22 maturation in cells exposed to UV. We further found that tumor suppressor gene phosphatase and tensin homolog (PTEN) expression was inversely correlated with miR-22 induction and UV-induced PTEN repression was attenuated by overexpression of a miR-22 inhibitor. Moreover, increased miR-22 expression significantly inhibited the activation of caspase signaling cascade, leading to enhanced cell survival upon UV radiation. Collectively, these results indicate that miR-22 is an important player in the cellular stress response upon UV radiation, which may promote cell survival via the repression of PTEN expression.

Bioinformatics prediction of miR-30a targets and its inhibition of cell proliferation of osteosarcoma by up-regulating the expression of PTEN

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Biao Zhong

2017-11-01

Full Text Available Abstract Background MiRNAs are frequently abnormally expressed in the progression of human osteosarcoma. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN is one of the tumor suppressors in various types of human cancer. In the present study, we detected how hsa-miR-30a-3p regulated PTEN and further tested the role of hsa-miR-30a-3p in the cell proliferation of osteosarcoma cells. Methods The levels of miR-30a were determined by real time PCR. The expression of PTEN was tested by western blotting analysis. Cell distribution of PTEN was observed with confocal laser scanning microscope. Cell viability was determined by MTT assay. Results The expression of miR-30a and PTEN was obviously decreased in MG-63, 143B and Saos-2 cells compared with primary osteoblasts. TargetScan analysis data showed miR-30a might bind with position 30-57 of 3’UTR of PTEN. Transfection with miR-30a-3p increased the level of PTEN in MG-63 cells, while transfection with miR-30a-3p inhibitor significantly decreased the expression of PTEN in osteosarcoma cells. Transfection with miR-30a-3p significantly inhibited cell proliferation of osteosarcoma cells, while miR-30a inhibitor obviously promoted cell viability of MG63 cells and Saos-2 cells. Inhibition of PTEN eliminated the proliferation inhibitory effect of miR-30a-3p. Conclusion Thus, all these findings revealed the anti-tumor effects of miR-30a in human osteosarcoma cells, which could be mediated by regulating the level of PTEN.

PTENp1, a natural sponge of miR-21, mediates PTEN expression to inhibit the proliferation of oral squamous cell carcinoma.

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Gao, Ling; Ren, Wenhao; Zhang, Linmei; Li, Shaoming; Kong, Xinjuan; Zhang, Hao; Dong, Jianwei; Cai, Guangfeng; Jin, Changxiong; Zheng, Danqing; Zhi, Keqian

2017-04-01

PTENp1, non-coding RNA (ncRNA) pseudogene, is involved in oral squamous cell carcinoma (OSCC). The precise effects mediated by PTENp1 transcripts within intricate regulatory networks involving molecular interactions with ancestral gene PTEN and tumorigenicity in OSCC remain unclear. Here, we found that PTENp1 was aberrantly expressed in OSCC. There was a positive correlation between the expression levels of PTENp1 and PTEN. Further, we showed that PTENp1 acted as a competing endogenous RNA that protects PTEN transcripts from being inhibited by miR-21, and consequently inhibited proliferation and colony formation and triggered S-G2/M cell cycle arrest through the AKT pathway. Also, the homogeneous relationship between expression of PTENp1 and PTEN was confirmed in OSCC tumor xenografts. Finally, low expression of PTENp1 and PTEN was negatively associated with histological differentiation and OSCC prognosis. The present work provided the first evidence for the extraordinary crosstalk among PTENp1, PTEN, and miR-21, and rendered a new light on the treatment of OSCC. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Molecular Mechanism of Nkx3.1 Deregulation and its Function in Murine Pten Prostate Cancer Model

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2006-09-01

One possible explanation is that Pten null cells have become ‘‘ addicted ’’ to high levels of PI3K/AKT activity and, consequently, are hypersensitive...H.H., Kertesz, N., Lesche, R., Whale , A.D., Martinez-Diaz, H., Rozengurt, N., Cardiff, R.D., et al. (2003). PTEN tumor suppressor regulates p53 protein

Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

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Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

2014-11-01

Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

Variable laterality of corticospinal tract axons that regenerate after spinal cord injury as a result of PTEN deletion or knock-down

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Willenberg, Rafer; Zukor, Katherine; Liu, Kai; He, Zhigang; Steward, Oswald

2016-01-01

Corticospinal tract (CST) axons from one hemisphere normally extend and terminate predominantly in the contralateral spinal cord. We previously showed that deleting PTEN in the sensorimotor cortex enables CST axons to regenerate after spinal cord injury and that some regenerating axons extend along the “wrong” side. Here, we characterize the degree of specificity of regrowth in terms of laterality. PTEN was selectively deleted via cortical AAV-Cre injections in neonatal PTEN-floxed mice. As adults, mice received dorsal hemisection injuries at T12 or complete crush injuries at T9. CST axons from one hemisphere were traced by unilateral BDA injections in PTEN-deleted mice with spinal cord injury and in non-injured PTEN-floxed mice that had not received AAV-Cre. In non-injured mice, 97.9 ± 0.7% of BDA-labeled axons in white matter and 88.5 ± 1.0% of BDA-labeled axons in grey matter were contralateral to the cortex of origin. In contrast, laterality of CST axons that extended past a lesion due to PTEN deletion varied across animals. In some cases, regenerated axons extended predominantly on the ipsilateral side, in other cases, axons extended predominantly contralaterally, and in others, axons were similar in numbers on both sides. Similar results were seen in analyses of cases from previous studies using shRNA-mediated PTEN knock-down. These results indicate that CST axons that extend past a lesion due to PTEN deletion or knock-down do not maintain the contralateral rule of the non-injured CST, highlighting one aspect for how resultant circuitry from regenerating axons may differ from that of the uninjured CST. PMID:26878190

Role of PTEN in the Tumor Microenvironment

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2010-06-01

fibroblasts (Fig. 2f, g), presumably owing to the constitutive Pten-independent activation of Erk1/2 by serum -stimulation23. Among the many expression...and provide rigorous validation proof. Using man- ual ground- truth , we compare the performance of the tensor classification framework with the k...tive hues in the standard H&E histological staining protocol. In an earlier effort, Pan and Huang (2005) devised a Bayesian supervised segmentation

Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis.

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Tabrizian, Tahmineh; Wang, Donghai; Guan, Fangxia; Hu, Zunju; Beck, Amanda P; Delahaye, Fabien; Huffman, Derek M

2017-06-01

Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of Apc However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP- Pten flox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific, Apc- and Pten -deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU-positive cells in the small intestine ( P  Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion ( P  Apc deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis. © 2017 Society for Endocrinology.

MiR-20a Induces Cell Radioresistance by Activating the PTEN/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma

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Zhang, Yuqin; Zheng, Lin; Ding, Yi; Li, Qi; Wang, Rong; Liu, Tongxin; Sun, Quanquan; Yang, Hua; Peng, Shunli; Wang, Wei; Chen, Longhua

2015-01-01

Purpose: To investigate the role of miR-20a in hepatocellular carcinoma (HCC) cell radioresistance, which may reveal potential strategies to improve treatment. Methods and Materials: The expression of miR-20a and PTEN were detected in HCC cell lines and paired primary tissues by quantitative real-time polymerase chain reaction. Cell radiation combined with colony formation assays was administrated to discover the effect of miR-20a on radiosensitivity. Bioinformatics prediction and luciferase assay were used to identify the target of miR-20a. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit phosphorylation of Akt, to verify whether miR-20a affects HCC cell radioresistance through activating the PTEN/PI3K/Akt pathway. Results: MiR-20a levels were increased in HCC cell lines and tissues, whereas PTEN was inversely correlated with it. Overexpression of miR-20a in Bel-7402 and SMMC-7721 cells enhances their resistance to the effect of ionizing radiation, and the inhibition of miR-20a in HCCLM3 and QGY-7701 cells sensitizes them to it. PTEN was identified as a direct functional target of miR-20a for the induction of radioresistance. Overexpression of miR-20a activated the PTEN/PI3K/Akt signaling pathway. Additionally, the kinase inhibitor LY294002 could reverse the effect of miR-20a–induced radioresistance. Conclusion: MiR-20a induces HCC cell radioresistance by activating the PTEN/PI3K/Akt pathway, which suggests that miR-20a/PTEN/PI3K/Akt might represent a target of investigation for developing effective therapeutic strategies against HCC

TGF-β1 stimulates migration of type II endometrial cancer cells by down-regulating PTEN via activation of SMAD and ERK1/2 signaling pathways.

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Xiong, Siyuan; Cheng, Jung-Chien; Klausen, Christian; Zhao, Jianfang; Leung, Peter C K

2016-09-20

PTEN acts as a tumor suppressor primarily by antagonizing the PI3K/AKT signaling pathway. PTEN is frequently mutated in human cancers; however, in type II endometrial cancers its mutation rate is very low. Overexpression of TGF-β1 and its receptors has been reported to correlate with metastasis of human cancers and reduced survival rates. Although TGF-β1 has been shown to regulate PTEN expression through various mechanisms, it is not yet known if the same is true in type II endometrial cancer. In the present study, we show that treatment with TGF-β1 stimulates the migration of two type II endometrial cancer cell lines, KLE and HEC-50. In addition, TGF-β1 treatment down-regulates both mRNA and protein levels of PTEN. Overexpression of PTEN or inhibition of PI3K abolishes TGF-β1-stimulated cell migration. TGF-β1 induces SMAD2/3 phosphorylation and knockdown of common SMAD4 inhibits the suppressive effects of TGF-β1 on PTEN mRNA and protein. Interestingly, TGF-β1 induces ERK1/2 phosphorylation and pre-treatment with a MEK inhibitor attenuates the suppression of PTEN protein, but not mRNA, by TGF-β1. This study provides important insights into the molecular mechanisms mediating TGF-β1-induced down-regulation of PTEN and demonstrates an important role of PTEN in the regulation of type II endometrial cancer cell migration.

Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.

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Weston, Matthew C; Chen, Hongmei; Swann, John W

2014-01-01

The Pten and Tsc1 genes both encode proteins that repress mechanistic target of rapamycin (mTOR) signaling. Disruption of either gene in the brain results in epilepsy and autism-like symptoms in humans and mouse models, therefore it is important to understand the molecular and physiological events that lead from gene disruption to disease phenotypes. Given the similar roles these two molecules play in the regulation of cellular growth and the overlap in the phenotypes that result from their loss, we predicted that the deletion of either the Pten or Tsc1 gene from autaptic hippocampal neurons would have similar effects on neuronal morphology and synaptic transmission. Accordingly, we found that loss of either Pten or Tsc1 caused comparable increases in soma size, dendrite length and action potential properties. However, the effects of Pten and Tsc1 loss on synaptic transmission were different. Loss of Pten lead to an increase in both excitatory and inhibitory neurotransmission, while loss of Tsc1 did not affect excitatory neurotransmission and reduced inhibitory transmission by decreasing mIPSC amplitude. Although the loss of Pten or Tsc1 both increased downstream mTORC1 signaling, phosphorylation of Akt was increased in Pten-ko and decreased in Tsc1-ko neurons, potentially accounting for the different effects on synaptic transmission. Despite the different effects at the synaptic level, our data suggest that loss of Pten or Tsc1 may both lead to an increase in the ratio of excitation to inhibition at the network level, an effect that has been proposed to underlie both epilepsy and autism.

C-reactive protein inhibits survivin expression via Akt/mTOR pathway downregulation by PTEN expression in cardiac myocytes.

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Beom Seob Lee

Full Text Available C-reactive protein (CRP is one of the most important biomarkers for arteriosclerosis and cardiovascular disease. Recent studies have shown that CRP affects cell cycle and inflammatory process in cardiac myocytes. Survivin is also involved in cardiac myocytes replication and apoptosis. Reduction of survivin expression is associated with less favorable cardiac remodeling in animal models. However, the effect of CRP on survivin expression and its cellular mechanism has not yet been studied. We demonstrated that treatment of CRP resulted in a significant decrease of survivin protein expression in a concentration-dependent manner in cardiac myocytes. The upstream signaling proteins of survivin, such as Akt, mTOR and p70S6K, were also downregulated by CRP treatment. In addition, CRP increased the protein and mRNA levels of PTEN. The siRNA transfection or specific inhibitor treatment for PTEN restored the CRP-induced downregulation of Akt/mTOR/p70S6K pathway and survivin protein expression. Moreover, pretreatment with a specific p53 inhibitor decreased the CRP-induced PTEN expression. ERK-specific inhibitor also blocked the p53 phosphorylation and PTEN expression induced by CRP. Our study provides a novel insight into CRP-induced downregulation of survivin protein expression in cardiac myocytes through mechanisms that involved in downregulation of Akt/mTOR/p70S6K pathway by expression of PTEN.

A multicenter study shows PTEN deletion is strongly associated with seminal vesicle involvement and extracapsular extension in localized prostate cancer.

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Troyer, Dean A; Jamaspishvili, Tamara; Wei, Wei; Feng, Ziding; Good, Jennifer; Hawley, Sarah; Fazli, Ladan; McKenney, Jesse K; Simko, Jeff; Hurtado-Coll, Antonio; Carroll, Peter R; Gleave, Martin; Lance, Raymond; Lin, Daniel W; Nelson, Peter S; Thompson, Ian M; True, Lawrence D; Brooks, James D; Squire, Jeremy A

2015-08-01

Loss of the phosphatase and tensin homolog (PTEN) tumor suppressor gene is a promising marker of aggressive prostate cancer. Active surveillance and watchful waiting are increasingly recommended to patients with small tumors felt to be low risk, highlighting the difficulties of Gleason scoring in this setting. There is an urgent need for predictive biomarkers that can be rapidly deployed to aid in clinical decision-making. Our objectives were to assess the incidence and ability of PTEN alterations to predict aggressive disease in a multicenter study. We used recently developed probes optimized for sensitivity and specificity in a four-color FISH deletion assay to study the Canary Retrospective multicenter Prostate Cancer Tissue Microarray (TMA). This TMA was constructed specifically for biomarker validation from radical prostatectomy specimens, and is accompanied by detailed clinical information with long-term follow-up. In 612 prostate cancers, the overall rate of PTEN deletion was 112 (18.3%). Hemizygous PTEN losses were present in 55/612 (9.0%) of cancers, whereas homozygous PTEN deletion was observed in 57/612 (9.3%) of tumors. Significant associations were found between PTEN status and pathologic stage (P free survival (number of events = 189), pre-operative prostate specific antigen (PSA) (P free survival in multivariate models, as were seminal vesicle invasion, extracapsular extension, and Gleason score, and preoperative PSA. Furthermore, these data demonstrate that the assay can be readily introduced at first diagnosis in a cost effective manner analogous to the use of FISH for analysis of HER2/neu status in breast cancer. Combined with published research beginning 17 years ago, both the data and tools now exist to implement a PTEN assay in the clinic. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc.

Loss of Cdh1 and Pten Accelerates Cellular Invasiveness and Angiogenesis in the Mouse Uterus1

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Lindberg, Mallory E.; Stodden, Genna R.; King, Mandy L.; MacLean, James A.; Mann, Jordan L.; DeMayo, Francesco J.; Lydon, John P.; Hayashi, Kanako

2013-01-01

ABSTRACT E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1d/d Ptend/d) in the mouse uterus. We observed that Cdh1d/d Ptend/d mice died at Postnatal Days 15–19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1d/d Ptend/d mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1d/d Ptend/d mice. However, complex hyperplasia was not found in the uteri of Cdh1d/d Ptend/d mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death. PMID:23740945

Assessing PIK3CA and PTEN in Early-Phase Trials with PI3K/AKT/mTOR Inhibitors

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Filip Janku

2014-01-01

Full Text Available Despite a wealth of preclinical studies, it is unclear whether PIK3CA or phosphatase and tensin homolog (PTEN gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CA or PTEN abnormalities, PIK3CA mutations were found in 9% (146/1,589, and PTEN loss and/or mutation was found in 13% (149/1,157. In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K/AKT/mammalian target of rapamycin (mTOR inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CA or PTEN aberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CA mutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.

Diffuse Gastric Ganglioneuromatosis: Novel Presentation of PTEN Hamartoma Syndrome—Case Report and Review of Gastric Ganglioneuromatous Proliferations and a Novel PTEN Gene Mutation

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Alexander J. Williams

2018-01-01

Full Text Available Gastrointestinal ganglioneuromatous proliferations are rare, most often found in the colon, and are three types: polypoid ganglioneuromas, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. We present a case of diffuse ganglioneuromatosis in the posterior gastric wall in a nine-year-old female. To our knowledge, this is the first reported case of diffuse ganglioneuromatosis located in the stomach. Only six cases of gastric ganglioneuromatous proliferations have previously been reported, two in English and none were diffuse ganglioneuromatosis. A diagnosis of diffuse ganglioneuromatosis is relevant for patient care because, unlike sporadic polypoid ganglioneuromas or ganglioneuromatous polyposis, most are syndromic. Diffuse ganglioneuromatosis is commonly associated with neurofibromatosis type 1, multiple endocrine neoplasia type 2b, and Cowden Syndrome, one of the phenotypes of PTEN hamartoma tumor syndrome. The patient had the noted gastric diffuse ganglioneuromatosis, as well as other major and minor criteria for Cowden syndrome. Genetic testing revealed a novel frameshift mutation in the PTEN gene in the patient, her father, paternal aunt, and the aunt’s son who is a paternal first cousin of the patient.

Effects of AdR-siPTEN on learning capability, memory and ...

African Journals Online (AJOL)

USER

2010-07-12

Jul 12, 2010 ... protein expression of a phosphatase and tensin homolog deleted on chromosome 10 (PTEN), ... disease (AD) and refers to a step-wise deterioration in cognitive ..... Pappas BA, de la Torre JC, Davidson CM (1996).Chronic ...

Potential value of PTEN in predicting cetuximab response in colorectal cancer: An exploratory study

International Nuclear Information System (INIS)

Razis, Evangelia; Galanidi, Eleni; Bai, Maria; Gikonti, Ioanna; Koukouma, Alona; Kafiri, Georgia; Papakostas, Pavlos; Kalogeras, Konstantine T; Kosmidis, Paris; Fountzilas, George; Briasoulis, Evangelos; Vrettou, Eleni; Skarlos, Dimosthenis V; Papamichael, Dimitrios; Kostopoulos, Ioannis; Samantas, Epaminontas; Xanthakis, Ioannis; Bobos, Mattheos

2008-01-01

The epidermal growth factor receptor (EGFR) is over-expressed in 70–75% of colorectal adenocarcinomas (CRC). The anti-EGFR monoclonal antibody cetuximab has been approved for the treatment of metastatic CRC, however tumor response to cetuximab has not been found to be associated with EGFR over-expression by immunohistochemistry (IHC). The aim of this study was to explore EGFR and the downstream effector phosphatase and tensin homologue deleted on chromosome 10 (PTEN) as potential predictors of response to cetuximab. CRC patients treated with cetuximab by the Hellenic Cooperative Oncology group, whose formalin-fixed paraffin-embedded tumor tissue was available, were included. Tissue was tested for EGFR and PTEN by IHC and fluorescence in situ hybridization (FISH). Eighty-eight patients were identified and 72 were included based on the availability of tissue blocks with adequate material for analysis on them. All patients, except one, received cetuximab in combination with chemotherapy. Median follow-up was 53 months from diagnosis and 17 months from cetuximab initiation. At the time of the analysis 53% of the patients had died. Best response was complete response in one and partial response in 23 patients. In 16 patients disease stabilized. Lack of PTEN gene amplification was associated with more responses to cetuximab and longer time to progression (p = 0.042). PTEN could be one of the molecular determinants of cetuximab response. Due to the heterogeneity of the population and the retrospective nature of the study, our results are hypothesis generating and should be approached with caution. Further prospective studies are needed to validate this finding

A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

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Arvai, Kevin J; Hsu, Ya-Hsuan; Lee, Lobin A; Jones, Dan

2015-01-01

Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC). These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC. We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β) growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC) markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5%) but not in tumors with downregulated but non-alternating PTEN expression (14.3%). There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases. In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt/β-catenin pathways. This

A Transition Zone Showing Highly Discontinuous or Alternating Levels of Stem Cell and Proliferation Markers Characterizes the Development of PTEN-Haploinsufficient Colorectal Cancer.

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Kevin J Arvai

Full Text Available Stepwise acquisition of oncogene mutations and deletion/inactivation of tumor suppressor genes characterize the development of colorectal cancer (CRC. These genetic events interact with discrete morphologic transitions from hyperplastic mucosa to adenomatous areas, followed by in situ malignant transformation and finally invasive carcinoma. The goal of this study was to identify tissue markers of the adenoma-carcinoma morphogenetic transitions in CRC.We analyzed the patterns of expression of growth regulatory and stem cell markers across these distinct morphologic transition zones in 735 primary CRC tumors. In 202 cases with preserved adenoma-adenocarcinoma transition, we identified, in 37.1% of cases, a zone of adenomatous epithelium, located immediately adjacent to the invasive component, that showed rapidly alternating intraglandular stretches of PTEN+ and PTEN- epithelium. This zone exactly overlapped with similar alternating expression of Ki-67 and inversely with the transforming growth factor-beta (TGF-β growth regulator SMAD4. These zones also show parallel alternating levels and/or subcellular localization of multiple cancer stem/progenitor cell (CSC markers, including β-catenin/CTNNB1, ALDH1, and CD44. PTEN was always re-expressed in the invasive tumor in these cases, unlike those with complete loss of PTEN expression. Genomic microarray analysis of CRC with prominent CSC-like expansions demonstrated a high frequency of PTEN genomic deletion/haploinsufficiency in tumors with CSC-like transition zones (62.5% but not in tumors with downregulated but non-alternating PTEN expression (14.3%. There were no significant differences in the levels of KRAS mutation or CTNNB1 mutation in CSC-like tumors as compared to unselected CRC cases.In conclusion, we have identified a distinctive CSC-like pre-invasive transition zone in PTEN-haploinsufficient CRC that shows convergent on-off regulation of the PTEN/AKT, TGF-β/SMAD and Wnt

von Neumann Morgenstern Preferences

DEFF Research Database (Denmark)

Vind, Karl

von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems......von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems...

von Neumann Morgenstern Preferences

DEFF Research Database (Denmark)

Vind, Karl

2000-01-01

von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems......von Neumann Morgenstern utility is generalized to von Neumann Morgenstern preferences. The proof is an application of simple hyperplane theorems...

Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice

OpenAIRE

Xu, Xiaoling; Kobayashi, Shogo; Qiao, Wenhui; Li, Cuiling; Xiao, Cuiying; Radaeva, Svetlana; Stiles, Bangyan; Wang, Rui-Hong; Ohara, Nobuya; Yoshino, Tadashi; LeRoith, Derek; Torbenson, Michael S.; Gores, Gregory J.; Wu, Hong; Gao, Bin

2006-01-01

Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from ...

MiR-21/PTEN Axis Promotes Skin Wound Healing by Dendritic Cells Enhancement.

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Han, Zhaofeng; Chen, Ya; Zhang, Yile; Wei, Aizhou; Zhou, Jian; Li, Qian; Guo, Lili

2017-10-01

A number of miRNAs associated with wound repair have been identified and characterized, but the mechanism has not been fully clarified. MiR-21 is one of wound-related lncRNAs, and the study aimed to explore the functional involvement of miR-21 and its concrete mechanism in wound healing. In this study, the rat model of skin wounds was established. The expression of miR-21, PTEN and related molecules of wound tissues or cells was determined by quantitative real-time PCR and Western blot, respectively. The regulatory role of miR-21 on PTEN was examined by luciferase reporter gene assay. Flow cytometry assay was applied to measure cell number changes. MiR-21 was upregulated at 6, 24, 48, 72 h after model establishment, and the increase reached a maximum at 24 h in wound tissues. MMP-9 expression presented the same tread as miR-21 and was significantly enhanced within 6 h of wound formation, and then remained to be increased to the maximum at 24 h. The increase of miR-21 was accompanied by the increase of cell total number and DCs ratio in wound fluids. MiR-21 overexpression significantly improved the healing of skin wounds and increased the ratio of DCs in rats. The results of using FL confirmed that miR-21 overexpression obviously promoted DCs differentiation. Additionally, miR-21 could activate AKT/PI3K signaling pathway via inhibition of PTEN. MiR-21 contributes to wound healing via inhibition of PTEN that activated AKT/PI3K signaling pathway to increase DCs. J. Cell. Biochem. 118: 3511-3519, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

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Fernández, S; Genis, L; Torres-Alemán, I

2014-08-07

Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

Increased plasma levels of FABP4 and PTEN is associated with more severe insulin resistance in women with gestational diabetes mellitus.

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Li, Yuan-yuan; Xiao, Rui; Li, Cai-ping; Huangfu, Jian; Mao, Jiang-feng

2015-02-08

The aim of this study was to investigate the relationship between plasma fatty acid binding protein 4 (FABP4), phosphatase and tensin homolog (PTEN), and insulin resistance in patients with gestational diabetes mellitus (GDM). Plasma FABP4 and PTEN were determined by ELISA in GDM patients (GDM group, n=30) and in euglycemic pregnant women (control group, n=30). The clinical features, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and lipid profiles were compared between the 2 groups. The influence of risk factors on insulin resistance, including BMI, lipid profiles, FABP4, and PTEN, were further investigated by multiple-factor stepwise regression analysis. Higher levels of BMI, ΔBMI, triglyceride (TG), fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), fasting insulin, HOMA-IR, FABP4, PTEN, and lower level of high-density lipoprotein cholesterol (HDL-C) were found in the GDM patients than in the controls (all Pinsulin resistance. GDM patients have more severe insulin resistance compared to euglycemic pregnant women. Higher levels of plasma FABP4 and PTEN are associated with increased insulin resistance and may participate in the pathogenesis of insulin resistance during gestation.

Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer.

Science.gov (United States)

Kluth, Martina; Runte, Frederic; Barow, Philipp; Omari, Jazan; Abdelaziz, Zaid M; Paustian, Lisa; Steurer, Stefan; Christina Tsourlakis, Maria; Fisch, Margit; Graefen, Markus; Tennstedt, Pierre; Huland, Hartwig; Michl, Uwe; Minner, Sarah; Sauter, Guido; Simon, Ronald; Adam, Meike; Schlomm, Thorsten

2015-11-15

The deletion of 16q23-q24 belongs to the most frequent chromosomal changes in prostate cancer, but the clinical consequences of this alteration have not been studied in detail. We performed fluorescence in situ hybridization analysis using a 16q23 probe in more than 7,400 prostate cancers with clinical follow-up data assembled in a tissue microarray format. Chromosome 16q deletion was found in 21% of cancers, and was linked to advanced tumor stage, high Gleason grade, accelerated cell proliferation, the presence of lymph node metastases (p Deletion was more frequent in ERG fusion-positive (27%) as compared to ERG fusion-negative cancers (16%, p deletions including phosphatase and tensin homolog (PTEN) (p deletion of 16q was linked to early biochemical recurrence independently from the ERG status (p deletion of 16q alone. Multivariate modeling revealed that the prognostic value of 16q/PTEN deletion patterns was independent from the established prognostic factors. In summary, the results of our study demonstrate that the deletion of 16q and PTEN cooperatively drives prostate cancer progression, and suggests that deletion analysis of 16q and PTEN could be of important clinical value particularly for preoperative risk assessment of the clinically most challenging group of low- and intermediated grade prostate cancers. © 2015 UICC.

Supplementary data: Variation in the PTEN-induced putative kinase ...

Indian Academy of Sciences (India)

Variation in the PTEN-induced putative kinase 1 gene associated with the increase risk of type 2 diabetes in northern Chinese. Yanchun Qu, Liang Sun, Ze Yang and Ruifa Han. J. Genet. 90, 125–128. Table 1. Clinical characteristics of cases and controls. Phenotype. T2DM. Controls. P value. Age (years). 49.5 ± 11.1. 50.4 ± ...

Melittin restores PTEN expression by down-regulating HDAC2 in human hepatocelluar carcinoma HepG2 cells.

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Hui Zhang

Full Text Available Melittin is a water-soluble toxic peptide derived from the venom of the bee. Although many studies show the anti-tumor activity of melittin in human cancer including glioma cells, the underlying mechanisms remain elusive. Here the effect of melittin on human hepatocelluar carcinoma HepG2 cell proliferation in vitro and further mechanisms was investigated. We found melittin could inhibit cell proliferation in vitro using Flow cytometry and MTT method. Besides, we discovered that melittin significantly downregulated the expressions of CyclinD1 and CDK4. Results of western Blot and Real-time PCR analysis indicated that melittin was capable to upregulate the expression of PTEN and attenuate histone deacetylase 2 (HDAC2 expression. Further studies demonstrated that knockdown of HDAC2 completely mimicked the effects of melittin on PTEN gene expression. Conversely, it was that the potential utility of melittin on PTEN expression was reversed in cells treated with a recombinant pEGFP-C2-HDAC2 plasmid. In addition, treatment with melittin caused a downregulation of Akt phosphorylation, while overexpression of HDAC2 promoted Akt phosphorylation. These findings suggested that the inhibitory of cell growth by melittin might be led by HDAC2-mediated PTEN upregulation, Akt inactivation, and inhibition of the PI3K/Akt signaling pathways.

The safe use of a PTEN inhibitor for the activation of dormant mouse primordial follicles and generation of fertilizable eggs.

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Deepak Adhikari

Full Text Available Primordial ovarian follicles, which are often present in the ovaries of premature ovarian failure (POF patients or are cryopreserved from the ovaries of young cancer patients who are undergoing gonadotoxic anticancer therapies, cannot be used to generate mature oocytes for in vitro fertilization (IVF. There has been very little success in triggering growth of primordial follicles to obtain fertilizable oocytes due to the poor understanding of the biology of primordial follicle activation.We have recently reported that PTEN (phosphatase and tensin homolog deleted on chromosome ten prevents primordial follicle activation in mice, and deletion of Pten from the oocytes of primordial follicles leads to follicular activation. Consequently, the PTEN inhibitor has been successfully used in vitro to activate primordial follicles in both mouse and human ovaries. These results suggest that PTEN inhibitors could be used in ovarian culture medium to trigger the activation of primordial follicle. To study the safety and efficacy of the use of such inhibitors, we activated primordial follicles from neonatal mouse ovaries by transient treatment with a PTEN inhibitor bpV(HOpic. These ovaries were then transplanted under the kidney capsules of recipient mice to generate mature oocytes. The mature oocytes were fertilized in vitro and progeny mice were obtained after embryo transfer.Long-term monitoring up to the second generation of progeny mice showed that the mice were reproductively active and were free from any overt signs or symptoms of chronic illnesses. Our results indicate that the use of PTEN inhibitors could be a safe and effective way of generating mature human oocytes for use in novel IVF techniques.

PTEN differentially regulates expressions of ICAM-1 and VCAM-1 through PI3K/Akt/GSK-3β/GATA-6 signaling pathways in TNF-α-activated human endothelial cells.

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Tsoyi, Konstantin; Jang, Hwa Jin; Nizamutdinova, Irina Tsoy; Park, Kyungok; Kim, Young Min; Kim, Hye Jung; Seo, Han Geuk; Lee, Jae Heun; Chang, Ki Churl

2010-11-01

Phosphotase and tensin homolog deleted on chromosome 10 (PTEN) is a potent negative regulator of PI3K/Akt pathway. Here, we tried to elucidate the role of PTEN in the regulation of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intracellular adhesion molecule (ICAM)-1, induced by TNF-α in human endothelial cells (ECs). Transfection with PTEN overexpressing vector resulted in the significant decrease in phosphorylation of Akt in TNF-α-treated ECs. PTEN strongly inhibited VCAM-1 but not ICAM-1, however this inhibitory effect was reversed by co-transfection with constitutively active-Akt (CA-Akt-HA) in TNF-α-stimulated ECs. Additionally, silencing of PTEN with specific siRNA showed significant increase of phosphor-Akt compared with TNF-α alone treated ECs. siPTEN significantly upregulated VCAM-1 but was indifferent to ICAM-1 in TNF-α-treated cells. Further, chromatin immunoprecipitation (ChIP) assay showed that PTEN targets GATA-6 but not IRF-1 binding to VCAM-1 promoter. In addition, GATA-6 is associated with glycogen synthesis kinase-3beta (GSK-3β) which is in turn regulated by PTEN-dependent Akt activity. Finally, PTEN significantly prevented monocyte adhesion to TNF-α-induced ECs probably through VCAM-1 regulation. It is concluded that PTEN selectively inhibits expression of VCAM-1 but not ICAM-1 through modulation of PI3K/Akt/GSK-3β/GATA-6 signaling cascade in TNF-α-treated ECs. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy.

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José A Del Campo

Full Text Available Hepatitis C virus (HCV infection has been related to increased risk of development of hepatocellular carcinoma (HCC while metformin (M and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP and phosphatase and tensin homolog (PTEN proteins while M inhibited mammalian target of rapamycin (mTOR and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.

Characterization of Heterogeneous Prostate Tumors in Targeted Pten Knockout Mice.

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Hanneke Korsten

Full Text Available Previously, we generated a preclinical mouse prostate tumor model based on PSA-Cre driven inactivation of Pten. In this model homogeneous hyperplastic prostates (4-5m developed at older age (>10m into tumors. Here, we describe the molecular and histological characterization of the tumors in order to better understand the processes that are associated with prostate tumorigenesis in this targeted mouse Pten knockout model. The morphologies of the tumors that developed were very heterogeneous. Different histopathological growth patterns could be identified, including intraductal carcinoma (IDC, adenocarcinoma and undifferentiated carcinoma, all strongly positive for the epithelial cell marker Cytokeratin (CK, and carcinosarcomas, which were negative for CK. IDC pattern was already detected in prostates of 7-8 month old mice, indicating that it could be a precursor stage. At more than 10 months IDC and carcinosarcoma were most frequently observed. Gene expression profiling discriminated essentially two molecular subtypes, denoted tumor class 1 (TC1 and tumor class 2 (TC2. TC1 tumors were characterized by high expression of epithelial markers like Cytokeratin 8 and E-Cadherin whereas TC2 tumors showed high expression of mesenchyme/stroma markers such as Snail and Fibronectin. These molecular subtypes corresponded with histological growth patterns: where TC1 tumors mainly represented adenocarcinoma/intraductal carcinoma, in TC2 tumors carcinosarcoma was the dominant growth pattern. Further molecular characterization of the prostate tumors revealed an increased expression of genes associated with the inflammatory response. Moreover, functional markers for senescence, proliferation, angiogenesis and apoptosis were higher expressed in tumors compared to hyperplasia. The highest expression of proliferation and angiogenesis markers was detected in TC2 tumors. Our data clearly showed that in the genetically well-defined PSA-Cre;Pten-loxP/loxP prostate tumor

PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma

NARCIS (Netherlands)

Boelens, M.C.; Nethe, M.; Klarenbeek, S.; de Ruiter, J.R.; Schut, E.; Bonzanni, N.; Zeeman, A.L.; Wientjens, E.; van der Burg, E.; Wessels, L.; van Amerongen, R.; Jonkers, J.

2016-01-01

Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary

Doença de von Willebrand e anestesia Enfermedad de von Willebrand y anestesia Von Willebrand's disease and anesthesia

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Fabiano Timbó Barbosa

2007-06-01

Full Text Available JUSTIFICATIVA E OBJETIVOS: A doença de von Willebrand ocorre devido à mutação no cromossomo 12 e é caracterizada por deficiência qualitativa ou quantitativa do fator de von Willebrand. A diversidade de mutações leva ao aparecimento das mais variadas manifestações clínicas possibilitando a divisão dos pacientes em vários tipos e subtipos clínicos. A coagulopatia se manifesta basicamente através da disfunção plaquetária associada à diminuição dos níveis séricos do fator VIII coagulante. O objetivo dessa revisão foi mostrar os cuidados relacionados aos pacientes portadores da doença de von Willebrand durante o período perioperatório. CONTEÚDO: Foram definidas as características da doença de von Willebrand quanto à fisiopatologia, à classificação, ao diagnóstico laboratorial, ao tratamento atual e aos cuidados com o manuseio do paciente no período perioperatório. CONCLUSÕES: A doença de von Willebrand é o distúrbio hemorrágico hereditário mais comum, porém ela é subdiagnosticada pela complexidade da própria doença. A correta classificação do paciente, o uso apropriado da desmopressina e a transfusão do fator de von Willebrand são medidas fundamentais para a realização do procedimento anestésico bem-sucedido.JUSTIFICATIVA Y OBJETIVOS: La enfermedad de von Willebrand ocurre debido a la mutación en el cromosoma 12 y se caracteriza por la deficiencia cualitativa o cuantitativa del factor de von Willebrand. La diversidad de mutaciones conlleva al aparecimiento de las más variadas manifestaciones clínicas posibilitando la división de los pacientes en varios tipos y subtipos clínicos. La coagulopatía se manifiesta básicamente a través de la disfunción plaquetaria asociada con la disminución de los niveles séricos del factor VIII coagulante. El objetivo de esa revisión fue mostrar los cuidados relacionados con las pacientes portadoras de la enfermedad de von Willebrand durante el per

Voltage-sensing phosphatase: its molecular relationship with PTEN.

Science.gov (United States)

Okamura, Yasushi; Dixon, Jack E

2011-02-01

Voltage-sensing phosphoinositide phosphatase (VSP) contains voltage sensor and cytoplasmic phosphatase domains. A unique feature of this protein is that depolarization-induced motions of the voltage sensor activate PtdIns(3,4,5)P(3) and PtdIns(4,5)P(2) phosphatase activities. VSP exhibits remarkable structural similarities with PTEN, the phosphatase and tensin homolog deleted on chromosome 10. These similarities include the cytoplasmic phosphatase region, the phosphoinositide binding region, and the putative membrane interacting C2 domain.

Homozygous deletion and expression of PTEN and DMBT1 in human primary neuroblastoma and cell lines.

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Muñoz, Jorge; Lázcoz, Paula; Inda, María Mar; Nistal, Manuel; Pestaña, Angel; Encío, Ignacio J; Castresana, Javier S

2004-05-01

Neuroblastoma is the most common pediatric solid tumor. Although many allelic imbalances have been described, a bona fide tumor suppressor gene for this disease has not been found yet. In our study, we analyzed 2 genes, PTEN and DMBT1, mapping 10q23.31 and 10q25.3-26.1, respectively, which have been found frequently altered in other kinds of neoplasms. We screened both genes for homozygous deletions in 45 primary neuroblastic tumors and 12 neuroblastoma cell lines. Expression of these genes in cell lines was assessed by RT-PCR analysis. We could detect 2 of 41 (5%) primary tumors harboring PTEN homozygous deletions. Three of 41 (7%) primary tumors and 2 of 12 cell lines presented homozygous losses at the g14 STS on the DMBT1 locus. All cell lines analyzed expressed PTEN, but lack of DMBT1 mRNA expression was detected in 2 of them. We tried to see whether epigenetic mechanisms, such as aberrant promoter hypermethylation, had any role in DMBT1 silencing. The 2 cell lines lacking DMBT1 expression were treated with 5-aza-2'-deoxycytidine; DMBT1 expression was restored in only one of them (MC-IXC). From our work, we can conclude that PTEN and DMBT1 seem to contribute to the development of a small fraction of neuroblastomas, and that promoter hypermethylation might have a role in DMBT1 gene silencing. Copyright 2004 Wiley-Liss, Inc.

PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma

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Mirjam C. Boelens

2016-08-01

Full Text Available Invasive lobular carcinoma (ILC is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC, the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC. Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development. These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling. In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K signaling as a potential therapeutic strategy for targeting CLC.

Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis.

Science.gov (United States)

Darido, Charbel; Georgy, Smitha R; Wilanowski, Tomasz; Dworkin, Sebastian; Auden, Alana; Zhao, Quan; Rank, Gerhard; Srivastava, Seema; Finlay, Moira J; Papenfuss, Anthony T; Pandolfi, Pier Paolo; Pearson, Richard B; Jane, Stephen M

2011-11-15

Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC. 2011 Elsevier Inc. All rights reserved.

The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells

International Nuclear Information System (INIS)

Soula-Rothhut, Mahdhia; Coissard, Cyrille; Sartelet, Herve; Boudot, Cedric; Bellon, Georges; Martiny, Laurent; Rothhut, Bernard

2005-01-01

Thrombospondin-1 (TSP-1) is a multidomain extracellular macromolecule that was first identified as natural modulator of angiogenesis and tumor growth. In the present study, we found that epidermal growth factor (EGF) up-regulated TSP-1 expression in FTC-133 (primary tumor) but not in FTC-238 (lung metastasis) thyroid cancer cells. Both EGF and TSP-1 induced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In FTC-133 cells, EGF induced proliferation in a TSP-1- and TIMP-1-dependent manner. In addition, we determined that re-expression of the tumor suppressor protein PTEN induced cell death, an effect that correlated with a block of Akt kinase phosphorylation. EGF-induced TSP-1 and TIMP-1 promoter activity and protein expression were inhibited in FTC-133 cells stably expressing wtPTEN but not in cells expressing mutant PTEN. Furthermore, we found that wtPTEN inhibited EGF-but not TSP-1-stimulated FTC-133 cell migration and also inhibited invasion induced by EGF and by TSP-1. Finally, an antibody against TSP-1 reversed EGF-stimulated FTC-133 cell invasion as well as the constitutive invasive potential of FTC-238 cells. Overall, our results suggest that PTEN can function as an important modulator of extracellular matrix proteins in thyroid cancer. Therefore, analyzing differential regulation of TSP-1 by growth factors such as EGF can be helpful in understanding thyroid cancer development

Avian Reovirus Protein p17 Functions as a Nucleoporin Tpr Suppressor Leading to Activation of p53, p21 and PTEN and Inactivation of PI3K/AKT/mTOR and ERK Signaling Pathways.

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Wei-Ru Huang

Full Text Available Avian reovirus (ARV protein p17 has been shown to regulate cell cycle and autophagy by activation of p53/PTEN pathway; nevertheless, it is still unclear how p53 and PTEN are activated by p17. Here, we report for the first time that p17 functions as a nucleoporin Tpr suppressor that leads to p53 nuclear accumulation and consequently activates p53, p21, and PTEN. The nuclear localization signal (119IAAKRGRQLD128 of p17 has been identified for Tpr binding. This study has shown that Tpr suppression occurs by p17 interacting with Tpr and by reducing the transcription level of Tpr, which together inhibit Tpr function. In addition to upregulation of PTEN by activation of p53 pathway, this study also suggests that ARV protein p17 acts as a positive regulator of PTEN. ARV p17 stabilizes PTEN by stimulating phosphorylation of cytoplasmic PTEN and by elevating Rak-PTEN association to prevent it from E3 ligase NEDD4-1 targeting. To activate PTEN, p17 is able to promote β-arrestin-mediated PTEN translocation from the cytoplasm to the plasma membrane via a Rock-1-dependent manner. The accumulation of p53 in the nucleus induces the PTEN- and p21-mediated downregulation of cyclin D1 and CDK4. Furthermore, Tpr and CDK4 knockdown increased virus production in contrast to depletion of p53, PTEN, and LC3 reducing virus yield. Taken together, our data suggest that p17-mediated Tpr suppression positively regulates p53, PTEN, and p21 and negatively regulates PI3K/AKT/mTOR and ERK signaling pathways, both of which are beneficial for virus replication.

SPINK1 Overexpression in Localized Prostate Cancer: a Rare Event Inversely Associated with ERG Expression and Exclusive of Homozygous PTEN Deletion.

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Huang, Kuo-Cheng; Evans, Andrew; Donnelly, Bryan; Bismar, Tarek A

2017-04-01

SPINK1 is proposed as potential prognostic marker in prostate cancer (PCA). However, its relation to PTEN and ERG in localized PCA remains unclear. The study population consisted of two independent cohorts of men treated by radical prostatectomy for localized PCA (discovery n = 218 and validation n = 129). Patterns of association between SPINK1 and each of ERG and PTEN were evaluated by immunohistochemistry and fluorescence in situ hybridization. Associations between SPINK1 expression and various pathologic parameters and clinical outcome were also investigated. SPINK1 was expressed in 15.3 % and 10.9 % of cases in the discovery and validation cohort, respectively. SPINK expression was observed in 5.56 % of high-grade prostatic intraepithelial neoplasia and 1.1 % of adjacent morphologically benign prostatic glands. SPINK1 and ERG expression were almost exclusive, with only 1.0 % of the cases co-expressing both in the same core sample. SPINK1 interfocal and within-core heterogeneity was noted in 29.2 % and 64.6 % of cases, respectively. SPINK1 expression was not significantly associated with PTEN deletion in the two cohorts (p = 0.871 for discovery cohort and p = 0.293 for validation cohort). While SPINK1 expression did occur with hemizygous PTEN deletion, there was a complete absence of SPINK1 expression in PCA showing homozygous PTEN deletion, which was confirmed in the validation cohort (p = 0.02). Despite SPINK1's association with higher Gleason score (>7) (p = 0.02), it was not associated with other pathological parameters or biochemical recurrence post-radical prostatectomy. We documented absolute exclusivity between SPINK1 overexpression and homozygous PTEN deletion in localized PCA. SPINK1 and ERG expressions are exclusive events in PCA. SPINK1 is not of added prognostic value in localized PCA.

PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma.

Science.gov (United States)

Boelens, Mirjam C; Nethe, Micha; Klarenbeek, Sjoerd; de Ruiter, Julian R; Schut, Eva; Bonzanni, Nicola; Zeeman, Amber L; Wientjens, Ellen; van der Burg, Eline; Wessels, Lodewyk; van Amerongen, Renée; Jonkers, Jos

2016-08-23

Invasive lobular carcinoma (ILC) is an aggressive breast cancer subtype with poor response to chemotherapy. Besides loss of E-cadherin, a hallmark of ILC, genetic inactivation of PTEN is frequently observed in patients. Through concomitant Cre-mediated inactivation of E-cadherin and PTEN in mammary epithelium, we generated a mouse model of classical ILC (CLC), the main histological ILC subtype. While loss of E-cadherin induced cell dissemination and apoptosis, additional PTEN inactivation promoted cell survival and rapid formation of invasive mammary tumors that recapitulate the histological and molecular features, estrogen receptor (ER) status, growth kinetics, metastatic behavior, and tumor microenvironment of human CLC. Combined inactivation of E-cadherin and PTEN is sufficient to cause CLC development. These CLCs showed significant tumor regression upon BEZ235-mediated inhibition of PI3K signaling. In summary, this mouse model provides important insights into CLC development and suggests inhibition of phosphatidylinositol 3-kinase (PI3K) signaling as a potential therapeutic strategy for targeting CLC. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signaling: a mechanism linking inflammation and oxidative stress with cancer.

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Tracy M Covey

2010-10-01

Full Text Available PTEN, a phosphoinositide-3-phosphatase, serves dual roles as a tumor suppressor and regulator of cellular anabolic/catabolic metabolism. Adaptation of a redox-sensitive cysteinyl thiol in PTEN for signal transduction by hydrogen peroxide may have superimposed a vulnerability to other mediators of oxidative stress and inflammation, especially reactive carbonyl species, which are commonly occurring by-products of arachidonic acid peroxidation. Using MCF7 and HEK-293 cells, we report that several reactive aldehydes and ketones, e.g. electrophilic α,β-enals (acrolein, 4-hydroxy-2-nonenal and α,β-enones (prostaglandin A(2, Δ12-prostaglandin J(2 and 15-deoxy-Δ-12,14-prostaglandin J(2 covalently modify and inactivate cellular PTEN, with ensuing activation of PKB/Akt kinase; phosphorylation of Akt substrates; increased cell proliferation; and increased nuclear β-catenin signaling. Alkylation of PTEN by α,β-enals/enones and interference with its restraint of cellular PKB/Akt signaling may accentuate hyperplastic and neoplastic disorders associated with chronic inflammation, oxidative stress, or aging.

Gemeinsam hilfreich oder einsam lästig? Beurteilung von praktikumsbegleitenden Weblogs von angehenden Lehrpersonen

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Nives Egger

2017-02-01

Full Text Available Weblogs werden an Hochschulen vermehrt zur Unterstützung von Lern- und Reflexionsprozessen eingesetzt, in der Lehrer/innenbildung auch zunehmend während der berufspraktischen Ausbildung. Die Studierenden beurteilen den Einsatz von Weblogs jedoch unterschiedlich. Dabei ist wenig bekannt, welchen Einfluss die Vergabe und das Erhalten von Peerfeedback auf den Beurteilungsprozess von praktikumsbegleitenden Weblogs sowie auf den Umfang von Blogpostings haben. Im folgenden Beitrag wird dieser Frage mittels einer Befragung von 74 angehenden Lehrpersonen nachgegangen, die praktikumsbegleitende Weblogs mit oder ohne Peerfeedback nutzten, um über herausfordernde Ereignisse im Praktikum zu reflektieren. Die Ergebnisse zeigen, dass Studierende, die Peerfeedback erhielten und andere Blogbeiträge kommentierten, den Weblogeinsatz nützlicher einschätzen sowie eine höhere Motivation und positivere Einstellung gegenüber den Einsatz von Weblogs aufweisen als Studierende, die ohne Peerfeedback bloggen. Keinen Einfluss hat Peerfeedback auf den Umfang der Blogbeiträge und auf die dafür aufgewendete Zeit.

Entwicklung und Anwendung von Methoden zur Bestimmung von Selen-Spezies in human-biologischem Material

OpenAIRE

Jäger, Thomas

2014-01-01

Selen ist essentieller Bestandteil von mehr als 25 physiologisch wichtigen menschlichen Enzymen. Der tägliche Bedarf wird überwiegend in Form von organischen Selenverbindungen wie Selenmethionin oder Selenocystein aus der Nahrung aufgenommen. Weitere Expositionswege sind die Einnahme von Nahrungsergänzungsmitteln zur Selensupplementation sowie die inhalative oder dermale Aufnahme von in erster Linie anorganischen Selenverbindungen oder elementarem Selen an Arbeitsplätzen der Selen-verarbeiten...

Aggregation und Management von Metadaten im Kontext von Europeana

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Gerda Koch

2017-09-01

Full Text Available Mit dem In-Beziehung-Setzen und Verlinken von Daten im Internet wird der Weg zur Umsetzung des semantischen Webs geebnet. Erst die semantische Verbindung von heterogenen Datenbeständen ermöglicht übergreifende Suchvorgänge und späteres „Machine Learning“. Im Artikel werden die Aktivitäten der Europäischen Digitalen Bibliothek im Bereich des Metadatenmanagements und der semantischen Verlinkung von Daten skizziert. Dabei wird einerseits ein kurzer Überblick zu aktuellen Forschungsschwerpunkten und Umsetzungsstrategien gegeben, und darüber hinaus werden einzelne Projekte und maßgeschneiderte Serviceangebote für naturhistorische Daten, regionale Kultureinrichtungen und Audiosammlungen beschrieben.

Cell surface area and membrane folding in glioblastoma cell lines differing in PTEN and p53 status.

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Simon Memmel

Full Text Available Glioblastoma multiforme (GBM is characterized by rapid growth, invasion and resistance to chemo-/radiotherapy. The complex cell surface morphology with abundant membrane folds, microvilli, filopodia and other membrane extensions is believed to contribute to the highly invasive behavior and therapy resistance of GBM cells. The present study addresses the mechanisms leading to the excessive cell membrane area in five GBM lines differing in mutational status for PTEN and p53. In addition to scanning electron microscopy (SEM, the membrane area and folding were quantified by dielectric measurements of membrane capacitance using the single-cell electrorotation (ROT technique. The osmotic stability and volume regulation of GBM cells were analyzed by video microscopy. The expression of PTEN, p53, mTOR and several other marker proteins involved in cell growth and membrane synthesis were examined by Western blotting. The combined SEM, ROT and osmotic data provided independent lines of evidence for a large variability in membrane area and folding among tested GBM lines. Thus, DK-MG cells (wild type p53 and wild type PTEN exhibited the lowest degree of membrane folding, probed by the area-specific capacitance C m = 1.9 µF/cm(2. In contrast, cell lines carrying mutations in both p53 and PTEN (U373-MG and SNB19 showed the highest C m values of 3.7-4.0 µF/cm(2, which corroborate well with their heavily villated cell surface revealed by SEM. Since PTEN and p53 are well-known inhibitors of mTOR, the increased membrane area/folding in mutant GBM lines may be related to the enhanced protein and lipid synthesis due to a deregulation of the mTOR-dependent downstream signaling pathway. Given that membrane folds and extensions are implicated in tumor cell motility and metastasis, the dielectric approach presented here provides a rapid and simple tool for screening the biophysical cell properties in studies on targeting chemo- or radiotherapeutically the

Von der Medienwirkungsbehauptung zur erziehungswissenschaftlichen Medienrezeptionsforschung. Vorschlag zur Analyse von Filmkommunikaten

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Barbara Drinck

2001-04-01

Full Text Available Im Hinblick auf die Erforschung spezifischer Zusammenhänge von Medienkonsum und der Herausbildung von Einstellungen und Handlungen wird eine konstruktivistische Theorieorientierung plausibilisiert, indem zunächst auf den Stand der Medienwirkungsforschung eingegangen und vor dem Hintergrund einer begründeten Kritik des Wirkungsverständnisses auf die Notwendigkeit einer medienrezeptionswissenschaftlichen Forschungsalternative hingewiesen wird. Weiterhin wird der Stand der (erziehungswissenschaftlichen Medienrezeptionsforschung erörtert. Sodann werden Elemente einer konstruktivistischen Methodologie von Medienrezeptionsforschung beschrieben, die am Beispiel der Rezeption von Filmen konkretisiert werden. Dabei wird das Konzept des Kommunikates (S.J. Schmidt als Ausgangspunkt genommen, ein Vorschlag für eine Beschreibungssprache für (Film- Kommunikate entwickelt und eine Adaption des Ansatzes filmischer Narration zur Sprache gebracht.

Alteration of major vault protein in human glioblastoma and its relation with EGFR and PTEN status.

Science.gov (United States)

Navarro, L; Gil-Benso, R; Megías, J; Muñoz-Hidalgo, L; San-Miguel, T; Callaghan, R C; González-Darder, J M; López-Ginés, C; Cerdá-Nicolás, M J

2015-06-25

Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Conventional therapy of surgical removal, radiation and chemotherapy is largely palliative. Major vault protein (MVP), the main component of the vault organelle has been associated with multidrug resistance by reducing cellular accumulation of chemotherapeutic agents. With regard to cancer, MVP has been shown to be overexpressed in drug resistance development and malignant progression. The aim of the present study was to evaluate the MVP gene dosage levels in 113 archival samples from GBM and its correlation with patients' survival and epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog (PTEN) gene dosages. Fluorescent in situ hybridization revealed polysomy of chromosome 7 in 76.1% of the GBMs and EGFR amplification in a 64.6% of the tumors. Genetic status of EGFR, PTEN and MVP copies was determined by multiplex ligation-dependent probe amplification (MLPA) technique. 31% of the tumors showed the EGFR is variant III mutation (EGFRvIII) mutation and 74.3% of them presented amplification of MVP gene. Amplification of EGFR and MVP was found in a 63.7% and 56.6% of the GBM, respectively. An inverse correlation between MVP and PTEN dosage values was observed. Besides, an inverse relationship between the survival of the patients treated with chemotherapy and the levels of MVP copies was determined. In conclusion, our study reveals an important role of MVP, together with EGFRvIII and PTEN, in the progression of GBM and proposes it as a novel and interesting target for new treatment approaches. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Fish oil suppresses cell growth and metastatic potential by regulating PTEN and NF-κB signaling in colorectal cancer.

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Shevali Kansal

Full Text Available Homeostasis in eukaryotic tissues is tightly regulated by an intricate balance of the prosurvival and antisurvival signals. The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10, a dual-specificity phosphatase, plays a functional role in cell cycle arrest and apoptosis. NF-κB and its downstream regulators (such as VEGF play a central role in prevention of apoptosis, promotion of inflammation and tumor growth. Therefore, we thought to estimate the expression of PTEN, Poly-ADP-ribose polymerase (PARP, NF-κBp50, NF-κBp65 and VEGF to evaluate the effect of supplementation of fish oil on apoptotic and inflammatory signaling in colon carcinoma. Male wistar rats in Group I received purified diet while Group II and III received modified diet supplemented with FO∶CO(1∶1&FO∶CO(2.5∶1 respectively. These were further subdivided into controls receiving ethylenediamine-tetra acetic-acid and treated groups received dimethylhydrazine-dihydrochloride (DMH/week for 4 weeks. Animals sacrificed 48 hours after last injection constituted initiation phase and that sacrificed after 16 weeks constituted post-initiation phase. We have analysed expression of PTEN, NF-κBp50, NF-κBp65 by flowcytometer and nuclear localization of NF-κB by immunofluorescence. PARP and VEGF were assessed by immunohistochemistry. In the initiation phase, animals receiving DMH have shown increased % of apoptotic cells, PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF however in post-initiation phase no significant alteration in apoptosis with decreased PTEN and increased PARP, NF-κBp50, NF-κBp65 and VEGF were observed as compared to control animals. On treatment with both ratios of fish oil in both the phases, augmentation in % of apoptotic cells, decreased PTEN, PARP, NF-κBp50, NF-κBp65 and VEGF were documented with respect to DMH treated animals with effect being more exerted with higher ration in post-initiation phase. Hence, fish oil activates

Neues über das Tertiär von Java und die mesozoischen Schichten von West-Borneo

NARCIS (Netherlands)

Martin, K.

1888-01-01

Die Monographie, welche unter dem Titel Die Fossilien von Java herausgegeben wird ¹), ist so weit fortgeschritten, dass sich aus den in ihr beschriebenen Gastropoden bereits eine Anzahl von Schlussfolgerungen ableiten lässt, welche für die in Bearbeitung begriffene, geologische Karte von Java von

Analytik von Minorlipiden: Ferulasäureester von Phytosterolen (gamma-Oryzanol) in Reis

OpenAIRE

Miller, Andreas

2005-01-01

Ferulasäureestern von Phytosterolen (γ-Oryzanol) werden antioxidative und cholesterinsenkende Eigenschaften zugeschrieben. Bisher beschriebene Methoden zur Analytik von γ-Oryzanol in Reis erforderten eine aufwendige Aufreinigung des Probenextrakts. In dieser Arbeit wurde basierend auf der on-line LC-GC eine Methode entwickelt, die die simultane Bestimmung von γ-Oryzanol-Gehalt und Sterylferulat-Verteilung ohne Aufreinigung des Probenextrakts erlaubt. Mit Hilfe der Technik wurden die natürlich...

Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migration of human melanoma cells and elicits PTEN elevation and inactivation of PI3K/AKT signaling

International Nuclear Information System (INIS)

Foster, James S; Fish, Lindsay M; Phipps, Jonathan E; Bruker, Charles T; Lewis, James M; Bell, John L; Solomon, Alan; Kestler, Daniel P

2013-01-01

The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity. Herein we have extended these studies to the effects of ODAM on cultured melanoma cell lines. The A375 and C8161 melanoma cell lines were stably transfected with ODAM and assayed for properties associated with tumorigenicity including cell growth, motility, and extracellular matrix adhesion. In addition, ODAM–transfected cells were assayed for signal transduction via AKT which promotes cell proliferation and survival in many neoplasms. ODAM expression in A375 and C8161 cells strongly inhibited cell growth and motility in vitro, increased cell adhesion to extracellular matrix, and yielded significant cytoskeletal/morphologic rearrangement. Furthermore, AKT activity was downregulated by ODAM expression while an increase was noted in expression of the PTEN (phosphatase and tensin homolog on chromosome 10) tumor suppressor gene, an antagonist of AKT activation. Increased PTEN in ODAM-expressing cells was associated with increases in PTEN mRNA levels and de novo protein synthesis. Silencing of PTEN expression yielded recovery of AKT activity in ODAM-expressing melanoma cells. Similar PTEN elevation and inhibition of AKT by ODAM was observed in MDA-MB-231 breast cancer cells while ODAM expression had no effect in PTEN-deficient BT-549 breast cancer cells. The apparent anti-neoplastic effects of ODAM in cultured melanoma and breast cancer cells are associated with increased PTEN expression, and suppression of AKT activity. This association should serve to clarify the clinical import of ODAM expression and any role it may serve as an indicator of tumor behavior

Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway

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Rachana Garg

2017-04-01

Full Text Available Summary: PKCε, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCε with other genetic alterations, as well as the effectors contributing to its tumorigenic and metastatic phenotype. Here, we demonstrate that PKCε cooperates with the loss of the tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCε overexpression and Pten loss individually and synergistically upregulate the production of the chemokine CXCL13, which involves the transcriptional activation of the CXCL13 gene via the non-canonical nuclear factor κB (NF-κB pathway. Notably, targeted disruption of CXCL13 or its receptor, CXCR5, in prostate cancer cells impaired their migratory and tumorigenic properties. In addition to providing evidence for an autonomous vicious cycle driven by PKCε, our studies identified a compelling rationale for targeting the CXCL13-CXCR5 axis for prostate cancer treatment. : Garg et al. find that PKCε overexpression cooperates with Pten loss to promote prostate cancer in mice. These two alterations together confer enhanced growth, tumorigenic, migratory and invasive capabilities to prostate epithelial cells, and promote the release of CXCL13, an effect that is mediated by the non-canonical NF-κB pathway. Keywords: PKCε, PTEN, CXCL13, NF-κB, prostate cancer, CXCR5, migration, proliferation, transgenic mice

KRAS and BRAF Mutations and PTEN Expression Do Not Predict Efficacy of Cetuximab-Based Chemoradiotherapy in Locally Advanced Rectal Cancer

Energy Technology Data Exchange (ETDEWEB)

Erben, Philipp, E-mail: philipp.erben@medma.uni-heidelberg.de [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Stroebel, Philipp [Pathologisches Institut, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Horisberger, Karoline [Chirurgische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Popa, Juliana; Bohn, Beatrice; Hanfstein, Benjamin [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Kaehler, Georg; Kienle, Peter; Post, Stefan [Chirurgische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Wenz, Frederik [Klinik fuer Strahlentherapie und Radioonkologie, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Hochhaus, Andreas [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany); Klinik fuer Innere Medizin II, Abteilung Haematologie/Onkologie, Universitaetsklinikum Jena, Jena (Germany); Hofheinz, Ralf-Dieter [III. Medizinische Klinik, Universitaetsmedizin Mannheim, Universitaet Heidelberg, Mannheim (Germany)

2011-11-15

Purpose: Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog (PTEN) (deleted on chromosome 10) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer. The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer (LARC) treated with cetuximab-based neoadjuvant chemoradiotherapy is unknown. Methods and Materials: We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy (45 Gy plus 5.4 Gy) in patients with LARC (stage uT3/4 or uN+). The status of KRAS and BRAF mutations was determined with direct sequencing, and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies. Tumor regression was evaluated by using standardized regression grading, and disease-free survival (DFS) was calculated according to the Kaplan-Meier method. Results: A total of 57 patients were available for analyses. A total of 31.6% of patients carried mutations in the KRAS genes. No BRAF mutations were found, while the loss of PTEN expression was observed in 9.6% of patients. Six patients achieved complete remission, and the 3-year DFS rate was 73%. No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers. Conclusions: In the present series, no BRAF mutation was detected. The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS.

KRAS and BRAF Mutations and PTEN Expression Do Not Predict Efficacy of Cetuximab-Based Chemoradiotherapy in Locally Advanced Rectal Cancer

International Nuclear Information System (INIS)

Erben, Philipp; Ströbel, Philipp; Horisberger, Karoline; Popa, Juliana; Bohn, Beatrice; Hanfstein, Benjamin; Kähler, Georg; Kienle, Peter; Post, Stefan; Wenz, Frederik; Hochhaus, Andreas; Hofheinz, Ralf-Dieter

2011-01-01

Purpose: Mutations in KRAS and BRAF genes as well as the loss of expression of phosphatase and tensin homolog (PTEN) (deleted on chromosome 10) are associated with impaired activity of antibodies directed against epidermal growth factor receptor in patients with metastatic colorectal cancer. The predictive and prognostic value of the KRAS and BRAF point mutations as well as PTEN expression in patients with locally advanced rectal cancer (LARC) treated with cetuximab-based neoadjuvant chemoradiotherapy is unknown. Methods and Materials: We have conducted phase I and II trials of the combination of weekly administration of cetuximab and irinotecan and daily doses of capecitabine in conjunction with radiotherapy (45 Gy plus 5.4 Gy) in patients with LARC (stage uT3/4 or uN+). The status of KRAS and BRAF mutations was determined with direct sequencing, and PTEN expression status was determined with immunohistochemistry testing of diagnostic tumor biopsies. Tumor regression was evaluated by using standardized regression grading, and disease-free survival (DFS) was calculated according to the Kaplan–Meier method. Results: A total of 57 patients were available for analyses. A total of 31.6% of patients carried mutations in the KRAS genes. No BRAF mutations were found, while the loss of PTEN expression was observed in 9.6% of patients. Six patients achieved complete remission, and the 3-year DFS rate was 73%. No correlation was seen between tumor regression or DFS rate and a single marker or a combination of all markers. Conclusions: In the present series, no BRAF mutation was detected. The presence of KRAS mutations and loss of PTEN expression were not associated with impaired response to cetuximab-based chemoradiotherapy and 3-year DFS.

Actin cytoskeleton organization, cell surface modification and invasion rate of 5 glioblastoma cell lines differing in PTEN and p53 status

International Nuclear Information System (INIS)

Djuzenova, Cholpon S.; Fiedler, Vanessa; Memmel, Simon; Katzer, Astrid; Hartmann, Susanne; Krohne, Georg; Zimmermann, Heiko; Scholz, Claus-Jürgen; Polat, Bülent; Flentje, Michael

2015-01-01

Glioblastoma cells exhibit highly invasive behavior whose mechanisms are not yet fully understood. The present study explores the relationship between the invasion capacity of 5 glioblastoma cell lines differing in p53 and PTEN status, expression of mTOR and several other marker proteins involved in cell invasion, actin cytoskeleton organization and cell morphology. We found that two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) exhibited the highest invasion rates through the Matrigel or collagen matrix. In DK-MG (p53wt/PTENwt) and GaMG (p53mut/PTENwt) cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG (p53wt/PTENmut), U373-MG and SNB19 (both p53mut/PTENmut) cells preferentially expressed F-actin in filopodia and lamellipodia. Scanning electron microscopy confirmed the abundant filopodia and lamellipodia in the PTEN mutated cell lines. Interestingly, the gene profiling analysis revealed two clusters of cell lines, corresponding to the most (U373-MG and SNB19, i.e. p53 and PTEN mutated cells) and less invasive phenotypes. The results of this study might shed new light on the mechanisms of glioblastoma invasion. - Highlights: • We examine 5 glioblastoma lines on the invasion capacity and actin cytoskeleton. • Glioblastoma cell lines mutated in both p53 and PTEN were the most invasive. • Less invasive cells showed much less lamellipodia, but more actin stress fibers. • A mechanism for the differences in tumor cell invasion is proposed

Actin cytoskeleton organization, cell surface modification and invasion rate of 5 glioblastoma cell lines differing in PTEN and p53 status

Energy Technology Data Exchange (ETDEWEB)

Djuzenova, Cholpon S., E-mail: djuzenova_t@ukw.de [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Fiedler, Vanessa [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Memmel, Simon [Lehrstuhl für Biotechnologie und Biophysik, Universität Würzburg, Biozentrum Am Hubland, 97070 Würzburg (Germany); Katzer, Astrid; Hartmann, Susanne [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); Krohne, Georg [Elektronenmikroskopie, Biozentrum, Universität Würzburg, Am Hubland, 97070 Würzburg (Germany); Zimmermann, Heiko [Hauptabteilung Biophysik and Kryotechnologie, Fraunhofer-Institut für Biomedizinische Technik, Lehrstuhl für Molekulare und Zelluläre Biotechnologie/Nanotechnologie, Universität des Saarlandes, Ensheimer Strasse 48, 66386 St. Ingbert (Germany); Scholz, Claus-Jürgen [Interdisciplinary Center for Clinical Research, University Hospital, Versbacher Strasse 7, 97078 Würzburg (Germany); Polat, Bülent; Flentje, Michael [Department of Radiation Oncology, University Hospital, Josef-Schneider-Strasse 11, D-97080 Würzburg (Germany); and others

2015-01-15

Glioblastoma cells exhibit highly invasive behavior whose mechanisms are not yet fully understood. The present study explores the relationship between the invasion capacity of 5 glioblastoma cell lines differing in p53 and PTEN status, expression of mTOR and several other marker proteins involved in cell invasion, actin cytoskeleton organization and cell morphology. We found that two glioblastoma lines mutated in both p53 and PTEN genes (U373-MG and SNB19) exhibited the highest invasion rates through the Matrigel or collagen matrix. In DK-MG (p53wt/PTENwt) and GaMG (p53mut/PTENwt) cells, F-actin mainly occurred in the numerous stress fibers spanning the cytoplasm, whereas U87-MG (p53wt/PTENmut), U373-MG and SNB19 (both p53mut/PTENmut) cells preferentially expressed F-actin in filopodia and lamellipodia. Scanning electron microscopy confirmed the abundant filopodia and lamellipodia in the PTEN mutated cell lines. Interestingly, the gene profiling analysis revealed two clusters of cell lines, corresponding to the most (U373-MG and SNB19, i.e. p53 and PTEN mutated cells) and less invasive phenotypes. The results of this study might shed new light on the mechanisms of glioblastoma invasion. - Highlights: • We examine 5 glioblastoma lines on the invasion capacity and actin cytoskeleton. • Glioblastoma cell lines mutated in both p53 and PTEN were the most invasive. • Less invasive cells showed much less lamellipodia, but more actin stress fibers. • A mechanism for the differences in tumor cell invasion is proposed.

Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway.

Science.gov (United States)

Nan, Yang; Guo, Liyun; Song, Yunpeng; Wang, Le; Yu, Kai; Huang, Qiang; Zhong, Yue

2017-08-01

Glioblastoma is a highly invasive and challenging tumor of the central nervous system. The mutation/deletion of the tumor suppressor phosphatase and tensin homolog (PTEN) gene is the main genetic change identified in glioblastomas. PTEN plays a critical role in tumorigenesis and has been shown to be an important therapeutic target. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 is commonly used to inhibit glioma cell growth via regulation of the PI3K/AKT signaling pathway. In this study, we examined the growth inhibitory effects of a combinatorial therapy of adenoviral-mediated PTEN (Ad-PTEN) and LY294002 on LN229 and U251 glioma cells in vitro and on tumor xenografts in vivo. In vitro, LN229 and U251 glioma cells were treated by combinatorial therapy with Ad-PTEN and LY294002. The growth ability was determined by MTT assay. The cell cycle distribution was analyzed by flow cytometry. Cell invasive ability was analyzed by transwell invasion assay and cell apoptosis analysis via FITC-Annexin V analysis. In vivo, U251 subcutaneous glioblastoma xenograft was used to assay anti-tumor effect of combinatorial therapy with Ad-PTEN and LY294002 by mean volume of tumors, immunohistochemistry and TUNEL method. The combinatorial treatment clearly suppressed cell proliferation, arrested the cell cycle, reduced cell invasion and promoted cell apoptosis compared with the Ad-PTEN or LY294002 treatment alone. The treatment worked by inhibiting the PI3K/AKT pathway. In addition, the growth of U251 glioma xenografts treated with the combination of Ad-PTEN and LY294002 was significantly inhibited compared with those treated with Ad-PTEN or LY294002 alone. Our data indicated that the combination of Ad-PTEN and LY294002 effectively suppressed the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach for glioma gene therapy that warrants further investigation.

Inhibition of PTEN and activation of Akt by menadione

OpenAIRE

Yoshikawa, Kyoko; Nigorikawa, Kiyomi; Tsukamoto, Mariko; Tamura, Namiko; Hazeki, Kaoru; Hazeki, Osamu

2007-01-01

Menadione (vitamin K3) has been shown to activate Erk in several cell lines. This effect has been shown to be due to the activation of EGF receptors (EGFR) as a result of inhibition of some protein tyrosine phosphatases. In the present study, we examined the effects of menadione on Akt in Chinese hamster ovary cells. The phosphorylation of Akt by menadione was not inhibited by AG1478, an inhibitor of EGFR. Menadione inhibited the lipid phosphatase activity of PTEN in a cell-free system. In an...

Der Briefwechsel zwischen Alexander von Humboldt und Karl Ernst von Baer

Directory of Open Access Journals (Sweden)

Thomas Schmuck

2012-10-01

Full Text Available Zusammenfassung Der kurze, nicht vollständig erhaltene Briefwechsel zwischen Alexander von Humboldt und Karl Ernst von Baer behandelt sehr verschiedene Themen: Politik, Kriegsgefahr, den Wissenschaftsbetrieb, Auszeichnungen und Tagungen, Embryologie und Cholera. Gemeinsam mit Briefen und Reden ergibt sich dabei ein differenziertes Bild der Beurteilung der beiden Wissenschaftler durch den jeweils anderen. Während Baer sich als Bewunderer Humboldts erweist, erscheint umgekehrt Humboldts Einschätzung Baers als ambivalent. Abstract The short, not completely preserved correspondence between Alexander von Humboldt and Karl Ernst von Baer deals with a wide range of subjects: politics and the danger of war, academic activities, scientific awards and conferences, aspects of embryology and the cholera. Letters to third persons and speeches, together with the correspondence between Humboldt and Baer show a differentiated pattern of mutual appraisal: While Baer always remained an admirer of the elder naturalist, Humboldt’s estimation was characterized by ambivalence.

Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN

Science.gov (United States)

Singh, Karmveer; Maity, Pallab; Krug, Linda; Meyer, Patrick; Treiber, Nicolai; Lucas, Tanja; Basu, Abhijit; Kochanek, Stefan; Wlaschek, Meinhard; Geiger, Hartmut; Scharffetter-Kochanek, Karin

2015-01-01

The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions () in mitochondria, either by chemical inhibition of complex I or by genetic silencing of -dismutating mitochondrial Sod2. The -dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of α1(I), α1(III), and α2(I) collagen, the hallmarks of skin ageing. Enhanced led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated -induced IGF-1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with , PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies. PMID:25520316

Evaluation von Bildungssoftware im Spannungsfeld von Objektivität und praktischer Anwendung

Directory of Open Access Journals (Sweden)

Cornelia Biffi

2002-05-01

Full Text Available Das Angebot an Bildungs- bzw. Lernsoftware umfasst eine breite Palette von sehr unterschiedlichen Produkten. Eigentliche Unterrichtssoftware, die speziell für den Unterricht hergestellt und auf Lehrmittel und Curriculum abgestimmt ist, gibt es kaum. Im Projekt «Lernsoftware Evaluation» des Pestalozzianums Zürich ermitteln Lehrpersonen die Qualität von Bildungssoftware, indem sie diese im Unterricht einsetzen und anhand eines Kriterienrasters beurteilen. Eine Analyse der in der Evaluation generierten Daten belegt die Problematik des Anspruchs einer objektiven Qualitätsbeurteilung. Es werden die Probleme bei der Anwendung von Kriterienraster und Beurteilungsmodus aufgezeigt und ermittelt, worin die subjektiven Qualitätsmassstäbe der Evaluierenden begründet sind. Diese Ausführungen sind Teil eines Forschungsprojekts für die Weiterentwicklung einer theoretisch fundierten, aber dennoch praxisnahen Evaluation von Bildungssoftware.

Dermal Delivery of Constructs Encoding Cre Recombinase to Induce Skin Tumors in PtenLoxP/LoxP;BrafCA/+ Mice

Directory of Open Access Journals (Sweden)

Marcel A. Deken

2016-12-01

Full Text Available Current genetically-engineered mouse melanoma models are often based on Tyr::CreERT2-controlled MAPK pathway activation by the BRAFV600E mutation and PI3K pathway activation by loss of PTEN. The major drawback of these models is the occurrence of spontaneous tumors caused by leakiness of the Tyr::CreERT2 system, hampering long-term experiments. To address this problem, we investigated several approaches to optimally provide local delivery of Cre recombinase, including injection of lentiviral particles, DNA tattoo administration and particle-mediated gene transfer, to induce melanomas in PtenLoxP/LoxP;BrafCA/+ mice lacking the Tyr::CreERT2 allele. We found that dermal delivery of the Cre recombinase gene under the control of a non-specific CAG promoter induced the formation of melanomas, but also keratoacanthoma and squamous cell carcinomas. Delivery of Cre recombinase DNA under the control of melanocyte-specific promoters in PtenLoxP/LoxP;BrafCA/+ mice resulted in sole melanoma induction. The growth rate and histological features of the induced tumors were similar to 4-hydroxytamoxifen-induced tumors in Tyr::CreERT2;PtenLoxP/LoxP;BrafCA/+ mice, while the onset of spontaneous tumors was prevented completely. These novel induction methods will allow long-term experiments in mouse models of skin malignancies.

[Friedrich Ludwig von Maydelli pildid Baltimaade ajaloost = Friedrich Ludwig von Maydells Baltische Geschichte in Bildern = Friedrich Ludwig von Maydell ́s Baltic history in images] / Ulrike Plath

Index Scriptorium Estoniae

Plath, Ulrike, 1972-

2014-01-01

Arvustus: Friedrich Ludwig von Maydelli pildid Baltimaade ajaloost = Friedrich Ludwig von Maydells Baltische Geschichte in Bildern = Friedrich Ludwig von Maydell ́s Baltic history in images. Eesti kunstimuuseum, Kadrioru kunstimuuseum. Tallinn 2013

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine.

Science.gov (United States)

Bai, Qiufang; Song, Dan; Gu, Li; Verkhratsky, Alexei; Peng, Liang

2017-04-01

Here, we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations, fluoxetine downregulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations, fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.

Automatisierung von HiL Tests

OpenAIRE

Asbach, Lennart; Ebrecht, Lars

2010-01-01

Automatisierung von HiL Tests. Darstellung und Bewertung einer praktischen Umsetzung. Das Poster zeigt die Motivation, die Durchführung, einen aktuellen Stand und einen Ausblick der Testautomatisierung im Bahnlabor RailSiTe. Als Beispiel dient der Konformitätstest von ETCS-Onboard Zugrechnern, um die Einführung von ETCS zu unterstützen.

Die Wirkung von Desacetylcefotaxin, einem Metaboliten von Cefotaxim, in vitro und auf die experimentelle Infektion mit Escherichia coli

OpenAIRE

Wirbelauer, J.; Hof, H.; Hacker, Jörg

2009-01-01

Die MHK-Werte von Desacetylcefotaxim gegen verschiedene, z. T. ampicillinresistente Stämme von Escherichia coH, die mit Hilfe einer Agardilutionsmethode erhoben wurden, waren höher als die von Cefotaxim und Ceftriaxon, jedoch niedriger als die von Cefoxitin. In einem Modell der systemischen Infektion der Maus mit einem plasmidtragenden, betalactamaseproduzierenden Stamm von E. coli führte die Therapie mit Desacetylcefotaxim zu einer starken Reduktion der Keime pro Leber. Im Vergleich zur Ther...

Constitutive insulin sensitivity and obesity my be caused by PTEN mutations

Directory of Open Access Journals (Sweden)

E A Pigarova

2012-12-01

Full Text Available Реферат по статье: Pal A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, Lachlan KL, Cooper NS, Linden H, Levy JC, Wakelam MJ, Walker L, Karpe F, Gloyn AL. PTEN mutations as a cause of constitutive insulin sensitivity and obesity. N Engl J Med. 2012 Sep 13;367(11:1002-11.

Cancer cell-oriented migration of mesenchymal stem cells engineered with an anticancer gene (PTEN: an imaging demonstration

Directory of Open Access Journals (Sweden)

Yang ZS

2014-03-01

Full Text Available Zhuo-Shun Yang,1,* Xiang-Jun Tang,2,* Xing-Rong Guo,1 Dan-Dan Zou,1 Xu-Yong Sun,3 Jing-Bo Feng,1 Jie Luo,1 Long-Jun Dai,1,4 Garth L Warnock4 1Hubei Key Laboratory of Stem Cell Research, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 2Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, Shiyan, People’s Republic of China; 3Guangxi Key Laboratory for Transplant Medicine, 303 Hospital of PLA, Nanning, People’s Republic of China; 4Department of Surgery, University of British Columbia, Vancouver, BC, Canada *These authors contributed equally to this work Background: Mesenchymal stem cells (MSCs have been considered to hold great potential as ideal carriers for the delivery of anticancer agents since the discovery of their tumor tropism. This study was performed to demonstrate the effects of phosphatase and tensin homolog (PTEN engineering on MSCs’ capacity for cancer cell-oriented migration. Methods: MSCs were engineered with a PTEN-bearing plasmid and the expression was confirmed with Western blotting. A human glioma cell line (DBTRG was used as the target cell; DBTRG cell-oriented migration of MSCs was monitored with a micro speed photographic system. Results: The expression of transfected PTEN in MSCs was identified by immunoblotting analysis and confirmed with cell viability assessment of target cells. The DBTRG cell-oriented migration of PTEN-engineered MSCs was demonstrated by a real-time dynamic monitoring system, and a phagocytosis-like action of MSCs was also observed. Conclusion: MSCs maintained their capacity for cancer cell-directed migration after they were engineered with anticancer genes. This study provides the first direct evidence of MSCs’ tropism post-anticancer gene engineering. Keywords: gene therapy, mesenchymal stem cells, phosphatase and tensin homolog, cancer

Eine Analyse des Zusammenhangs zwischen dem Konsum von Alkopops und dem Problemverhalten von Jugendlichen

OpenAIRE

Metzner, Cornelia Beate Isabel

2007-01-01

Zielsetzung: In dieser Arbeit wird untersucht, ob bei Jugendlichen ein Zusammenhang zwischen dem Konsum von Alkopops einerseits und dem sonstigen Alkoholtrinkverhalten, dem Konsum von Zigaretten und illegalen Drogen sowie weiteren Risikoverhaltensweisen andererseits besteht, ferner ob sich Unterschiede im Verhalten von Jungen und Mädchen ergeben. Theoretischer und empirischer Hintergrund: �Alkopops�, d. h. Mischgetränke diverser Hersteller aus Likör bzw. Schnaps und Limonade sowie wein- ...

Tumour-associated neutrophils and loss of epithelial PTEN can promote corticosteroid-insensitive MMP-9 expression in the chronically inflamed lung microenvironment.

Science.gov (United States)

Vannitamby, Amanda; Seow, Huei Jiunn; Anderson, Gary; Vlahos, Ross; Thompson, Michelle; Steinfort, Daniel; Irving, Louis B; Bozinovski, Steven

2017-12-01

Matrix metalloproteinase-9 (MMP-9) is increased in a number of pathological lung conditions, where the proteinase contributes to deleterious remodelling of the airways. While both lung cancer and COPD are associated with increased MMP-9 expression, the cellular and molecular drivers of MMP-9 remain unresolved. In this study, MMP-9 transcript measured within the tumour region from patients with non-small-cell lung cancer (NSCLC) and coexisting COPD was found to be uniformly increased relative to adjacent tumour-free tissue. MMP-9 gene expression and immunohistochemistry identified tumour-associated neutrophils, but not macrophages, as a predominant source of this proteinase. In addition, PTEN gene expression was significantly reduced in tumour and there was evidence of epithelial MMP-9 expression. To explore whether PTEN can regulate epithelial MMP-9 expression, a small interfering (si)RNA knockdown strategy was used in Beas-2B bronchial epithelial cells. PTEN knockdown by siRNA selectively increased MMP-9 expression in response to lipopolysaccharide in a corticosteroid-insensitive manner. In summary, tumour-associated neutrophils represent an important source of MMP-9 in NSCLC, and loss of epithelial PTEN may further augment steroid-insensitive expression. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Titanisierung von Implantatoberflächen

Science.gov (United States)

Zimmermann, Hanngörg; Heinlein, Markus; Guldner, Norbert W.

Titan gilt seit Jahrzehnten als einer der wichtigsten Implantatwerkstoffe in der Medizin. Neben den guten mechanischen Eigenschaften (Leichtigkeit, hohe Festigkeit etc.), besitzen Titanimplantate vor allem eine hervorragende Körperverträglichkeit, so dass die Implantate optimal in den humanen Organismus integriert werden [1]. Ist jedoch aufgrund der Anforderungen an das Implantat eine hohe Flexibilität und/ oder Elastizität gefragt, so scheidet der Werkstoff Titan aufgrund seiner spröden und unflexiblen Materialeigenschaften aus. Die Folge ist der Einsatz von Implantatmaterialien, sowohl künstlichen als auch biologischen Ursprungs, welche nicht selten eine unzureichende Biokompatibilität aufweisen und somit zu Fremdköper- und immunologischen Reaktionen und Einkapselung des Implantates führen können. Die Erhöhung der Körperverträglichkeit, eine Adaption an das biologische Umfeld und eine hohe Biokompatibilität sind demzufolge die wichtigsten Eigenschaften bei der bedarfsgerechten Herstellung von Implantaten und Implantatoberflächen. Zur Gestaltung von innovativen, biokompatiblen Oberflächen stehen unterschiedliche technische Lösungsansätze zur Verfügung. Zum einen besteht die Möglichkeit, geeignete Oberflächeneigenschaften aus dem Grundmaterial selbst zu optimieren. Dies geschieht unter anderem durch Modifikation der Werkstoffoberflächen in Form von Texturierungen und Oberflächenrauhigkeiten. Zum anderen können die Oberflächeneigenschaften unabhängig von denen des Trägermaterials gestaltet werden. Durch Funktionalisierung der Oberflächen mit geeigneten Beschichtungen oder der Zugabe von Medikamenten (Drug Eluting) werden die Kunststoffimplantate dahingehend verändert, dass eine Steigerung der Körperakzeptanz erreicht wird. Die Titanbeschichtung von Implantatoberflächen kombiniert die positiven Materialeigenschaften von Titan und Polymer.

The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere.

Science.gov (United States)

Li, Jing; Davies, Barry R; Han, Sufang; Zhou, Minhua; Bai, Yu; Zhang, Jingchuan; Xu, Yan; Tang, Lily; Wang, Huiying; Liu, Yuan Jie; Yin, Xiaolu; Ji, Qunsheng; Yu, De-Hua

2013-10-02

Activation of the PI3K/AKT pathway is a common phenomenon in cancer due to multiple mechanisms, including mutation of PI3KCA, loss or mutation of PTEN, or over-expression of receptor tyrosine kinases. We recently developed a novel AKT kinase inhibitor, AZD5363, and demonstrated that HGC27, a cell line harboring both PI3KCA mutation and PTEN loss, displayed the greatest sensitivity to this AKT inhibitor in vitro and in vivo. To further elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer (GC) and identify GC patients with both PI3KCA mutations and PTEN loss, we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in tumor samples from a cohort of Chinese GC patients. We demonstrated that GC cells with PI3KCA mutations were selectively sensitive to AZD5363. Disease linkage studies showed that PI3KCA activating mutations or PTEN loss were found in 2.7% (4/150) and 23% (14/61) of Chinese GC patients respectively. To further dissect the role of PI3KCA mutation and PTEN loss in response to AKT inhibition, we tested the antitumor activity of AZD5363 in two patient-derived GC xenograft (PDGCX) models harboring either PI3KCA mutation or PTEN loss. Our data indicated that AZD5363 monotherapy treatment led to a moderate response in the PI3KCA mutant PDGCX model. Whilst monotherapy AZD5363 or Taxotere were ineffective in the PTEN negative PDGCX model, significant anti-tumor activity was observed when AZD5363 was combined with Taxotere. Our results indicated that PI3KCA mutation is an important determinant of response to AKT inhibition in GC and combination with AZD5363 can overcome innate resistance to Taxotere in a PTEN loss PDGCX model. It is suggested that AKT inhibitor is an attractive option for treatment of a new segment of GC patients with aberrant PI3K/AKT signaling.

Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer.

Science.gov (United States)

Carver, Brett S; Chapinski, Caren; Wongvipat, John; Hieronymus, Haley; Chen, Yu; Chandarlapaty, Sarat; Arora, Vivek K; Le, Carl; Koutcher, Jason; Scher, Howard; Scardino, Peter T; Rosen, Neal; Sawyers, Charles L

2011-05-17

Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival. Copyright © 2011 Elsevier Inc. All rights reserved.

High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

Directory of Open Access Journals (Sweden)

Jehnan Liu

2015-03-01

Conclusion: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

Conditional Loss of Pten in Myogenic Progenitors Leads to Postnatal Skeletal Muscle Hypertrophy but Age-Dependent Exhaustion of Satellite Cells.

Science.gov (United States)

Yue, Feng; Bi, Pengpeng; Wang, Chao; Li, Jie; Liu, Xiaoqi; Kuang, Shihuan

2016-11-22

Skeletal muscle stem cells (satellite cells [SCs]) are normally maintained in a quiescent (G 0 ) state. Muscle injury not only activates SCs locally, but also alerts SCs in distant uninjured muscles via circulating factors. The resulting G Alert SCs are adapted to regenerative cues and regenerate injured muscles more efficiently, but whether they provide any long-term benefits to SCs is unknown. Here, we report that embryonic myogenic progenitors lacking the phosphatase and tensin homolog (Pten) exhibit enhanced proliferation and differentiation, resulting in muscle hypertrophy but fewer SCs in adult muscles. Interestingly, Pten null SCs are predominantly in the G Alert state, even in the absence of an injury. The G Alert SCs are deficient in self-renewal and subjected to accelerated depletion during regeneration and aging and fail to repair muscle injury in old mice. Our findings demonstrate a key requirement of Pten in G 0 entry of SCs and provide functional evidence that prolonged G Alert leads to stem cell depletion and regenerative failure. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

PTP1B promotes aggressiveness of breast cancer cells by regulating PTEN but not EMT.

Science.gov (United States)

Liu, Xue; Chen, Qian; Hu, Xu-Gang; Zhang, Xian-Chao; Fu, Ti-Wei; Liu, Qing; Liang, Yan; Zhao, Xi-Long; Zhang, Xia; Ping, Yi-Fang; Bian, Xiu-Wu

2016-10-01

Metastasis is a complicated, multistep process and remains the major cause of cancer-related mortality. Exploring the molecular mechanisms underlying tumor metastasis is crucial for development of new strategies for cancer prevention and treatment. In this study, we found that protein tyrosine phosphatase 1B (PTP1B) promoted breast cancer metastasis by regulating phosphatase and tensin homolog (PTEN) but not epithelial-mesenchymal transition (EMT). By detecting PTP1B expression of the specimens from 128 breast cancer cases, we found that the level of PTP1B was higher in breast cancer tissues than the corresponding adjacent normal tissues. Notably, PTP1B was positively associated with lymph node metastasis (LNM) and estrogen receptor (ER) status. In vitro, disturbing PTP1B expression obviously attenuated cell migration and invasion. On the contrary, PTP1B overexpression significantly increased migration and invasion of breast cancer cells. Mechanistically, PTP1B knockdown upregulated PTEN, accompanied with an abatement of AKT phosphorylation and the expression of matrix metalloproteinase 2 (MMP2) and MMP7. Conversely, forced expression of PTP1B reduced PTEN and increased AKT phosphorylation as well as the expression of MMP2 and MMP7. Notably, neither EMT nor stemness of breast cancer cells was regulated by PTP1B. We also found that PTP1B acted as an independent prognostic factor and predicted poor prognosis in ER-positive breast cancer patients. Taken together, our findings provide advantageous evidence for the development of PTP1B as a potential therapeutic target for breast cancer, especially for ER-positive breast cancer patients.

Nutzerorientiertes Management von materiellen und immateriellen Informationsobjekten

OpenAIRE

Hübsch, Chris

2001-01-01

Schaffung einer stabilen, erweiterbaren und skalierbaren Infrastruktur für die Bereitstellung von Diensten im Umfeld von Bibliotheken und ähnlichen wissensanbietenden Einrichtungen unter Verwendung von XML-RPC und Python.

MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4

International Nuclear Information System (INIS)

Wei, Xueju; Wang, Weibin; Wang, Lanlan; Zhang, Yuanyuan; Zhang, Xian; Chen, Mingtai; Wang, Fang; Yu, Jia; Ma, Yanni; Sun, Guotao

2016-01-01

Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240.

Science.gov (United States)

Fenton, Tim R; Nathanson, David; Ponte de Albuquerque, Claudio; Kuga, Daisuke; Iwanami, Akio; Dang, Julie; Yang, Huijun; Tanaka, Kazuhiro; Oba-Shinjo, Sueli Mieko; Uno, Miyuki; Inda, Maria del Mar; Wykosky, Jill; Bachoo, Robert M; James, C David; DePinho, Ronald A; Vandenberg, Scott R; Zhou, Huilin; Marie, Suely K N; Mischel, Paul S; Cavenee, Webster K; Furnari, Frank B

2012-08-28

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

Developing a PTEN-ERG Signature to Improve Molecular Risk Stratification in Prostate Cancer

Science.gov (United States)

2017-10-01

performed exploratory data analysis on all clinically annotated prostate cancer datasets available from the public domain and through the collaboration...with GenomeDX. We used statistical summaries and data visualizations techniques (e.g., principal component analysis , hierarchical clustering) to...associated with PTEN loss on genetically homogeneous ERG-positive and ERG- negative backgrounds. Timeline (Months) Major Task 2: Perform CAGE analysis

Die Verteilung und Eigenschaften von Bodenformen in der Deutschen Bucht, eine Rekonstruktion der Karten von Ulrich (1973)

DEFF Research Database (Denmark)

Winter, Christian; Lefebvre, Alice; Benninghoff, Markus

2015-01-01

Entstehung, Gestalt und Dynamik von Bodenformen in vergleichsweise kleinen Untersuchungsgebieten ist die Arbeit von ULRICH (1973) über die Verteilung von Bodenformen in der Deutschen Bucht bis heute die einzige verfügbare zusammenhängende Darstellung für die deutsche Nordseeküste. Die analogen Karten und die...

Effect of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on Akt protein expression is more effective in head and neck cancer cell lineages that retain PTEN protein expression.

Science.gov (United States)

Pontes, Flávia Sirotheau C; Pontes, Hélder A R; de Souza, Lucas L; de Jesus, Adriana S; Joaquim, Andrea M C; Miyahara, Ligia A N; Fonseca, Felipe P; Pinto Junior, Décio S

2018-03-01

The aim of this study was to evaluate the expression of Akt, PTEN, Mdm2 and p53 proteins in three different head and neck squamous cell carcinoma (HNSCC) cell lines (HN6, HN19 and HN30), all of them treated with epidermal growth factor (EGF) and 17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90 protein. Immunofluorescence and western blot were performed in order to analyze the location and quantification, respectively, of proteins under the action 17-AAG and EGF. Treatment with EGF resulted in increased levels of Akt, PTEN and p53 in all cell lineages. The expression of Mdm2 was constant in HN30 and HN6 lineages, while in HN19 showed slightly decreased expression. Under the action 17-AAG, in HN6 and HN19, the expression of PTEN and p53 proteins was suppressed, while Akt and Mdm2 expression was reduced. Finally, in the HN30 cell lineage were absolute absence of expression of Akt, Mdm2 and p53 and decreased expression of PTEN. These data allow us to speculate on the particular utility of 17-AAG for HNSCC treatment through the inhibition of Akt protein expression, especially in the cases that retain the expression of PTEN protein. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

˝FLUMINENSIA˝ VON FRAN KURELAC

Directory of Open Access Journals (Sweden)

Leopoldina Veronika Banaš

1990-01-01

Full Text Available Das Buch "Fluminensia" (1862 von Fran Kurelac enthält die für die Schulfestlichkeiten geschriebenen Reden, Gelegenheitsgedichte - Ehrengedichte den bedeutenden und verdienstvollen Zeitgenossen gewidmet: dem Bischof von Senj und Modrus" Mirko Ožegović, Bartol Zmajic von Bakar, dem kroatischen Ban Josip Jelačić u.a. Danach folgen Aufrufe ("Proglasi" aus stürmischem 1848, gerichtet auf die Granzlandbewohner, Deutscher, ungarische Kroaten, Rumänen und Slawonier. Die Aufrufe wurden von Kurelac im Namen der Banalregierung beschrieben. Am Ende des Buches steht eine sprachwissenschaftliche Abhandlung über die ubstantivbiegung. Die für die Schulfestlichkeiten geschreibenen Reden sind wissenschaftliche Inhalte, essaystisch-didaktisch gestalltet, mit der Meldung über die Bedeutung der Wisenschaft, über die Bedeutung und Rolle der Sprache und des Buches für den Fortschritt des Volkes. Der Verfasser widmete dieses Buch seinen ehemaligen Schülern. "Fluminensia" nimmt eine wichtige Stelle in literarischer und sprachwissenschaftlicher Schöpfung auf dem Gebiet von Rijeka und Kroatien im 19. Jahrhundert ein.

Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes

NARCIS (Netherlands)

Zhou, X.; Hampel, H.; Thiele, H.; Gorlin, R. J.; Hennekam, R. C.; Parisi, M.; Winter, R. M.; Eng, C.

2001-01-01

The molecular aetiology of Proteus syndrome (PS) remains elusive. Germline mutations in PTEN cause Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, which are hereditary hamartoma syndromes. Some features-eg, macrocephaly, lipomatosis, and vascular malformations-can be seen in all three

Von der Vielfalt einer Institution

OpenAIRE

Kabaum, Marcel; Buck, Marc Fabian

2013-01-01

Von der Vielfalt von Universitäten bzw. higher education institutions (HEIs) zu sprechen heißt, sich dem Dickicht an Komplexität zu stellen, das sich zwischen ihren Ideen und Realitäten ausbreitet. Der Text führt in den Sammelband "Ideen und Realitäten von Universitäten" ein und hebt die verschiedenen disziplinären Sichtweisen sowie die internationale Breite - Deutschland, Südamerika, USA, Afghanistan und China - der Beiträge hervor. (DIPF/Orig.)

High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients.

Science.gov (United States)

Masaki, Taro; Wang, Yun; DiGiovanna, John J; Khan, Sikandar G; Raffeld, Mark; Beltaifa, Senda; Hornyak, Thomas J; Darling, Thomas N; Lee, Chyi-Chia R; Kraemer, Kenneth H

2014-05-01

We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population. © 2014 Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Beeinflussung der Wirkung von Ernährungsinformation durch Framing: Analyse am Beispiel von Folsäure

OpenAIRE

Lensch, Kathrin; Hartmann, Monika; Simons, Johannes

2011-01-01

Die Bereitstellung und verbrauchergerechte Aufbereitung von Informationen stellt eine Möglichkeit dar, Konsumenten darin zu unterstützen, Gesundheitsaspekte vermehrt in das Kauf- und Essverhalten zu integrieren. In der Verhaltensökonomik gelten Framing-Effekte als wichtige Bestimmungsfaktoren für die Wahrnehmung von Informationen. Im Rahmen des vorliegenden Beitrags werden Framing-Effekte am Beispiel von Ernährungsinformationen über Folsäure mit Hilfe eines Experiments untersucht. Die Ergebni...

Der Einfluss von sozialer Ungleichheit und kulturellen Unterschieden auf die Wahrnehmung von finanziellen und Arbeitsplatzrisiken: Überlegungen zur Risikogesellschaft

OpenAIRE

Abbott, David; Quilgars, Deborah; Jones, Anwen

2006-01-01

Der vorliegende Artikel beruht auf Daten einer Studie, die sich mit der Frage beschäftigt, wie verschiedene soziale und kulturelle Gruppen die Risiken von Einkommens- und Arbeitsplatzverlust wahrnehmen und darauf reagieren. Autoren wie LASH, DOUGLAS und LUPTON betonten die Bedeutung von Gruppenzugehörigkeit und sozialen Kategorien für die Strukturierung der Reaktionsweisen auf verschiedene Risikoarten. Sie sprechen daher lieber von Risikokulturen als von der Risikogesellschaft. Trotzdem erken...

Prognostic and predictive value of p-Akt, EGFR, and p-mTOR in early breast cancer

Energy Technology Data Exchange (ETDEWEB)

Lazaridis, Georgios; Lambaki, Sofia [Hospital, Department of Pathology, Thessaloniki (Greece); Karayannopoulou, Georgia [Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki (Greece). Dept. of Pathology; Eleftheraki, Anastasia G. [Data Office, Athens (Greece). Section of Biostatistics; Papaspirou, Irene [Alexandra Hospital, Athens (Greece). Dept. of Pathology; Bobos, Mattheos [Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki (Greece). Lab. of Molecular Oncology; Efstratiou, Ioannis [Papageorgiou Hospital, Thessaloniki (Greece). Dept. of Pathology; Pentheroudakis, George [Ioannina Univ. Hospital, Ioannina (Greece). Dept. of Medical Oncology; Zamboglou, Nikolaos [Klinikum Offenbach (Germany). Dept. of Radiation Oncology; Fountzilas, George [Hospital, Department of Pathology, Thessaloniki (Greece); Aristotle Univ. of Thessaloniki School of Medicine, Thessaloniki (Greece). Lab. of Molecular Oncology

2014-07-15

. Formalinfixierte und in Paraffin eingebettete (FFPE) Tumorgewebeproben von 997 Patienten, welche im Rahmen von 2 adjuvanten Phase-III-Studien zytostatisch behandelt wurden, wurden auf EGFR, PTEN, p-Akt, pmTOR und PIK3CA-Mutationsstatus untersucht. Diese Marker wurden in Assoziation mit ausgewaehlten Patienten- und Tumorcharakteristika, immunhistochemischen Mammakarzinomsubtypen, dem krankheitsfreien Ueberleben (DFS) sowie dem Gesamtueberleben (OS) evaluiert. Die Expression von p-mTOR war negativ mit der Expression von EGFR, jedoch signifikant positiv mit PTEN und p-Akt473 sowie dem Nachweis von PIK3CA-Mutationen assoziiert. Die EGFR-Expression war signifikant positiv mit der Proteinexpression von p-Akt473 und p-Akt308 sowie PIK3CA-Wildtyp-Tumoren assoziiert. Die p-Akt308-Expression war ebenfalls signifikant positiv mit der Expression von p-Akt473 assoziiert. In der univariaten Analyse war sowohl die EGFR (p = 0,016), als auch die Koexpression von EGFR und p-mTOR (p = 0,015) mit einem schlechteren OS assoziiert. Unter den Patienten mit p-Akt308-negativen oder gering exprimierenden Tumoren konnte bei denjenigen, die mit einer Hormontherapie behandelt wurden, ein signifikant vermindertes Risiko fuer ein Rezidiv als auch fuer den Tod (jeweils p = 0,013 und p < 0,001) nachgewiesen werden. In der Subgruppenanalyse von Patienten mit lokoregionaerem Rezidiv konnte eine Assoziation von positivem EGFR-Status sowie mTOR-Expression mit einem jeweils erhoehten (p = 0,034) bzw. verminderten (p < 0,001) Risiko fuer das Auftreten von Fruehrezidiven nachgewiesen werden. In der multivariaten Analyse behielten die niedrigen p-Akt308-Werte und die Koexpression von EGFR und p-mTOR ihren prognostischen Wert. Eine niedrige Expression von p-Akt308 bei Patienten, die eine Hormontherapie nach einer adjuvanten Chemotherapie erhielten, war mit einem verbesserten DFS und OS assoziiert. Die Koexpression von EGFR und p-mTOR war mit einem schlechteren OS assoziiert. (orig.)

A PTEN-COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance.

Science.gov (United States)

Yan, Xiaoyan; Zhang, Chuanbao; Liang, Tingyu; Yang, Fan; Wang, Haoyuan; Wu, Fan; Wang, Wen; Wang, Zheng; Cheng, Wen; Xu, Jiangnan; Jiang, Tao; Chen, Jing; Ding, Yaozhong

2017-10-17

Collagen XVII expression has recently been demonstrated to be correlated with the tumor malignance. While Collagen XVII is known to be widely distributed in neurons of the human brain, its precise role in pathogenesis of glioblastoma multiforme (GBM) is unknown. In this study, we identified and characterized a new PTEN-COL17A1 fusion gene in GMB using transcriptome sequencing. Although fusion gene did not result in measurable fusion protein production, its presence is accompanied with high levels of COL17A1 expression, revealed a novel regulatory mechanism of Collagen XVII expression by PTEN-COL17A1 gene fusion. Knocked down Collagen XVII expression in glioma cell lines resulted in decreased tumor invasiveness, along with significant reduction of MMP9 expression, while increased Collagen XVII expression promotes invasive activities of glioma cells and associated with GBM recurrences. Together, our results uncovered a new PTEN-COL17A1 fusion gene and its novel regulatory role in Collagen XVII expression and GBM malignance, and demonstrated that COL17A1 could serve as a useful prognostic biomarker and therapeutic targets for GBM.

Redoxspeziation von endlagerrelevanten Elementen mit Hilfe von Trennmethoden gekoppelt an ein Massenspektrometer mit induktiv gekoppeltem Plasma

OpenAIRE

Graser, Carl-Heinrich

2015-01-01

Im Rahmen dieser Arbeit wurden Redoxspeziationsanalysen von Eisen, Neptunium und Plutonium per CE-SF-ICP-MS durchgeführt. Durch Optimierung der Trennparameter konnten Trennungen der Pu Oxidationsstufen III bis VI und Trennungen der Np Oxidationsstufen IV bis VI binnen 15 Minuten mit einer Nachweisgrenze von 10-12 M durchgeführt werden. Die Trennung der Fe Oxidationsstufen II und III gelang in weniger als 5 Minuten mit einer Nachweisgrenze von 5-10-8 M.

Medien und Berufsvorstellungen von Kindern: eine experimentelle Studie zum Einfluss von Kinderbüchern auf das Berufsspektrum von Kindergartenkindern

OpenAIRE

Brüggemann, Tim; Gehrau, Volker; Handrup, Jutta

2015-01-01

"Der Beitrag thematisiert zunächst den Stand der beruflichen Orientierung von Jugendlichen sowie die pädagogischen Bemühungen beim Übergang Schule-Beruf, insbesondere im Hinblick auf eine Erweiterung des häufig engen Spektrums von Berufen, die bei der Berufswahl berücksichtig werden. Dabei richten sich die Bestrebungen, diesem Problem entgegenzuwirken, bislang vor allem auf Jugendliche. Anschließend wird anhand vorliegender Ergebnisse aus der Medienforschung diskutiert, in welcher Weise Masse...

Cancer/testis Antigen-Plac1 Promotes Invasion and Metastasis of Breast Cancer through Furin/NICD/PTEN Signaling Pathway.

Science.gov (United States)

Li, Yongfei; Chu, Jiahui; Li, Jun; Feng, Wanting; Yang, Fan; Wang, Yifan; Zhang, Yanhong; Sun, Chunxiao; Yang, Mengzhu; Vasilatos, Shauna N; Huang, Yi; Fu, Ziyi; Yin, Yongmei

2018-04-28

Plac1 is a cancer-testis antigen that plays a critical role in promoting cancer initiation and progression. However, the clinical significance and mechanism of Plac1 in cancer progression remains elusive. Here we report that Plac1 is an important oncogenic and prognostic factor which physically interacts with Furin to drive breast cancer invasion and metastasis. We have shown that Plac1 expression positively correlates with clinical stage, lymph node metastasis, HR status and overall patient survival. Overexpression of Plac1 promoted invasion and metastasis of breast cancer cells in vitro and in vivo. Co-immunoprecipitation and immunofluorescence cell staining assays revealed that interaction of Plac1 and Furin degraded Notch1 and generated Notch1 intracellular domain (NICD) that could inhibit PTEN activity. These findings are consistent with the results of microarray study in MDA-MB-231 cells overexpressing Plac1. A rescue study showed that inhibition of Furin and overexpression of PTEN in Plac1 overexpression cells blocked Plac1-induced tumor cell progression. Taken together, our findings suggest that functional interaction between Plac1 and Furin enhances breast cancer invasion and metastasis and the Furin/NICD/PTEN axis may act as an important therapeutic target for breast cancer treatment. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Science.gov (United States)

Alexander, Matthew S.; Casar, Juan Carlos; Motohashi, Norio; Vieira, Natássia M.; Eisenberg, Iris; Marshall, Jamie L.; Gasperini, Molly J.; Lek, Angela; Myers, Jennifer A.; Estrella, Elicia A.; Kang, Peter B.; Shapiro, Frederic; Rahimov, Fedik; Kawahara, Genri; Widrick, Jeffrey J.; Kunkel, Louis M.

2014-01-01

Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which results in dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmdmdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmdmdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle–specific miR-486 overexpression in Dmdmdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle. PMID:24789910

Lars von Triers film

DEFF Research Database (Denmark)

Nielsen, Lisbeth Overgaard

2007-01-01

Afhandlingen undersøger Lars von Triers filmæstetik, som den kommer til udtryk i spillefilmene fra perioden 1984-2007. Afhandlingen analyserer de enkelte films stil, virkningsstrategi og betydningsdannelse.......Afhandlingen undersøger Lars von Triers filmæstetik, som den kommer til udtryk i spillefilmene fra perioden 1984-2007. Afhandlingen analyserer de enkelte films stil, virkningsstrategi og betydningsdannelse....

PTP1B Deficiency Enables the Ability of a High-Fat Diet to Drive the Invasive Character of PTEN-Deficient Prostate Cancers.

Science.gov (United States)

Labbé, David P; Uetani, Noriko; Vinette, Valérie; Lessard, Laurent; Aubry, Isabelle; Migon, Eva; Sirois, Jacinthe; Haigh, Jody J; Bégin, Louis R; Trotman, Lloyd C; Paquet, Marilène; Tremblay, Michel L

2016-06-01

Diet affects the risk and progression of prostate cancer, but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that prostate cancer progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high-fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (encoding PTP1B) enables a highly invasive disease. Prostate cancer in Pten(-/-)Ptpn1(-/-) mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding. Prostate-specific overexpression of PTP1B was not sufficient to initiate prostate cancer, arguing that it acted as a diet-dependent modifier of prostate cancer development in Pten(-/-) mice. Our findings offer a preclinical rationale to investigate the anticancer effects of PTP1B inhibitors currently being studied clinically for diabetes treatment as a new modality for management of prostate cancer. Cancer Res; 76(11); 3130-5. ©2016 AACR. ©2016 American Association for Cancer Research.

Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes.

NARCIS (Netherlands)

Menko, F.H.; Kneepkens, C.M.; Leeuw, N. de; Peeters, E.A.; Maldergem, L. van; Kamsteeg, E.J.; Davidson, R.; Rozendaal, L.; Lasham, C.A.; Peeters-Scholte, C.M.; Jansweijer, M.C.E.; Hilhorst-Hofstee, Y.; Gille, J.J.P.; Heins, Y.M.; Nieuwint, A.W.; Sistermans, E.A.

2008-01-01

Infantile juvenile polyposis is a rare disease with severe gastrointestinal symptoms and a grave clinical course. Recently, 10q23 microdeletions involving the PTEN and BMPR1A genes were found in four patients with infantile juvenile polyposis. It was hypothesized that a combined and synergistic

Dr. von Braun Briefing Walt Disney

Science.gov (United States)

1965-01-01

Dr. von Braun began his association with Walt Disney in the 1950s when the rocket scientist appeared in three Disney television productions related to the exploration of space. Years later, Dr. von Braun invited Disney and his associates to tour the Marshall Space Flight Center (MSFC) in Huntsville, Alabama. This photograph is dated April 13, 1965. From left are R.J. Schwinghamer from the MSFC, Disney, B.J. Bernight, and Dr. von Braun.

The GAS5/miR-222 Axis Regulates Proliferation of Gastric Cancer Cells Through the PTEN/Akt/mTOR Pathway.

Science.gov (United States)

Li, Yanhua; Gu, Junjiao; Lu, Hong

2017-12-01

Several lines of evidence have indicated that growth arrest-specific transcript 5 (GAS5) functions as a tumor suppressor and is aberrantly expressed in multiple cancers. GAS5 was found to be downregulated in gastric cancer (GC) tissues, and ectopic expression of GAS5 inhibited GC cell proliferation. The present study aimed to explore the underlying mechanisms of GAS5 involved in GC cell proliferation. GAS5 and miR-222 expressions in GC cell lines were estimated by quantitative real-time polymerase chain reaction. The effects of GAS5 and miR-222 on GC cell proliferation were assessed by MTT assay and 5-bromo-2-deoxyuridine (BrdU) incorporation assays. The interaction between GAS5 and miR-222 was confirmed by luciferase reporter assay and RNA immunoprecipitation assay. The protein levels of the phosphatase and tensin homolog (PTEN), phosphorylated protein kinase B (Akt) (p-Akt), Akt, phosphorylated mammalian target of rapamycin (mTOR) (p-mTOR), and mTOR were determined by western blot. GAS5 was downregulated and miR-222 was upregulated in GC cells. GAS5 directly targeted and suppressed miR-222 expression. GAS5 overexpression and miR-222 inhibition suppressed cell proliferation, increased PTEN protein level and decreased p-Akt and p-mTOR protein levels in GC cells while GAS5 knockdown and miR-222 overexpression exhibited the opposite effects. Moreover, mechanistic analyses revealed that GAS5 regulated GC cell proliferation through the PTEN/Akt/mTOR pathway by negatively regulating miR-222. GAS5/miR-222 axis regulated proliferation of GC cells through the PTEN/Akt/mTOR pathway, which facilitated the development of lncRNA-directed therapy against this deadly disease.

Der Einfluß der Ablauforganisation auf die Effizienz von Entscheidungen: Eine empirische Untersuchung am Beispiel von Bilanzanalysen

OpenAIRE

Gemünden, Hans Georg

1987-01-01

Der vorliegende Beitrag widmet sich einem in der Organisationstheorie stark vernachlässigten Problem: der Ablauforganisation von Entscheidungen. Am Beispiel von Bilanzanalysen wird empirisch geprüft, in welcher Weise eine Gliederung des Prozesses nach Verrichtungen oder Objekten die Qualität der Analyse beeinflußt. Hierzu wird ein validiertes Konzept zur Messung der Qualität von Bilanzanalysen entwickelt. Es wird gezeigt, wie man mittels prozeßbegleitender experimenteller Organisationsforschu...

Von Onlineplattformen und mittelalterlichen Märkten

Directory of Open Access Journals (Sweden)

Claudius Gräbner

2017-12-01

Full Text Available Mit der zunehmenden Digitalisierung und Vernetzung ökonomischer Systeme haben plattformbasierte Interaktionsbeziehungen stark an Bedeutung gewonnen. Hier werden zwei oder mehr Nutzungsgruppen durch eine dritte Seite, die Plattform, zusammengebracht. Die Interaktion wird in solchen zweiseitigen Märkten von den Plattformbetreibern kontrolliert. Kreditkartensysteme, Softwaremärkte oder werbefinanzierte Online-Communities stellen typische Beispiele dar. Da die Analyse von zweiseitigen Märkten mit Gleichgewichtsmodellen aufgrund der algebraischen Struktur des Problems in der Regel nicht praktikabel ist, präsentieren wir im vorliegenden Beitrag ein agentenbasiertes Modell, welches in einem kürzlich erschienenen Artikel ausführlicher diskutiert wird. Anhand von illustrativen Beispielen verdeutlichen wir die Implikationen eines agentenbasierten Ansatzes für die Innovationsökonomik im Allgemeinen und das Studium von Technologieentwicklung im Besonderen.

Verbesserung der Symmetrie von Hirnaufnahmen entlang der Sagittalebene

Science.gov (United States)

Ens, Konstantin; Wenzel, Fabian; Fischer, Bernd

Die lokale Symmetrie von Hirnscans entlang der Sagittalebene zu ermitteln und zu modizifieren, ist für eine Reihe neurologischer Anwendungen interessant. Beispielsweise kann der voxelweise Vergleich von rechter und linker Hirnhälfte nur dann Aufschluss über die Lokalisierung von Läsionen geben, wenn durch Transformation ein Hirnscan eine möglichst hohe Symmetrie aufweist. Ein weiteres Anwendungsgebiet ist die Visualisierung von medialen Hirnschnitten, für die die Trennfläche beider Hirnhälfte möglichst eben sein sollte. Diese Arbeit stellt die Entwicklung eines Verfahrens vor, mit dessen Hilfe die Symmetrie von Hirnaufnahmen entlang der Sagittalebene verbessert werden kann. Dies geschieht unter Verwendung von aktiven Konturen, die mit Hilfe einer neuartigen Kostenfunktion gesteuert werden. Experimente am Ende der Arbeit mit strukturellen Kernspinaufnahmen demonstrieren die Leistungsfähigkeit des Verfahrens.

Jacob Stael von Holstein ja palladionism eesti arhitektuuris / Ants Hein

Index Scriptorium Estoniae

Hein, Ants, 1952-

2005-01-01

Sõjaväeinsenerist ja arhitektist Jacob Stael von Holsteinist (1628, Pärnu-1679), tema kavandatud hoonetest ja rollist 17. sajandi II poole arhitektuuris. Fabian von Ferseni Toompeal Lossiplatsil asunud elamust (lammutati 1894) ja Maardu mõisahoonest, Hans von Ferseni Mäo mõisahoonest Järvamaal, Otto Wilhelm von Ferseni majast Toompeal, Axel von Roseni majast Tallinnas Pikk t. 28 (1670-74), Otto Reinhold von Taube majast Tartus (hävinud), J. S. von Holsteini enda hoonetest: majast Tallinnas Toompea 1, Anija mõisahoonest, elamust Riias jm. Bibliograafia lk. 452

Deletion of PTEN Produces Deficits in Conditioned Fear and Increases Fragile X Mental Retardation Protein

Science.gov (United States)

Lugo, Joaquin N.; Smith, Gregory D.; Morrison, Jessica B.; White, Jessika

2013-01-01

The phosphatase and tensin homolog detected on chromosome 10 (PTEN) gene product modulates activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The PI3K pathway has been found to be involved in the regulation of the fragile X mental retardation protein, which is important for long-term depression and in the formation of new…

Deletion of the N-terminus of IKKγ induces apoptosis in keratinocytes and impairs the AKT/PTEN signaling pathway

International Nuclear Information System (INIS)

Leis, Hugo; Sanchis, Ana; Perez, Paloma

2007-01-01

The regulatory subunit IKKγ/NEMO is crucial for skin development and function and although devoid of kinase activity, loss of IKKγ function completely abolishes the activation of NF-κB by all pro-inflammatory cytokines. To inhibit the IκB kinase (IKK) complex in keratinocytes, we have used a dominant negative approach by generating stable transfectants of an N-terminal deletion of IKKγ (IKKγ-DN97) that uncouples formation of the IKK complex. Expression of this mutant in PB keratinocytes (PB-IKKγ-DN97) delayed growth kinetics, caused morphological changes and dramatically augmented apoptosis even in the absence of pro-apoptotic stimuli, as determined by cell morphology, TUNEL and caspase-3 cleavage. Moreover, in PB-IKKγ-DN97 cells, TNF-α and IL-1 treatment failed to induce degradation of IκBα, phosphorylation of p65 on Ser 536 and nuclear translocation which, consequently, reduced κB-binding activity. In PB-IKKγ-DN97 cells, accumulation of IκBα correlated with a downregulation of AKT activity and an increase of PTEN protein levels whereas pro-apoptotic p53 target genes Bax and Puma were upregulated. These effects were most likely mediated through IKK since coexpression of the wild-type form of IKKγ in keratinocytes partially reversed apoptosis and reduced PTEN expression. Thus, our data suggest a negative cross-talk mechanism involving PTEN and NF-κB, critical for the anti-apoptotic role of NF-κB in keratinocytes

A note on derivations of Murray–von Neumann algebras

Science.gov (United States)

Kadison, Richard V.; Liu, Zhe

2014-01-01

A Murray–von Neumann algebra is the algebra of operators affiliated with a finite von Neumann algebra. In this article, we first present a brief introduction to the theory of derivations of operator algebras from both the physical and mathematical points of view. We then describe our recent work on derivations of Murray–von Neumann algebras. We show that the “extended derivations” of a Murray–von Neumann algebra, those that map the associated finite von Neumann algebra into itself, are inner. In particular, we prove that the only derivation that maps a Murray–von Neumann algebra associated with a factor of type II1 into that factor is 0. Those results are extensions of Singer’s seminal result answering a question of Kaplansky, as applied to von Neumann algebras: The algebra may be noncommutative and may even contain unbounded elements. PMID:24469831

A note on derivations of Murray-von Neumann algebras.

Science.gov (United States)

Kadison, Richard V; Liu, Zhe

2014-02-11

A Murray-von Neumann algebra is the algebra of operators affiliated with a finite von Neumann algebra. In this article, we first present a brief introduction to the theory of derivations of operator algebras from both the physical and mathematical points of view. We then describe our recent work on derivations of Murray-von Neumann algebras. We show that the "extended derivations" of a Murray-von Neumann algebra, those that map the associated finite von Neumann algebra into itself, are inner. In particular, we prove that the only derivation that maps a Murray-von Neumann algebra associated with a factor of type II1 into that factor is 0. Those results are extensions of Singer's seminal result answering a question of Kaplansky, as applied to von Neumann algebras: The algebra may be noncommutative and may even contain unbounded elements.

Analyse der pharmazeutischen Versorgungssituation von Patienten mit Psoriasis-Arthritis auf Basis von Routinedaten der Gesetzlichen Krankenversicherung.

Science.gov (United States)

Sondermann, Wiebke; Ventzke, Julia; Matusiewicz, David; Körber, Andreas

2018-03-01

Die Psoriasis-Arthritis (PsA) gehört zu den chronisch entzündlichen Gelenkerkrankungen. Trotz zahlreicher versorgungswissenschaftlicher Studien in Deutschland liegen zur pharmazeutischen Versorgungssituation von PsA-Patienten bisher kaum aktuelle Ergebnisse vor. Mit Hilfe einer systematischen Literaturrecherche sowie anhand von Routinedaten der Allgemeinen Ortskrankenkasse (AOK) Rheinland/Hamburg wird ein aktueller Überblick über die pharmazeutische Versorgung von PsA-Patienten in Deutschland gegeben. Selektiert wurden Versicherte aus dem ambulanten und stationären Bereich, die im 1. und 2. Quartal des Jahres 2014 die gesicherte Abrechnungsdiagnose Psoriasis-Arthritis L40.5+ aufwiesen. Anschließend wurden auf Basis dieser "vorab definierten" Kohorte die Arzneimitteldaten für 5 Jahre (01.01.2010-31.12.2014) abgerufen. Es konnten insgesamt n  =  3205 Versicherte (45 % männlich, 55 % weiblich) der AOK Rheinland/Hamburg mit einer gesicherten PsA-Diagnose selektiert werden. Das Durchschnittsalter betrug 58,9 Jahre. 53,7 % der PsA-Patienten wurden mit systemischen PsA-relevanten Arzneimitteln versorgt. Nichtsteroidale Antirheumatika (NSAR) wurden am häufigsten verordnet, gefolgt von systemischen Glucocorticoiden. Von den selektierten PsA-Patienten, die eine Systemtherapie erhielten, wurden 72,1 % mittels einer Disease-modifying-antirheumatic-Drug (DMARD)-Monotherapie behandelt, gefolgt von der Kombinationstherapie aus DMARDs und Biologika (20,9 %). Die pharmakologische Therapie der PsA muss eine Gewährleistung zwischen adäquater Versorgung der PsA mit Verhinderung der Krankheitsprogression und ökonomischer Verantwortung darstellen. © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Rezension von: Gabriele Dietze: Weiße Frauen in Bewegung. Genealogien und Konkurrenzen von Race- und Genderpolitiken. Bielefeld: transcript Verlag 2013.

Directory of Open Access Journals (Sweden)

Philipp Dorestal

2014-03-01

Full Text Available Gabriele Dietze zeichnet das Verhältnis der Kategorien Race und Gender innerhalb der US-amerikanischen Geschichte von der Mitte des 19. Jahrhunderts bis zur Präsidentschaftswahl von Barack Obama nach. Dabei demonstriert sie anhand von zentralen Figuren der weißen Frauenbewegung deren ambivalente Positionen, die oftmals für progressive Inhalte wie das Eintreten für Frauenrechte stehen, gleichzeitig aber dann Anliegen von African Americans nicht artikulieren oder gar zum Schweigen bringen. Ebenso zeigt Dietze mithilfe von Texten einiger schwarzer Autor_innen sowie anhand berühmter Gerichtsprozesse, dass schwarze Emanzipation nicht notwendigerweise mit feministischen Positionen einhergehen musste, sondern sich vielmehr eine Konkurrenzsituation zwischen Race und Gender entspann.

MiR-155 promotes cell proliferation and inhibits apoptosis by PTEN signaling pathway in the psoriasis.

Science.gov (United States)

Xu, Longjiang; Leng, Hong; Shi, Xin; Ji, Jiang; Fu, Jinxiang; Leng, Hong

2017-06-01

MicroRNAs (miRNAs) have been demonstrated to contribute to malignant progression in psoriasis development. The purposes of the study was to evaluated the effects of miRNA-155 on cell proliferation, migration and apoptosis in psoriasis development via PTEN singaling pathway and identify its direct target protein. Quantitative real-time RT-PCR (qRT-PCR) was performed to examine the level of miR-155 in psoriasis cells, miR-155 was downregulated in a psoriasis cell line Hacat by transfected with small interfering RNA (siRNA), respectively. Cell survival was detected by the MTT assay and colony formation assay. Cell migration and invasion were measured via wound-healing assayand transwell assay. In addition, cell cycle and apoptosis about psoriasis cells was measured by flow cytometry. In this study, qRT-PCR assay showed that the expressions of miR-155 mRNA in psoriasis tissues were significantly higher than that in normal tissues. The assays about cell growth and proliferation showed that miR-155 knockdown led to a significant decrease in cell proliferation which was determined by MTT assay and colony formation assay compared to those of Lv-NC cells. Flow cytometry analysis showed that depletion of miR-155 could cause cell cycle change and the number of apoptotic cells was significantly increased in Lv-miR155 cells compared with control cells. In addition, the expression of several apoptosis-related factors were dramatically changed, such as PTEN, PIP 3 , AKT, p-AKT, Bax and Bcl-2. Our findings indicate that down-regulation of miR-155 significantly inhibits proliferation, migration, invasion and promotes apoptosis through PTEN singaling pathway in psoriasis cells. miR-155 might function as an oncogene miRNA in the progress of psoriasis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Wohnquartiersbeschreibung: ein Instrument zur Regionalisierung von Nachbarschaften

OpenAIRE

Hoffmeyer-Zlotnik, Jürgen H. P.

2001-01-01

'Ausgehend von der Annahme, daß soziale Differenzierung sich in räumlicher Differenzierung niederschlägt, bietet eine Beschreibung der Struktur des näheren Wohnumfeldes die Möglichkeit, das Wohnquartier als Handlungsraum und Sozialisationsinstanz zur Interpretation von Umfragedaten zu nutzen. Das vorliegende Instrumentarium erlaubt es, das Wohnquartier unabhängig von Zensusdaten über Merkmale, die in der eigenen Umfrage erhoben werden, zu charakterisieren.' (Autorenreferat) 'The general hy...

Optimized sampling of hydroperoxides and investigations of the water vapour dependence of hydroperoxide formation during ozonolysis of alkenes; Optimierung der Probenahme von Hydroperoxiden und Untersuchungen zur Wasserdampfabhaengigkeit der Bildung von Hydroperoxiden bei der Ozonolyse von Alkenen

Energy Technology Data Exchange (ETDEWEB)

Becker, K.H.; Plagens, H.

1997-06-01

There are several sampling methods for hydroperoxides none of which is particularly reliable. The authors therefore tested three new methods in order to optimize hydroperoxide sampling and, using the optimized sampling procedure, to investigate the water vapour dependence of hydroperoxide formation during ozonolysis of alkenes. (orig.) [Deutsch] Fuer die Probenahme von Hydroperoxiden existieren verschiedene Verfahren, von denen bisher keines als besonders zuverlaessig angesehen werden konnte. Daher wurden in dieser Arbeit drei Verfahren getestet, um die Probenahme von Hydroperoxiden zu optimieren und mit dem entsprechenden Verfahren die Wasserdampfabhaengigkeit der Bildung von Hydroperoxiden bei der Ozonolyse von Alkenen zu untersuchen. (orig.)

Homopteren von Java, gesammelt von Herrn Edw. Jacobson

NARCIS (Netherlands)

Melichar, L.

1914-01-01

Herr Edw. Jacobson hat auf Java in den Jahren 1908— 1910 Homopteren gesammelt und mir die Bearbeitung des gesammelten Materiales übertragen. Die Jacobson’sche Ausbeute ist insoferne bemerkenswert, als dieselbe viele Mikrohomopteren enthält, welche von nichtfachkundigen Sammlern gewöhnlich nicht

[Anja Wilhelmi. Lebensweltlen von Frauen der deutschen Oberschicht im Baltikum (1800-1939). Eine Untersuchung anhand von Autobiographien] / Alexander Ewig

Index Scriptorium Estoniae

Ewig, Alexander, 1980-

2011-01-01

Arvustus: Wilhelmi, Anja. Lebenswelten von Frauen der deutschen Oberschicht im Baltikum (1800-1939). Eine Untersuchung anhand von Autobiographien. (Veröffentlichungen des Nordost-Instituts, 10.) (Wiesbaden : HArrassowitz 2008)

Phenotype selection reveals coevolution of muscle glycogen and protein and PTEN as a gate keeper for the accretion of muscle mass in adult female mice.

Directory of Open Access Journals (Sweden)

Mandy Sawitzky

Full Text Available We have investigated molecular mechanisms for muscle mass accretion in a non-inbred mouse model (DU6P mice characterized by extreme muscle mass. This extreme muscle mass was developed during 138 generations of phenotype selection for high protein content. Due to the repeated trait selection a complex setting of different mechanisms was expected to be enriched during the selection experiment. In muscle from 29-week female DU6P mice we have identified robust increases of protein kinase B activation (AKT, Ser-473, up to 2-fold if compared to 11- and 54-week DU6P mice or controls. While a number of accepted effectors of AKT activation, including IGF-I, IGF-II, insulin/IGF-receptor, myostatin or integrin-linked kinase (ILK, were not correlated with this increase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN was down-regulated in 29-week female DU6P mice. In addition, higher levels of PTEN phosphorylation were found identifying a second mechanism of PTEN inhibition. Inhibition of PTEN and activation of AKT correlated with specific activation of p70S6 kinase and ribosomal protein S6, reduced phosphorylation of eukaryotic initiation factor 2α (eIF2α and higher rates of protein synthesis in 29-week female DU6P mice. On the other hand, AKT activation also translated into specific inactivation of glycogen synthase kinase 3ß (GSK3ß and an increase of muscular glycogen. In muscles from 29-week female DU6P mice a significant increase of protein/DNA was identified, which was not due to a reduction of protein breakdown or to specific increases of translation initiation. Instead our data support the conclusion that a higher rate of protein translation is contributing to the higher muscle mass in mid-aged female DU6P mice. Our results further reveal coevolution of high protein and high glycogen content during the selection experiment and identify PTEN as gate keeper for muscle mass in mid-aged female DU6P mice.

Clarifying the link between von Neumann and thermodynamic entropies

Science.gov (United States)

Deville, Alain; Deville, Yannick

2013-01-01

The state of a quantum system being described by a density operator ρ, quantum statistical mechanics calls the quantity - kTr( ρln ρ), introduced by von Neumann, its von Neumann or statistical entropy. A 1999 Shenker's paper initiated a debate about its link with the entropy of phenomenological thermodynamics. Referring to Gibbs's and von Neumann's founding texts, we replace von Neumann's 1932 contribution in its historical context, after Gibbs's 1902 treatise and before the creation of the information entropy concept, which places boundaries into the debate. Reexamining von Neumann's reasoning, we stress that the part of his reasoning implied in the debate mainly uses thermodynamics, not quantum mechanics, and identify two implicit postulates. We thoroughly examine Shenker's and ensuing papers, insisting upon the presence of open thermodynamical subsystems, imposing us the use of the chemical potential concept. We briefly mention Landau's approach to the quantum entropy. On the whole, it is shown that von Neumann's viewpoint is right, and why Shenker's claim that von Neumann entropy "is not the quantum-mechanical correlate of thermodynamic entropy" can't be retained.

Privatiserung von Geschichte. Probleme einer differenzierten Aufarbeitung

Directory of Open Access Journals (Sweden)

Birthe Kundrus

2000-11-01

Full Text Available Ausgangspunkt der Untersuchung von Vera Neumann ist die These, daß im Krieg Erlebtes und Erlittenes in den Wiederaufbau- und Wirtschaftswunderjahren Westdeutschlands einem Thematisierungstabu unterlegen sei. Anhand von 50 Interviews, die in den 80er Jahren im Rahmen des von Lutz Niethammer geleiteten Projekts „Lebensgeschichte und Sozialgeschichte im Ruhrgebiet 1930–1960“ (LUSIR entstanden sind und die sie jetzt anhand der Tonbandprotokolle und Abschriften ein zweites Mal auswertet, möchte die Historikerin diese Verschüttungen aufspüren. Im Anschluß an Niethammers These der „Privatisierung von Geschichte“ will sie zeigen, daß seelische und körperliche Kriegsfolgen wie Deprivations- und Überlastungsgefühle, der Verlust von Angehörigen und Kriegsbeschädigungen „privatisiert“, d.h. an die Familien übertragen wurden. Dort seien dann in erster Linie die weiblichen Familienmitglieder mit der Versorgungs- und Pflegearbeit konfrontiert worden. An vier Fallbeispiele schließt sich eine detaillierte Auswertung des gesamten Interviewmaterials an. Diesen Teilen folgt ein Abschnitt zur staatlichen Kriegsopferversorgung in der frühen Bundesrepublik.

Erzeugung gleichverteilter Stichproben von Lozenge-Teilungen mittels Kopplung von Markovketten

OpenAIRE

Keller, Peter

2011-01-01

Aus dem Inhalt: 1 Einleitung 2 Eigenschaften der Lozengeteilungen 3 Coupling From The Past (CFTP) 4 Simulation von uniform verteilten Lozengeteilungen 5 Programmlisting und Diskussion der Implementierung 6 Ausblick A Anhang

Visualisierung von typisierten Links in Linked Data

Directory of Open Access Journals (Sweden)

Georg Neubauer

2017-09-01

Full Text Available Das Themengebiet der Arbeit behandelt Visualisierungen von typisierten Links in Linked Data. Die wissenschaftlichen Gebiete, die im Allgemeinen den Inhalt des Beitrags abgrenzen, sind das Semantic Web, das Web of Data und Informationsvisualisierung. Das Semantic Web, das von Tim Berners Lee 2001 erfunden wurde, stellt eine Erweiterung zum World Wide Web (Web 2.0 dar. Aktuelle Forschungen beziehen sich auf die Verknüpfbarkeit von Informationen im World Wide Web. Um es zu ermöglichen, solche Verbindungen wahrnehmen und verarbeiten zu können sind Visualisierungen die wichtigsten Anforderungen als Hauptteil der Datenverarbeitung. Im Zusammenhang mit dem Sematic Web werden Repräsentationen von zuhammenhängenden Informationen anhand von Graphen gehandhabt. Der Grund des Entstehens dieser Arbeit ist in erster Linie die Beschreibung der Gestaltung von Linked Data-Visualisierungskonzepten, deren Prinzipien im Rahmen einer theoretischen Annäherung eingeführt werden. Anhand des Kontexts führt eine schrittweise Erweiterung der Informationen mit dem Ziel, praktische Richtlinien anzubieten, zur Vernetzung dieser ausgearbeiteten Gestaltungsrichtlinien. Indem die Entwürfe zweier alternativer Visualisierungen einer standardisierten Webapplikation beschrieben werden, die Linked Data als Netzwerk visualisiert, konnte ein Test durchgeführt werden, der deren Kompatibilität zum Inhalt hatte. Der praktische Teil behandelt daher die Designphase, die Resultate, und zukünftige Anforderungen des Projektes, die durch die Testung ausgearbeitet wurden.

Diffusion von Leerstelleninseln auf Cu(111)

NARCIS (Netherlands)

Verheij, Laurens K.; Schlößer, Dietmar; Rosenfeld, Georg

1998-01-01

Die zufällige Bewegung von Leerstelleninseln wurde bisher vorwiegend in einem Bild beschrieben, das von der Diffusion einzelner Atome ausgeht. In diesem Bild kann man Inseldiffusion durch die Einstein-Beziehung für Brownsche Bewegung ((Δ r)2 = 4 D Δ t) beschreiben. Für die Diffusionskonstante D wird

[Heinz von zur Mühlen. Das Bürgertum Fordert Blut. Ein Bolschewistiches Flugblatt von 1918] / Paul Kaegbein

Index Scriptorium Estoniae

Kaegbein, Paul

2007-01-01

Arvustus: Heinz von zur Mühlen. Das Bürgertum Fordert Blut. Ein Bolschewistiches Flugblatt von 1918. In : Ostseeprovinzen, baltische Staaten und das Nationale. Münster : LIT, 2005, lk. 403-414. 1918. aastast pärit lendlehest, mille käekirja järgi otsustades on kirjutanud Viktor Kingissepp

The effect of intense intermittent training with and without taking vitamin E on mRNA expression of p53/PTEN tumor suppressing genes in prostate glands of male rats

Directory of Open Access Journals (Sweden)

Mohammad Esmaeil Afzalpour

2016-11-01

Full Text Available Physical activity and diet are the most important modifiable determinants of cancer risk. The objective of this study was to examine the effect of intense intermittent training with and without taking vitamin E on expression of p53 and PTEN tumor suppressing genes in the prostate gland of male rats. For this purpose, 50 Sprague-Dawley male rats were randomly assigned into 5 groups: [1] control (CON, n = 10, [2] sham (S, n = 10, [3] intense intermittent training (IIT, n = 10, [4] intense intermittent training + vitamin E (IIT + VE, n = 10, [5] vitamin E (VE, n = 10. Protocol of this study was implemented for 6 days per week for 6 weeks, with observing the overload principle on the motorized treadmill. After implementing training protocol, expression rate of p53 and PTEN genes reduced significantly (p<0.000, p<0.031, respectively. Taking vitamin E with intermittent training caused significant reduction in p53 expression (p<0.013, while it caused significant increase in expression of PTEN (p<0.035. These results showed that intense intermittent training reduces expression of p53 and PTEN tumor suppressing genes and taking supplementation vitamin E along with this type of training could cause different effects in expression of these tumor suppressor genes.

Pharmakobotanische Untersuchungen von Lavendelsorten auf dem Plattensee- Plateau

Directory of Open Access Journals (Sweden)

Tóth, Frida

2014-09-01

Full Text Available Auf dem Hof Dörgicsei Levendula Major GmbH wurden 9 Lavendelsorten (6 Sorten von Lavandula angustifolia und 3 Sorten von Lavandula x intermedia untersucht. Neben den morphologischen und Wachstumseigenschaften wurden auch Frisch- und Trockengewichte bewertet. Quantitative und qualitative Untersuchungen von den Blüten- und Ätherischöldrogen wurden auch durchgeführt. Die statistische Analyse zeigte signifikant höhere Erträge bei den Sorten L. angustifolia ’Essence Purple’ und L. x intermedia ’Edelweiss’. Gehalt und Zusammensetzung von ätherischem Öl war eindeutig bei der Sorte L. angustifolia ’Ellagance Purple’ am günstigsten.

Speziation von Gadolinium-MRT-Kontrastmitteln in Umweltmatrizes

OpenAIRE

Lindner, Uwe

2017-01-01

Gd-Kontrastmittel werden in der Medizin für die Magnetresonanztomographie (MRT) benötigt, um einen besseren Bildkontrast zu erzielen. Nach der Anwendung gelangen diese Arzneimittel über das Abwasser in die Klärwerke und von dort in die jeweiligen anliegenden Oberflächengewässer. Somit wird es notwendig, den Verbleib der Gd-MRT-Kontrastmittel in der Umwelt zu verfolgen und aufzuklären. In dieser Arbeit werden für die Analyse von Umweltproben Methoden zur Speziesanalytik von Gd-Kontrastmitteln ...

Spectral theory and quotients in Von Neumann algebras | West ...

African Journals Online (AJOL)

In this note we consider to what extent the functional calculus and the spectral theory in von Neumann algebras are preserved by the taking of quotients relative to two-sided ideals of the von Neumann algebra. Keywords:von Neumann algebra, functional calculus, spectral theory, quotient algebras. Quaestiones ...

Correlation analysis of expressions of PTEN and p53 with the value obtained by magnetic resonance spectroscopy and apparent diffusion coefficient in the tumor and the tumor-adjacent area in magnetic resonance imaging for glioblastoma.

Science.gov (United States)

Li, Yunyun; Ji, Feng; Jiang, Yuzhi; Zhao, Ting; Xu, Chongfu

2018-01-01

To explore the correlation of the expression levels of phosphate and tension homology deleted on chromosome ten (PTEN) and p53 of glioblastoma multiforme (GBM) with the value obtained by magnetic resonance spectroscopy (MRS) and apparent diffusion coefficient (ADC) in the tumor and the tumor-adjacent area in magnetic resonance imaging (MRI). A total of 38 patients were operated for GBM. All the patients had received diffusion-weighted imaging (DWI) and MRS prior to surgery. ADC of water molecules and values of metabolite indexes of MRS, including n-acetyl aspartate (NAA), choline (Cho) and creatine (Cr), were recorded, and the ratios of Cho/NAA, Cho/Cr and NAA/Cr were calculated. Hematoxylin-eosin (H&E) staining was done to examine the morphology of tumor and of tumor-adjacent tissues; immunohistochemistry (IHC) was performed to examine the expressions of PTEN and p53 in the tumor and the tumor-adjacent area. Finally, the correlations of the expressions of PTEN and p53 with ADC, Cho/NAA, Cho/Cr and NAA/Cr of the tumor and the tumor-adjacent area were analyzed. H&E staining showed that GBM tissues had disordered morphology, different sizes of cells, large cell nuclei and significant cell heterogeneity. IHC indicated that the expression level of p53 protein in the tumor was significantly higher than in the tumor-adjacent tissues (pCorrelation analysis indicated that PTEN levels in the tumor and the tumor-adjacent area were positively correlated with ADC in the corresponding area, while p53 in the tumor and the tumor-adjacent area was negatively correlated with ADC in the corresponding area. Cho/NAA and Cho/Cr in the tumor were positively correlated with p53 in the tumor, but negatively correlated with PTEN in the tumor. However, NAA/Cr of the tumor was irrelevant to the levels of PTEN and p53. The test results of DWI and MRS of patients with GBM can accurately reflect the inactivation or mutation of PTEN and p53.

[Albert Reder Ritter von Schellmann (1826-1904)].

Science.gov (United States)

Schmidt, G; Holubar, K

1990-01-01

Albert Reder von Schellmann (1826-1904) was an important syphilidologist of the Vienna Medical School in the second half of the nineteenth century. He went in for the dualistic concept of the origin of syphilis and ulcer caused by soft chancre. In 1870 - Reder became head of a third dermato-syphilidologic department in the "Josephinum" in Vienna, where military surgeons got their medical education. At the same time the two full professorships of dermatosyphilidology in the Vienna General Hospital were held by Ferdinand von Hebra (1816-1880) and Carl Ludwig Sigmund von Ilanor (1810-1883).

PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma

International Nuclear Information System (INIS)

Chiosea, Simion I; Nikiforova, Marina N; Grandis, Jennifer R; Lui, Vivian W Y; Diergaarde, Brenda; Maxwell, Jessica H; Ferris, Robert L; Kim, Seungwon W; Luvison, Alyssa; Miller, Megan

2013-01-01

Recent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway. PIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]). Overall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma

Overexpression of miR-21 in stem cells improves ovarian structure and function in rats with chemotherapy-induced ovarian damage by targeting PDCD4 and PTEN to inhibit granulosa cell apoptosis.

Science.gov (United States)

Fu, Xiafei; He, Yuanli; Wang, Xuefeng; Peng, Dongxian; Chen, Xiaoying; Li, Xinran; Wang, Qing

2017-08-14

Chemotherapy-induced premature ovarian failure (POF) is a severe complication affecting tumor patients at a childbearing age. Mesenchymal stem cells (MSCs) can partially restore the ovarian structure and function damaged by chemotherapy. miR-21 is a microRNA that can regulate cell apoptosis. This study discusses the repair effect and mechanism of MSCs overexpressing miR-21 on chemotherapy-induced POF. Rat MSCs and granulosa cells (GCs) were isolated in vitro. MSCs were transfected with miR-21 lentiviral vector (LV-miR-21) to obtain MSCs stably expressing miR-21 (miR-21-MSCs). The microenvironment of an ovary receiving chemotherapy was mimicked by adding phosphamide mustard (PM) into the cellular culture medium. The apoptosis rate and the mRNA and protein expression of target genes PTEN and PDCD4 were detected in MSCs. Apoptosis was induced by adding PM into the culture medium for GCs, which were cocultured with miR-21-MSCs. The apoptosis rate and the mRNA and protein expression of PTEN and PDCD4 were detected. The chemotherapy-induced POF model was built into rats by intraperitoneal cyclophosphamide injection. miR-21-MSCs were transplanted into the bilateral ovary. The rats were sacrificed at 15, 30, 45, and 60 days after the last injection. The ovarian weights, follicle count, estrous cycle, and sex hormone levels (estradiol (E2) and follicle-stimulating hormone (FSH)) were detected. Apoptosis of GCs was determined by TUNEL assay. The miR-21 and mRNA and protein expression of PTEN and PDCD4 were determined. The apoptosis decreased in MSCs transfected with miR-21. The mRNA and protein expression of target genes PTEN and PDCD4 was downregulated. GCs cocultured with miR-21-MSCs showed a decreased apoptosis, an upregulation of miR-21, and a downregulation of PTEN and PDCD4. Following the injection of miR-21-MSCs, the ovarian weight and follicle counts increased; E 2 levels increased while FSH levels decreased, with less severe apoptosis of GCs. The miR-21 expression

Das Geschäftsmodell von Retail Banken im Wandel der Digitalisierung

OpenAIRE

Messikommer, Cédric

2016-01-01

Der Prozess der Digitalisierung führt in unterschiedlichen Branchen zu tiefgreifenden Veränderungen. Dazu gehört auch der Finanzsektor, dessen Umfeld von erodierenden Margen und Tiefstzinsen geprägt ist. Die Digitalisierung hat weitreichende Auswirkungen auf die Geschäftsmodelle von Banken und speziell von Retail Banken. Deren Basisdienstleistungen werden zunehmend von neuen Mitbewerbern mit modernster Internet-Technologie angeboten. Damit sind wesentliche Teile der Wertschöpfungskette von Re...

The need for company information manuals - Benefits of industry-wide standard solutions; Notwendigkeit von Betriebshandbuechern - Vorteile von Branchen-Standardloesungen

Energy Technology Data Exchange (ETDEWEB)

Sporleder, R.; Winter, G. [Stadtwerke Rostock AG (Germany)

2000-07-01

The paper explains the need for and the usefulness of company information manuals for companies of the energy sector. (orig./CB) [German] Im folgenden wird anhand von Kernsaetzen die Notwendigkeit von Betriebshandbuechern begruendet. Es wird offensichtlich, dass Geschaeftsfuehrungen von sicherheitsrelevanten Unternehmen wohlberaten sind, die in verschiedenen Vorschriften geforderte betriebliche Umsetzung des Inhalts dieser Vorschriften auf die firmeninternen Organisationsstrukturen vorzunehmen. Diese Umsetzung hilft intern, die betrieblichen Verantwortlichkeiten festzulegen, Verfahrensablaeufe zu bestimmen und erhoeht im Schadensfall erheblich die Chance fuer die jeweilige Geschaeftsfuehrung, den strafrechtlichen Vorwurf des Organisationsverschuldens abzuwehren. (orig./CB)

Die Rolle von RANK-Ligand und Osteoprotegerin bei Osteoporose

Directory of Open Access Journals (Sweden)

Hofbauer LC

2004-01-01

Full Text Available Receptor activator of nuclear factor (NF- κB ligand (RANKL, sein zellulärer Rezeptor RANK und der Decoy-Rezeptor Osteoprotegerin (OPG stellen ein essentielles Zytokinsystem für die Zellbiologie von Osteoklasten dar. Verschiedene Untersuchungen belegen die Bedeutung von Störungen des OPG/RANKL/RANK-Systems bei der Pathogenese metabolischer Knochenerkrankungen. In dieser Arbeit werden die wichtigsten Störungen des OPG/RANKL/RANK-Systems bei verschiedenen Osteoporoseformen dargestellt. Östrogenrezeptor- (ER- Agonisten wie 17 β-Östradiol, Raloxifen und Genistein stimulieren die osteoblastäre Produktion von OPG durch Aktivierung von ER- α in vitro, während Lymphozyten von Patientinnen mit Östrogenmangel RANKL überexprimieren. Die parenterale Gabe von OPG vermag den mit Östrogenmangel assoziierten Knochenverlust im Tiermodell und in einer kleineren klinischen Studie zu verhindern. Glukokortikoide und Immunsuppressiva steigern gleichzeitig die RANKL-Expression und hemmen die OPG-Produktion in osteoblastären Zellen in vitro. Glukokortikoide sind auch in vivo imstande, die OPG-Serumspiegel deutlich zu reduzieren. Dagegen hemmen biomechanische Reize in vitro die RANKL-Produktion und steigern die OPG-Produktion. Ein Fehlen dieser biomechanischen Reize bei längerer Immobilisierung kann daher den RANKL/OPG-Quotienten steigern, während die tierexperimentelle Immobilisierungs-Osteoporose durch die parenterale Gabe von OPG gemildert werden kann.

Arbeitszeiten von Professorinnen und Professoren in Deutschland 2016

OpenAIRE

Weihs, Claus; Hernández Rodríguez, Tanja; Doeckel, Maximilian; Marty, Christoph; Wormer, Holger

2018-01-01

In dieser Studie werden belastbare Prognoseintervalle der wöchentlichen Gesamtarbeitszeit von Universitätsprofessorinnen und -professoren aus Daten einer Umfrage aus dem Jahre 2016 und a-priori Informationen aus früheren Studien bestimmt. Neben der Gesamtarbeitszeit werden auch Teilarbeitszeiten zum Beispiel für Lehre und Forschung ermittelt. Die Ergebnisse von frequentistischer und Bayesianischer Analyse werden verglichen. Aus den gültigen Fragebögen von aktiven Vollzeit arbeitenden Universi...

IAS 25, Bilanzierung von Finanzinvestitionen (Accounting for Investments)

OpenAIRE

Steiner, Manfred

1997-01-01

IAS 25, Bilanzierung von Finanzinvestitionen (Accounting for Investments). - In: Rechnungslegung nach International Accounting Standards (IAS) / hrsg. von Jörg Baetge ... - Stuttgart : Schäffer-Poeschel, 1997. - S. 923-953

Politische Bildung im Kontext von Regierung, Unterricht und Zucht

Directory of Open Access Journals (Sweden)

Thomas Rucker

2014-02-01

Full Text Available Johann Friedrich Herbart (1776-1841 gilt als der Begründer der wissenschaftlichen Pädagogik. In diesem Beitrag wird zu zeigen versucht, dass Herbart die Unterstützung politischer Bildung als eine Aufgabe von Regierung, Unterricht und Zucht bestimmt und in seinem Werk wichtige „Bausteine“ für eine Theorie der politischen Bildung unter den Bedingungen von Erziehung vorlegt hat. Nach Herbart ist das politische Selbst- und Weltverhältnis auf Sachverhalte bezogen, die nicht nur die Lebensführung einzelner Menschen, sondern die Lebensführung einer Mehrzahl von Menschen betreffen. Nicht das Zusammenleben von Menschen generell ist jedoch Orientierungsgesichtspunkt des politischen Selbst- und Weltverhältnisses, sondern nur das problematisch gewordene Zusammenleben. Politik ergibt sich nach Herbart aus einem Konflikt hinsichtlich der Frage, wie das Zusammenleben von Menschen geregelt sein sollte. Während die Regierung lediglich mittelbar einen Beitrag zur politischen Bildung leistet, indem sie die Voraussetzungen für Unterricht und Zucht bereitstellt, fungieren die beiden zuletzt genannten Formen von Erziehung als die eigentlichen Medien, in denen die politische Bildung im Sinne Herbarts ihren Ort hat.

The prognostic value of SUMO1/Sentrin specific peptidase 1 (SENP1) in prostate cancer is limited to ERG-fusion positive tumors lacking PTEN deletion

International Nuclear Information System (INIS)

Burdelski, Christoph; Menan, Devi; Tsourlakis, Maria Christina; Kluth, Martina; Hube-Magg, Claudia; Melling, Nathaniel; Minner, Sarah; Koop, Christina; Graefen, Markus; Heinzer, Hans; Wittmer, Corinna; Sauter, Guido; Simon, Ronald; Schlomm, Thorsten; Steurer, Stefan; Krech, Till

2015-01-01

Posttranscriptional protein modification by SUMOylation plays an important role in tumor development and progression. In the current study we analyzed prevalence and prognostic impact of the de-SUMOylation enzyme SENP1 in prostate cancer. SENP1 expression was analyzed by immunohistochemistry on a tissue microarray containing more than 12,400 prostate cancer specimens. Results were compared to tumor phenotype, ERG status, genomic deletions of 3p, 5q, 6q and PTEN, and biochemical recurrence. SENP1 immunostaining was detectable in 34.5 % of 9,516 interpretable cancers and considered strong in 7.3 %, moderate in 14.9 % and weak in 12.3 % of cases. Strong SENP1 expression was linked to advanced pT stage (p < 0.0001), high Gleason grade (p < 0.0001), positive lymph node status (p = 0.0019), high pre-operative PSA levels (p = 0.0037), and PSA recurrence (p < 0.0001). SENP1 expression was strongly associated with positive ERG fusion status as determined by both in situ hybridization (FISH) and immunohistochemistry as well as with PTEN deletions. Detectable SENP1 immunostaining was found in 41 % of ERG positive and in 47 % of PTEN deleted cancers but in only 30 % of ERG negative and 30 % of PTEN non-deleted cancers (p < 0.0001 each). Deletions of 3p, 5q, and 6q were unrelated to SENP1 expression. Subset analyses revealed that the prognostic impact of SENP1 expression was solely driven by the subgroup of ERG positive, PTEN undeleted cancers. In this subgroup, the prognostic role of SENP1 expression was independent of the preoperative PSA level, tumor stage, Gleason grade, and the status of the resection margin. SENP1 expression has strong prognostic impact in a molecularly defined subset of cancers. This is per se not surprising as the biologic impact of each individual molecular event is likely to be dependent on its cellular environment. However, such findings challenge the concept of finding clinically relevant molecular signatures that are equally applicable to all

Saage tuttavaks : Elisabeth ja Karl von Hoerschelmann / Mai Levin

Index Scriptorium Estoniae

Levin, Mai, 1942-

2004-01-01

Kuraator M. Levin kuni 10. X 2004 Adamson-Ericu muuseumis avatud näitusest "Tuntud ja tundmatud Elisabeth von Rosendorff-Hoerschelmann ja Karl von Hoerschelmann". Enamik töid on kunstnike laste Konstantin Hoerschelmanni ja Anna Röder-Hoerschelmanni omand. Elisabeth Rosendorff (1898-1984) sündis Virumaal Maidlas eesti perekonnas, Karl von Hoerschelmann (1899-1951) Sevastoopolis saksa perekonnas

Von Willebrand protein binds to extracellular matrices independently of collagen.

OpenAIRE

Wagner, D D; Urban-Pickering, M; Marder, V J

1984-01-01

Von Willebrand protein is present in the extracellular matrix of endothelial cells where it codistributes with fibronectin and types IV and V collagen. Bacterial collagenase digestion of endothelial cells removed fibrillar collagen, but the pattern of fibronectin and of von Willebrand protein remained undisturbed. Exogenous von Willebrand protein bound to matrices of different cells, whether rich or poor in collagen. von Willebrand protein also decorated the matrix of cells grown in the prese...

Bewertung von Fahrzeuggeräuschen

Science.gov (United States)

Genuit, Klaus; Schulte-Fortkamp, Brigitte; Fiebig, André; Haverkamp, Michael

Bei der Wahrnehmung und Beurteilung eines Automobils sind unzählige Merkmale und Eigenschaften von Bedeutung. Dabei können Merkmale objektiv-technisch beschrieben werden, wie Angaben zur Motorisierung, Höchstgeschwindigkeit, Drehmoment, zulässige Zuladung, Verbrauch usw. Daneben sind weitere Eigenschaften von Bedeutung, die sich einer einfachen objektiv-technischen Beschreibung entziehen. Hier sind Begriffe zu nennen, wie Sicherheit, allgemeine Qualitätsanmutung, Design, Ergonomie, Komfort, Haptik, Fahrdynamik, Zuverlässigkeit, die deutlich schwieriger objektiv erfassbar und beschreibbar sind (Abb. 4.1).

Baron von Zach's business relations with the Munich entrepreneur Joseph von Utzschneider (German Title: Geschäftsbeziehungen des Barons von Zach zu dem Münchner Unternehmer Joseph von Utzschneider)

Science.gov (United States)

Schneider, Ivo

The relationship between the astronomer von Zach on the one side and the entrepreneur Joseph von Utzschneider and his partner Georg von Reichenbach on the other dates presumably from the year 1807 when Zach spent two months in Munich. Already in the same year Zach had ordered an instrument for himself and began to solicit business for the institute of Reichenbach, Utzschneider, and Liebherr, which was founded in 1804. One of the clients canvassed by Zach was the director of the observatory in Naples Zuccari. Zuccari had ordered the whole equipment for the new observatory from this institute in 1813. The instruments for Naples, which were completed in 1814, were sent accompanied by Reichenbach by land and sea to their destination where Reichenbach supervised their setup. At that time Reichenbach had separated from Utzschneider who kept the optical institute in Benediktbeuern with his new partner Joseph von Fraunhofer whereas Reichenbach became owner of the mathematical-mechanical institute in Munich. For personal and economical reasons Utzschneider began soon after to produce not only optical glass but also optical devices similar to those offered by Reichenbach. As soon as two institutes in Munich competed against each other on the market for sophisticated geodetical and astronomical instruments Zach sided with Utzschneider. Zach's main professional argument for this decision was that both competitors got the optical glass for their instruments from Utzschneider's optical institute in Benediktbeuern. This meant that Utzschneider had first choice and so the optical part of his instruments could be considered as better than that of Reichenbach`s instruments. Zach's role as an agent in Italy and France for the sale of products coming from Utzschneider's manufactories is highlighted by three of Zach's letters to Utzschneider from 1817 and 1818, two of which are reproduced here for the first time.

Research, design and education, Von Humboldt revisited

NARCIS (Netherlands)

Bax, M.F.T.; Doevendans, C.H.; Trum, H.M.G.J.; Langenhuizen, Anja; Ouwerkerk, Marieke van; Rosemann, Jurgen

2001-01-01

This paper is a result of reflection on the interrelation design-research-cultivation, and on the interpretation of Von Humboldt's maxim: 'Einheit von Forschung und Lehre', which governed the academic world in the past two centuries. It is argued that 'Forschung' should be interpreted as 'Research

John von Neumann selected letters

CERN Document Server

2005-01-01

John von Neuman was perhaps the most influential mathematician of the twentieth century, especially if his broad influence outside mathematics is included. Not only did he contribute to almost all branches of mathematics and created new fields, but he also changed post-World War II history with his work on the design of computers and with being a sought-after technical advisor to many figures in the U.S. military-political establishment in the 1940s and 1950s. The present volume is the first substantial collection of (previously mainly unpublished) letters written by von Neumann to colleagues, friends, government officials, and others. The letters give us a glimpse of the thinking of John von Neumann about mathematics, physics, computer science, science management, education, consulting, politics, and war. Readers of quite diverse backgrounds will find much of interest in this fascinating first-hand look at one of the towering figures of twentieth century science.

Muuga / Mary von Grünewaldt ; tõlk. Mati Sirkel

Index Scriptorium Estoniae

Grünewaldt, Mary von

2004-01-01

Leo Zoegelt ostetud Muuga mõisahoone korrastamisest ja uue hoone ehitamisest C. T. von Neffi kunstikogu paigutamise tarbeks. Tütre mälestused. Tõlgitud raamatust: Skizzen und Bilder aus dem Leben Carl Timoleon von Neff / Mary von Grünewaldt. Darmstadt, 1887

Untersuchungen zur Farbreaktion von Amilorid, Chlorhexidin und Proguanil mit Hypobromit

OpenAIRE

Huth, Silke

2004-01-01

Bei der Reaktion von Amiloridhydrochlorid (1· HCl) mit Brom in alkalischer Lösung wird ein gelbbraunes Dehydrierungsprodukt erhalten, daß als 3-(3-Amino-1,2,4-oxadiazol-5-yl)-5-chlor-2,6-pyrazindiamin (6) identifiziert werden konnte. Durch Vergleich von Massen- und NMR-Spektren der Verbindung 6 mit Spektren von 1· HCl und Referenzsubstanzen I-III konnte auf die verbindung 6 geschlossen werden. Die Struktur wurde durch eine Röntgenstrukturanalyse abgesichert. Erhitzen von Amiloridhydrochlorid ...

Hullud päevad von Krahlis

Index Scriptorium Estoniae

2006-01-01

Von Krahli Teatris mängitakse neil päevi neli korda Peeter Jalaka lavastuses Tõnu Kõrvitsa kammeroopereid "Tuliaed" ja "Mu luiged, mu mõtted", mille aluseks on luuletaja Marie Heibergi saatus. Libreto autor on Maarja Kangro. Kammerooperid tulevad lavale Von Krahli Teatri ja Nargen Opera koostöös. Esitavad Kädy Plaas, Helen Lokuta, Nargen Opera koor ja Tallinna Kammerorkester, dirigent Tõnu Kaljuste

Diagnosis and management of von Willebrand disease: guidelines for primary care.

Science.gov (United States)

Yawn, Barbara; Nichols, William L; Rick, Margaret E

2009-12-01

Von Willebrand disease is an inherited condition characterized by deficiency of von Willebrand factor, which is essential in hemostasis. The National Heart, Lung, and Blood Institute has released new evidence-based guidelines for the diagnosis and management of the disease. There are three major subtypes of von Willebrand disease, classified as partial quantitative deficiency (low levels) of von Willebrand factor (type 1), qualitative deficiency (type 2), or virtually complete deficiency (type 3). Diagnosis is usually made by reviewing the patient's personal and family history of bleeding and by clinical evaluation for more common reasons for bleeding, supplemented with laboratory tests. Assessment may be used to determine bleeding risk before surgery and other invasive procedures, and to diagnose reasons for unexplained hemorrhaging. Von Willebrand factor levels of 30 IU per dL or lower are required for the definite diagnosis of inherited von Willebrand disease. Persons with levels of 30 to 50 IU per dL may not have the disease, but may need agents to increase von Willebrand factor levels during invasive procedures or childbirth. Treatment is tailored to the subtype of the disease: increasing plasma concentration of von Willebrand factor by releasing endogenous stores with desmopressin or replacing nonexistent or ineffective von Willebrand factor by using human plasma-derived, viral-inactivated concentrates; treatment is often combined with hemostatic agents that have mechanisms other than increasing von Willebrand factor. Regular prophylaxis is seldom required, and treatment is initiated before planned invasive procedures or in response to bleeding.

Von Willebrand disease protects against arterial thrombosis

NARCIS (Netherlands)

Sanders, Y.V.; Eikenboom, J.C.; De Wee, E.M.; Van Der Bom, J.G.; Cnossen, M.H.; Degenaar-Dujardin, M.E.; Fijnvandraat, K.; Kamphuisen, P.W.; Laros-Van Gorkum, B.A.; Meijer, K.; Mauser -Bunschoten, E.P.; Leebee k, F.W.

Background and Aims: Von Willebrand disease (VWD) is caused by reduced levels of or dysfunctional von Willebrand factor (VWF) and is characterized by a bleeding tendency. It is well known that individuals with high VWF levels have a higher risk for arterial thrombosis. Although it has never been

Entwicklung von Antikörper-Mikroarray : von Biophysik der Mikrospot-Reaktion bis zur Hochdurchsatzanalyse der Proteine

OpenAIRE

Kusnezow, Wlad

2007-01-01

Obwohl Protein-Mikroarrays ursprünglich aus dem gut entwickelten und fest etablierten DNA-Pendant entstanden sind, repräsentierte jedoch die Umstellung der Mikroarray-Technik von der DNA- auf die Proteinanalyse aufgrund der enormen physikalisch-chemischen Variabilität der Proteine, deren relativ niedrigen Stabilität und der komplexen Mikrospot-Kinetik eine große technologische Herausforderung. Deshalb setzt das Vorhaben, die Technik der Antikörper–Mikroarrays von ihrem konzeptuellen Zustand a...

Ein „neuer" javanischer Fundort von Phrynoglossus laevis laevis ( Gthr.)

NARCIS (Netherlands)

Brongersma, L.D.

1935-01-01

In der herpetologischen Sammlung, die dem Rijksmuseum van Natuurlijke Historie, Leiden, vor etwa hundert Jahre von Boie und Macklot übersandt wurde, befanden sich zwei Exemplare von Phrynoglossus laevis laevis (Gthr.). Diese Stücke wurden von Van Kampen (1923, p. 232 Fussnote: Oxyglossus laevis) in

The 5-lipoxygenase inhibitor tepoxalin induces oxidative damage and altered PTEN status prior to apoptosis in canine osteosarcoma cell lines.

Science.gov (United States)

Loftus, J P; Cavatorta, D; Bushey, J J; Levine, C B; Sevier, C S; Wakshlag, J J

2016-06-01

The 5-lipoxygenase (5-LOX) inhibitor tepoxalin has been shown to slow canine osteosarcoma (OSA) tumour xenografts growth, yet the mechanisms are poorly elucidated. Further examination of tepoxalin in canine OSA cell lines shows that tepoxalin treated cells undergo apoptosis through caspase-3 activation and annexin staining. Interestingly, apoptosis is superseded by an increase in reactive oxygen species (ROS), as measured by activation of dihydrorhodamine 123 and mitosox. This increase in ROS appears to be related to the 5-LOX inhibitor regardless of cellular 5-LOX status, and was not observed after treatment with the tepoxalin metabolite RWJ20142. Additionally, 5-LOX inhibition by tepoxalin appears to increase phosphatase and tensin (PTEN) homolog activity by preventing its alkylation or oxidation. PTEN modification or inhibition allows phosphoinositide-3 (PI3) kinase activity thereby heightening activation of protein kinase B (AKT) phosphorylation. Our data suggest that off target oxidation and LOX inhibition play roles in the apoptotic response. © 2014 John Wiley & Sons Ltd.

Der Zusammenhang von Partnermarktopportunitäten aus dem Freundeskreis und der Stabilität von Paarbeziehungen : Eine Analyse mit den Daten des Partnermarktsurvey

OpenAIRE

Häring, Armando

2014-01-01

"Der Beitrag analysiert den Zusammenhang zwischen Partnermarktoportunitäten aus dem Freundeskreis und der Stabilität von Paarbeziehungen. Unter Verwendung des theoretischen Konzepts der Theorie der Interaktionsgelegenheiten sowie von Annahmen der Austauschtheorie und der Familienökonomie, werden mögliche Zusammenhänge zwischen gemeinsamen Freundeskreisen mit dem Partner, Partnermarktgelegenheiten aus dem Freundeskreis (sex ratio) und der Stabilität von Paarbeziehungen diskutiert. Der Beitrag ...

Fragen - Nachfragen - Echofragen. Formen und Funktionen von Interrogationen im gesprochenen Deutsch

Directory of Open Access Journals (Sweden)

Rost-Roth, Martina

2003-01-01

Full Text Available Präsentiert werden Befunde aus einer empirischen Untersuchung zu Nachfragen und anderen Fragen in mündlichen Kommunikationen. Ausgangspunkt ist die Beobachtung, daß Beschreibungen von Nachfragen nur in geringer Zahl vorliegen, aus sehr unterschiedlichen Bereichen stammen (Konversationsanalyse, grammatische Beschreibungen von Fragen und Literatur zu Echofragen und sich Beschreibungen von Nachfrageformen sowie Nachfragefunktionen und die jeweils unterstellten Form-Funktions-Bezüge - auch in den einzelnen Bereichen - vielfach widersprechen. Vor diesem Hintergrund ist zentales Anliegen der Untersuchung, einen übergeordneten Analyserahmen für die Befassung mit Frageformen und Fragefunktionen zu entwickeln, der die Beschreibung von Nachfragen in einer allgemeineren Beschreibung von Interrogationen verortet. Das Besondere von Nachfragen wird darin gesehen, daß es sich um Interrogationen handelt, die auf andere sprachliche Äußerungen Bezug nehmen. Hier sind wiederum verschiedene Mittel zu unterscheiden, die für die Unterscheidung von Echofragen und anderen Nachfragen bestimmend sind. In diesem Zusammenhang wird gezeigt, daß auch der Art der Bezugnahme besondere Bedeutung für die Bestimmung von Nachfrageformen und Nachfragefunktionen zukommt. Anhand der Analysen von empirischen Fragevorkommen im gesprochenen Deutsch werden zunächst verschiedene 'Strukturtypen' differenziert. Die Vergleiche von Nachfragen und anderen Fragen zeigen vor allem Unterschiede in Hinblick auf die Frequenz verbloser und elliptischer Frageformulierungen. Daran anschließend werden Nachfragefunktionen im Bereich der Verständnissicherung sowie andere Nachfragefunktionen erörtert. Bei der Suche nach einem gemeinsamen Nenner für sehr unterschiedliche Nachfragefunktionen erweisen sich als zentrale Funktionsparameter :1. die Fokussierungsleistung (über die Bezugnahme auf vorausgehende Äußerungen der Gesprächspartner sowie 2. der Interrogativmodus (über die

Análise do gene PTEN por hibridização in situ fluorescente no carcinoma de células renais

Directory of Open Access Journals (Sweden)

Eurico Cleto Ribeiro de Campos

Full Text Available OBJETIVO: avaliar a frequência de deleção do gene PTEN no carcinoma de células renais e o impacto da deleção nas taxas de sobrevida global e livre de doença. MÉTODOS: foram analisados 110 pacientes portadores de carcinoma de células renais submetidos à nefrectomia radical ou parcial entre os anos de 1980 e 2007. Em 53 casos foi possível a análise do gene PTEN pelo método de hibridização in situ fluorescente através da técnica de "tissue microarray". Para a análise estatística, os pacientes foram classificados em dois grupos, de acordo com a presença ou ausência de deleção. RESULTADOS: o tempo médio de seguimento foi de 41,9 meses. Deleção hemizigótica foi identificada em 18 pacientes (33,9%, ao passo que deleção homozigótica esteve presente em três (5,6%. Em aproximadamente 40% dos casos analisados havia deleção. Monossomia e trissomia foram detectadas, respectivamente, em nove (17% e dois pacientes (3,8%. Em 21 pacientes (39,6%, a análise por hibridização in situ do gene PTEN foi normal. Não houve diferenças estatisticamente significativas nas taxas de sobrevida global (p=0,468 e livre de doença (p=0,344 entre os pacientes portadores ou não de deleção. Foram fatores independentes para a sobrevida global: estádio clínico TNM, sintomatologia ao diagnóstico, alto grau de Fuhrmann performance status (Ecog e recorrência tumoral. A livre de doença foi influenciada unicamente pelo estádio clínico TNM. CONCLUSÃO: deleção do gene PTEN no CCR foi detectada com frequência de aproximadamente 40% e sua presença não foi determinante de menores taxas de sobrevida, permanecendo os fatores prognósticos tradicionais como determinantes da evolução dos pacientes.

Borel reductibility and classification of von neumann algebras

DEFF Research Database (Denmark)

Sasyk, R.; Törnquist, Asger Dag

2009-01-01

We announce some new results regarding the classification problem for separable von Neumann algebras. Our results are obtained by applying the notion of Borel reducibility and Hjorth's theory of turbulence to the isomorphism relation for separable von Neumann algebras....

Ööklubi Club von Überlingen = Club von Überlingen

Index Scriptorium Estoniae

2008-01-01

Ööklubi Club von Überlingen (Madara 22A, Tallinn) sisekujundusest. Sisearhitekt: Taavi Aunre (Boom.ee OÜ). Taavi Aunrest, tema tähtsamad tööd. I-II korruse plaan, 11 värv. vaadet, foto T. Aunrest

Von den Liven von Oesel / August Ludwig Schlözer

Index Scriptorium Estoniae

Schlözer, August Ludwig

2008-01-01

Avaldatud Eberhard Winkleri initsiatiivil A. L. Schlözeri teose põhjal: Gesammelte Nachrichten von den Ueberresten der Liven, in Livland und Kurland. (1770), mis moodustab osa teosest: Schlözer, August Ludwig. M. Johann Joseph Haigold's Beylagen zum Neuveränderten Russland. Zweiter Theil. Riga und Leipzig, 1770

Ellis Von Creveld Syndrome

Directory of Open Access Journals (Sweden)

Afshar H

1999-01-01

Full Text Available One patient with Ellis Von Creveld syndrome contains: dwarfism, congenital heart"ndisease, ectodermal dysplasia, polyductyly, an abnormally wide labial frenum and maxillary"nmolars with single root.

Proof of pipeline strength based on measurements of inspection pigs; Festigkeitsnachweis von Pipelines aufgrund der Messergebnisse von Pruefmolchen

Energy Technology Data Exchange (ETDEWEB)

De la Camp, H.J.; Feser, G.; Hofmann, A.; Wolf, B.; Schmidt, H. [TUeV Sueddeutschland Bau und Betrieb GmbH, Muenchen (Germany); Herforth, H.E.; Juengling, K.H.; Schmidt, W. [TUeV Anlagentechnik GmbH, Berlin-Schoeneberg (Germany). Unternehmensgruppe TUeV Rheinland/Berlin-Brandenburg

2002-01-01

The report is aimed at collecting and documenting the state of the art and the extensive know how of experts and pipeline operators with regard to judging the structural integrity of pipelines. In order to assess the actual mechanical strength of pipelines based on measurement results obtained by inspection pigs, guidance is given for future processing, which eventually can be used as a basis for an industry standard. A literature study of the commercially available types of inspection pigs describes and synoptically lists the respective pros and cons. In essence the report comprises besides check lists of operating data for the pipeline and the pig runs mainly the evaluation of defects and respective calculating procedures. Included are recommendations regarding maintenance planning, verification of defects as well as repetition of pig runs. (orig.) [German] Ziel des Berichtes ist die Erfassung und Dokumentation zum derzeitigen Stand der Technik und des vorhandenen umfangreichen Know-how von Sachverstaendigen und Pipelinebetreibern auf dem Gebiet der sicherheitstechnischen Beurteilung von Pipelines. Fuer den Festigkeitsnachweis von Pipelines aufgrund der Messergebnisse von Pruefmolchen wurde ein Leitfaden als Basis fuer die zukuenftige Vorgehensweise erstellt, der eventuell die Grundlage eines normativen Regelwerkes bilden kann. In einer Literaturstudie wurden die auf dem Markt befindlichen Pruefmolchtypen zusammenfassend beschrieben und ihre Vor- und Nachteile tabellarisch gegenuebergestellt und bewertet. Neben der Erstellung von Checklisten fuer notwendige Daten zum Betrieb der Pipeline und der Molchlaeufe bildet die Fehlerbewertung mit entsprechenden Berechnungsverfahren den Hauptteil dieses Berichtes. Hinweise zur Instandhaltungsplanung (Fehlerverifikation und Molchlaufwiederholung) werden gegeben. (orig.)

Entwicklung von Extraktions- und Absorptionssystemen auf Basis ionischer Flüssigkeiten für die Entschwefelung von Kohlenwasserstoffen

OpenAIRE

Kuhlmann, Esther

2008-01-01

Da die Anforderungen an den Schwefelgehalt der fossilen Brennstoffe - nicht zuletzt durch gesetzliche Richtlinien bezüglich der Schadstoffemissionen - im Laufe der Zeit ständig gestiegen sind, sind effektive Entschwefelungsverfahren für fossile Brennstoffe von hohem Interesse. Die derzeitige Entschwefelungstechnologie basiert auf dem HDS-Verfahren, alternative Verfahren sind aber wünschenswert, insbesondere wenn Anwendungen einen Schwefelgehalt von weit unter 10 ppm erforderlich machen. Daher...

Rhizostomeen von Manila

NARCIS (Netherlands)

Stiasny, G.

1924-01-01

Die hier beschriebene kleine Scyphomedusen-Sammlung wurde von Herrn Director P. B. Sivickis, Dept. of Zoology, University of Philippines, Manila, dem Rijksmuseum van Natuurlijke Historie in Leiden überwiesen. Das Material wurde im December 1922 in Manila-bay gefischt und befindet sich in bestem

A bicategorical approach to Morita equivalence for von Neumann algebras

International Nuclear Information System (INIS)

Brouwer, R. M.

2003-01-01

We relate Morita equivalence for von Neumann algebras to the ''Connes fusion'' tensor product between correspondences. In the purely algebraic setting, it is well known that rings are Morita equivalent if they are equivalent objects in a bicategory whose 1-cells are bimodules. We present a similar result for von Neumann algebras. We show that von Neumann algebras form a bicategory, having Connes's correspondences as 1-morphisms, and (bounded) intertwiners as 2-morphisms. Further, we prove that two von Neumann algebras are Morita equivalent iff they are equivalent objects in the bicategory. The proofs make extensive use of the Tomita-Takesaki modular theory

Von Mumien, Cyborgs und Röntgenbildern

Directory of Open Access Journals (Sweden)

Regina Schleicher

2004-03-01

Full Text Available Unter dem Titel Techniken der Reproduktion liegt ein Sammelband vor, der die Beiträge einer Tagung an der Universität Paderborn vom Dezember 2001 enthält. In enger Verknüpfung verschiedener disziplinärer Perspektiven werden Schlaglichter auf eine Vielzahl von Themen geworfen, die sich mit dem Begriff „Reproduktion“ verbinden. Dabei wird deutlich, wie eng die Geschichte der Medien und die Entwicklung von Technologien der biologischen Fortpflanzung miteinander verzahnt sind.

Ungleiche Ungleichheiten:Zu den Gemeinsamkeiten und Unterschieden von Sexismus und Rassismus

OpenAIRE

Späte, K. (Katrin)

2011-01-01

Sexismus durchzieht fast alle gesellschaftlichen Teilbereiche und deren Grundlagen, im Kern ging es schon Jahrtausende lang um die Rechtfertigung der Herrschaft von Männern über Frauen. Die Minderwertigkeit „der Frau“ wurde unter Rückgriff auf natürliche Begebenheiten bewiesen. Die Grundlage sowohl von Sexismus als auch von Rassismus ist eine Konstruktion: Beim Sexismus die des „weiblichen Geschlechts“, beim Rassismus die der „Rasse“. Während sich die Benennung des Objekts von Rassismus im...

Gespiegelte Planeten – Die Anordnung der Pyramiden von Gizeh

OpenAIRE

Jelitto, Hans

2000-01-01

Antike Bauwerke wurden wiederholt auf astronomische Zusammenhänge hin untersucht, so z. B. ihre Ausrichtung in Bezug auf die Bewegung von Sonne oder Sternen. Vor diesem Hintergrund wurden für die Pyramiden von Gizeh drei ungewöhnliche Gleichungen entdeckt, die die Pyramidengrößen mit einer Genauigkeit von ca. 0,1 % festlegen. Gleichzeitig legen diese drei Gleichungen nahe, die drei Pyramiden in der Reihenfolge Mykerinos-, Chefren- und Cheopspyramide den inneren drei Planeten unseres Sonnensys...

Exploring the Hypersensitivity of PTEN Deleted Prostate Cancer Stem Cells to WEE1 Tyrosine Kinase Inhibitors

Science.gov (United States)

2015-12-01

performed the clonogenic survival assay using LAPC4 as a model as these cell form well defined colonies compared to C42B cells. This assay revealed that...cells. Future studies with other PTEN deficient models are important to validate the effectiveness of WEE1 inhibitors to tackle recurrent PC...Amplifications and missense mutations Cixutumumab (IMC-A12), Dalotuzumab (MK-0646; h7C10), Linsitinib ( OSI -906) EPHA5 12% LAC, 10% SCLC, 9% SAC, Lung

Exploring the Hypersensitivity of PTEN Deleted Prostate Cancer Stem Cells to WEE1 Tyrosine Kinase Inhibitors

Science.gov (United States)

2015-12-01

AWARD NUMBER: W81XWH-14-1-0251 TITLE: Exploring the Hypersensitivity of PTEN Deleted Prostate Cancer Stem Cells to WEE1 Tyrosine Kinase... Tyrosine Kinase Inhibitors 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0251 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Kiran Mahajan 5d...ABSTRACT Central to all cycling cells-including prostate cancer stem cells- is the expression of WEE1 tyrosine kinase. WEE1 monitors duplication of

Bedeutung von Umwelt- und Organismusfaktoren bei Autoaggressionen

OpenAIRE

Rohmann, Ulrich H.; Elbing, Ulrich; Hartmann, Hellmut

1988-01-01

In der vorliegenden Arbeit werden übergeordnete Hypothesen zu autoaggressiven Verhaltensweisen formuliert, wobei prozeßhafte Abläufe von umweltbezogenen und organischen Variablen angenommen werden. Eine solche dynamische Beziehung hat ihre Bedeutung sowohl für verursachende als auch aufrechterhaltende Faktoren. In einer Querschnittuntersuchung lassen sich Korrelationen von Tageszeit- und Tätigkeitscharakteristiken (umweltbezogene Variablen) zur Autoaggressionshäufigkeit und Pulsfrequenz (Orga...

A new von Mises probabilistic formula for quartet invariants

International Nuclear Information System (INIS)

Giacovazzo, C.; Camalli, M.; Spagna, R.

1989-01-01

Von Mises formulas for quartet invariants, even is useful in most cases of practical interest, suffer from some systematic errors. A new von Mises formula is suggested with better theoretical features. (orig.)

Pure Jauch-Piron states on von Neumann algebras

International Nuclear Information System (INIS)

Hamhalter, J.

1993-01-01

We study Jauch-Piron states and two-valued measures on von Neumann algebra. We prove as the main result that, under some set-theoretical assumption, a pure state of a von Neumann algebra A not containing a central abelian portion is Jauch-Piron if and only if it is σ-additive. Moreover, we show that this result holds for type I factor indenpendently on the set-theoretical axiomatics. As a consequence we obtain a lucid characterization of pure Jauch-Piron states on von Neumann algebras acting on a Hilbert space with real-nonmeasurable dimension (this can be viewed as a generalization of the paper). We also characterize the von Neumann algebras whose logic of projections is Jauch-Piron. Finally, we prove that every two-valued measure on the projection logic of A, where A contains no type I 2 central portion, has to be concentrated at an abelian direct summand of A. (orig.)

Die Rolle von Osteoklasten bei der arthritischen Knochenerosion

Directory of Open Access Journals (Sweden)

Schett G

2003-01-01

Full Text Available Knöcherne Erosionen stellen eine wesentliche Ursache für die funktionelle Einschränkung von Patienten mit rheumatoider Arthritis dar. Bis vor kurzem war über den Pathomechanismus dieser Veränderungen nur wenig bekannt. Dieser Review faßt die letzten Erkenntnisse über die Ausbildung einer Knochenschädigung bei entzündlichen Gelenkerkrankungen zusammen und fokussiert insbesondere die Rolle von Osteoklasten. Es wird ein Überblickzu den Hinweisen für eine Präsenz von Osteoklasten im entzündlich veränderten Gelenk gegeben. Weiters werden die Faktoren diskutiert, die die Osteoklastogenese im Rahmen einer Gelenkentzündung aktivieren können. Hier wird im besonderen auf die Rolle von Receptor-Activator of Nuclear Factor Kappa B Ligand (RANKL eingegangen. Im weiteren werden die Auswirkungen einer Osteoklastenhemmung in den verschiedenen Arthritismodellen zusammengefaßt und Möglichkeiten einer therapeutischen Nutzung bei rheumatoider Arthritis diskutiert.

miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model.

Science.gov (United States)

Su, Song; Luo, De; Liu, Xiangdong; Liu, Jiang; Peng, Fangyi; Fang, Cheng; Li, Bo

2017-10-31

A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir- miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir- miR-494 , and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H 2 O 2 -induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H 2 O 2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir- miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats ( P <0.05 or 0.01). After H 2 O 2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group ( P <0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor ( P <0.01). Moreover, HIRI + agomir- miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN , leading to the activation of PI3K/AKT signaling pathway. © 2017 The Author(s).

MDM2 regulates hypoxic hypoxia-inducible factor 1α stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner.

Science.gov (United States)

Joshi, Shweta; Singh, Alok R; Durden, Donald L

2014-08-15

Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor containing an inducibly expressed HIF1α subunit and a constitutively expressed HIF1β subunit. Under hypoxic conditions, the HIF1α subunit accumulates because of a decrease in the rate of proteolytic degradation, and the resulting HIF1α-HIF1β heterodimers undergo post-translational modifications that promote transactivation. Previous reports suggest that amplified signaling through PI3K enhances HIF1-dependent gene expression; however, its role is controversial, and the mechanism is unclear. Using genetically engineered PTEN-deficient cell lines, we demonstrate that PTEN specifically inhibited the accumulation of HIF1α in response to hypoxia. Furthermore, we report that in glioblastoma cell lines, inhibition of PI3K pathway, using pan as well as isoform-specific PI3K inhibitors SF1126, PF4691502, BEZ-235, GDC0941, and TGX221 blocked the induction of HIF1α protein and its targets vascular endothelial growth factor, HK1, and GLUT1 mRNA in response to hypoxia. Herein, we describe the first evidence that HIF1α can be degraded under hypoxic conditions via the 26 S proteasome and that MDM2 is the E3 ligase that induces the hypoxic degradation of HIF1α. Moreover, the action of MDM2 on HIF1α under hypoxia occurs in the cytoplasm and is controlled by the PTEN-PI3K-AKT signaling axis. These data strongly suggest a new role for PTEN in the regulation of HIF1α and importantly that PI3K-AKT activation is required for the hypoxic stabilization of HIF1α and that hypoxia alone is not sufficient to render HIF1α resistant to proteasomal cleavage and degradation. Moreover, these findings suggest new therapeutic considerations for PI3K and/or AKT inhibitors for cancer therapeutics. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner*

Science.gov (United States)

Joshi, Shweta; Singh, Alok R.; Durden, Donald L.

2014-01-01

Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor containing an inducibly expressed HIF1α subunit and a constitutively expressed HIF1β subunit. Under hypoxic conditions, the HIF1α subunit accumulates because of a decrease in the rate of proteolytic degradation, and the resulting HIF1α–HIF1β heterodimers undergo post-translational modifications that promote transactivation. Previous reports suggest that amplified signaling through PI3K enhances HIF1-dependent gene expression; however, its role is controversial, and the mechanism is unclear. Using genetically engineered PTEN-deficient cell lines, we demonstrate that PTEN specifically inhibited the accumulation of HIF1α in response to hypoxia. Furthermore, we report that in glioblastoma cell lines, inhibition of PI3K pathway, using pan as well as isoform-specific PI3K inhibitors SF1126, PF4691502, BEZ-235, GDC0941, and TGX221 blocked the induction of HIF1α protein and its targets vascular endothelial growth factor, HK1, and GLUT1 mRNA in response to hypoxia. Herein, we describe the first evidence that HIF1α can be degraded under hypoxic conditions via the 26 S proteasome and that MDM2 is the E3 ligase that induces the hypoxic degradation of HIF1α. Moreover, the action of MDM2 on HIF1α under hypoxia occurs in the cytoplasm and is controlled by the PTEN-PI3K-AKT signaling axis. These data strongly suggest a new role for PTEN in the regulation of HIF1α and importantly that PI3K-AKT activation is required for the hypoxic stabilization of HIF1α and that hypoxia alone is not sufficient to render HIF1α resistant to proteasomal cleavage and degradation. Moreover, these findings suggest new therapeutic considerations for PI3K and/or AKT inhibitors for cancer therapeutics. PMID:24982421

Portrait of Dr. Von Braun with Walt Disney, 1954.

Science.gov (United States)

1954-01-01

Marshall Center Director Dr. Wernher Von Braun is pictured with Walt Disney during a visit to the Marshall Space Flight Center in 1954. In the 1950s, Dr. Von Braun while working in California on the Saturn project, also worked with Disney studios as a technical director in making three films about Space Exploration for television. Disney's tour of Marshall in 1965 was Von Braun's hope for a renewed public interest in the future of the Space Program at NASA.

Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

Science.gov (United States)

Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

2011-01-01

Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

Automatische Ableitung und Anwendung von Regeln für die Rekonstruktion von Fassaden aus heterogenen Sensordaten

OpenAIRE

Becker, Susanne

2011-01-01

3D-Stadtmodelle finden seit einigen Jahren in immer stärkerem Maß und in den verschiedensten Bereichen Verwendung. Sie bilden unter anderem die Grundlage bei Stadtplanungen, für virtuelle Stadtrundgänge oder für die Berechnung von Simulationen. Internetdiensten wie Google Earth oder Microsoft Bing Maps ist es zu verdanken, dass 3D-Darstellungen von Gebäuden mittlerweile auch für eine breite Öffentlichkeit allgegenwärtig sind. Die erhöhte Nachfrage nach 3D-Gebäudemodellen verlangt nach effizie...

The classification problem for von Neumann factors

DEFF Research Database (Denmark)

Sasyk, R.; Törnquist, Asger Dag

2009-01-01

We prove that it is not possible to classify separable von Neumann factors of types II, II or III, 0 ≤ λ ≤ 1, up to isomorphism by a Borel measurable assignment of "countable structures" as invariants. In particular the isomorphism relation of type II factors is not smooth. We also prove...... that the isomorphism relation for von Neumann II factors is analytic, but is not Borel....

α(V)β(6) integrin expression is induced in the POET and Pten(pc-/-) mouse models of prostatic inflammation and prostatic adenocarcinoma.

Science.gov (United States)

Garlick, David S; Li, Jing; Sansoucy, Brian; Wang, Tao; Griffith, Leeanne; Fitzgerald, Tj; Butterfield, Julie; Charbonneau, Bridget; Violette, Shelia M; Weinreb, Paul H; Ratliff, Timothy L; Liao, Chun-Peng; Roy-Burman, Pradip; Vietri, Michele; Lian, Jane B; Stein, Gary S; Altieri, Dario C; Languino, Lucia R

2012-01-01

Chronic inflammation is proposed to prime the development of prostate cancer. However, the mechanisms of prostate cancer initiation and development are not completely understood. The α(v)β(6) integrin has been shown to play a role in epithelial development, wound healing and some epithelial cancers [1, 2]. Here, we investigate the expression of α(v)β(6) in mouse models of prostatic inflammation and prostate cancer to establish a possible relationship between inflammation of the prostate, α(v)β(6) expression and the progression of prostate cancer. Using immunohistochemical techniques, we show expression of α(v)β(6) in two in vivo mouse models; the Pten(pc)-/- model containing a prostate- specific Pten tumor suppressor deletion that causes cancer, and the prostate ovalbumin-expressing transgenic (POET) inflammation mouse model. We show that the α(v)β(6) integrin is induced in prostate cancer and inflammation in vivo in these two mouse models. α(v)β(6) is expressed in all the mice with cancer in the Pten(pc-/-) model but not in age-matched wild-type mice. In the POET inflammation model, α(v)β(6) is expressed in mice injected with activated T-cells, but in none of the control mice. In the POET model, we also used real time PCR to assess the expression of Transforming Growth Factor Beta 1 (TGFβ1), a factor in inflammation that is activated by α(v)β(6). In conclusion, through in vivo evidence, we conclude that α(v)β(6) integrin may be a crucial link between prostatic inflammation and prostatic adenocarcinoma.

Schmetterlinge von Madeira

NARCIS (Netherlands)

Martin, K.

1941-01-01

Wer auf einer ozeanischen Insel Schmetterlinge sammeln will, darf seine Erwartungen nicht zu hoch spannen; aber dennoch waren meine Frau und ich sehr enttäuscht, als uns auf einer Reise nach Madeira von einer dort angesessenen, gebildeten Dame gesagt wurde, sie habe auf der Insel niemals einen

Downregulation of PI3-K/Akt/PTEN pathway and activation of mitochondrial intrinsic apoptosis by Diclofenac and Curcumin in colon cancer.

Science.gov (United States)

Rana, Chandan; Piplani, Honit; Vaish, Vivek; Nehru, Bimla; Sanyal, S N

2015-04-01

Phosphatidylinositol 3-kinase (PI3-K)/PTEN/Akt signaling is over activated in various tumors including colon cancer. Activation of this pathway regulates multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth that underlie the biology of a cancer cell. In the present study, the chemopreventive effects have been observed of Diclofenac, a preferential COX-2 inhibitory non-steroidal anti-inflammatory drugs, and Curcumin, a natural anti-inflammatory agent, in the early stage of colorectal carcinogenesis induced by 1,2-dimethylhydrazine dihydrochloride in rats. The tumor-promoting role of PI3-K/Akt/PTEN signal transduction pathway and its association with anti-apoptotic family of proteins are also observed. Both Diclofenac and Curcumin downregulated the PI3-K and Akt expression while promoting the apoptotic mechanism. Diclofenac and Curcumin administration significantly increased the expression of pro-apoptotic Bcl-2 family members (Bad and Bax) while decreasing the anti-apoptotic Bcl-2 protein. An up-regulation of cysteine protease family apoptosis executioner, such as caspase-3 and -9, is seen. Diclofenac and Curcumin inhibited the Bcl-2 protein by directly interacting at the active site by multiple hydrogen bonding, as also evident by negative glide score of Bcl-2. These drugs stimulated apoptosis by increasing reactive oxygen species (ROS) generation and simultaneously decreasing the mitochondrial membrane potential (ΔΨ M). Diclofenac and Curcumin showed anti-neoplastic effects by downregulating PI3-K/Akt/PTEN pathway, inducing apoptosis, increasing ROS generation, and decreasing ΔΨ M. The anti-neoplastic and apoptotic effects were found enhanced when both Diclofenac and Curcumin were administered together, rather than individually.

Effect of Jianpi Jiedu Recipe on angiogenesis and the PTEN/PI3K/AKT signaling pathway in the course of Helicobacter pylori-induced gastric cancer in C57BL/6 mice

Directory of Open Access Journals (Sweden)

Ning-Ning Liu

2018-01-01

Full Text Available Objective: To reveal the effect of Jianpi Jiedu recipe (JPJDR on angiogenesis and the PTEN (Phosphatase and tensin homolog deleted on chromosome ten/PI3K/AKT signaling pathway in the course of H. pylori infection-induced carcinogenesis of gastric mucosa in C57BL/6 mice. Methods: Two-hundred C57BL/6 mice were randomly divided into five groups (control group, model group, JPJDR low-dose group, JPJDR medium-dose group, and JPJDR high-dose group, 40 in each group. A mouse model of gastric cancer, induced by H. pylori standard strain infection, was established. The mice of JPJDR low-dose, middle-dose, and high-dose groups were intragastrically administered 250, 500, and 1000 mg/kg JPJDR per day, respectively. After 72 weeks, the H. pylori infection in gastric mucosa of the mice was analyzed by rapid urease test; the pathological changes in the gastric mucosa of mice were assessed by histopathological examination, and micro-vessel density (MVD, vascular endothelial growth factor (VEGF, and PTEN/PI3K/AKT levels were determined. Results: The incidence of gastric cancer in each group (control group, model group, JPJDR low-dose, medium-dose, high-dose group was 0%, 26.3%, 13.2%, 10%, and 7.5% respectively. The incidence of gastric cancer in the Chinese medicine group was significantly lower than that of the model group (P = 0.020, P = 0.023, P = 0.007. The expression of MVD and VEGF in the model group was significantly higher than that in the control group (P = 0.002, P < 0.001, while the expression of MVD and VEGF decreased in the Chinese medicine group. The expression of p-PTEN and p-AKT in the model group was significantly higher than that in the control group (All P < 0.001, while Chinese medicine could reduce the expression of p-PTEN and p-AKT to varying extents. Conclusion: Long-term infection of C57BL/6 mice with H. pylori induces gastric carcinogenesis, by increasing gastric mucosal MVD, promoting the expression of VEGF, inhibiting the activity of

Von Neumann's impossibility proof: Mathematics in the service of rhetorics

Science.gov (United States)

Dieks, Dennis

2017-11-01

According to what has become a standard history of quantum mechanics, in 1932 von Neumann persuaded the physics community that hidden variables are impossible as a matter of principle, after which leading proponents of the Copenhagen interpretation put the situation to good use by arguing that the completeness of quantum mechanics was undeniable. This state of affairs lasted, so the story continues, until Bell in 1966 exposed von Neumann's proof as obviously wrong. The realization that von Neumann's proof was fallacious then rehabilitated hidden variables and made serious foundational research possible again. It is often added in recent accounts that von Neumann's error had been spotted almost immediately by Grete Hermann, but that her discovery was of no effect due to the dominant Copenhagen Zeitgeist. We shall attempt to tell a story that is more historically accurate and less ideologically charged. Most importantly, von Neumann never claimed to have shown the impossibility of hidden variables tout court, but argued that hidden-variable theories must possess a structure that deviates fundamentally from that of quantum mechanics. Both Hermann and Bell appear to have missed this point; moreover, both raised unjustified technical objections to the proof. Von Neumann's argument was basically that hidden-variables schemes must violate the ;quantum principle; that physical quantities are to be represented by operators in a Hilbert space. As a consequence, hidden-variables schemes, though possible in principle, necessarily exhibit a certain kind of contextuality. As we shall illustrate, early reactions to Bohm's theory are in agreement with this account. Leading physicists pointed out that Bohm's theory has the strange feature that pre-existing particle properties do not generally reveal themselves in measurements, in accordance with von Neumann's result. They did not conclude that the ;impossible was done; and that von Neumann had been shown wrong.

50th birthday of Christian von Ferber

Directory of Open Access Journals (Sweden)

2011-06-01

Full Text Available On May 15, 2011 Christian von Ferber - member of the Editorial Board of "Condensed Matter Physics" and renowned expert in the fields of soft matter physics and complex systems - celebrated his 50th birthday. The Editorial board of CMP, colleagues and friends warmy congratulate Christian von Ferber and wish him and his family continuing good health and to enjoy many adventures and discoveries in his future scientific travels!

Budke, Alexandra; Kanwischer, Detlef; Pott, Andreas (Hg.), Internetgeographien : Beobachtungen zum Verhältnis von Internet, Raum und Gesellschaft / [rezensiert von] Helmut Klüter

OpenAIRE

Klüter, Helmut

2009-01-01

Rezensiertes Werk: Internetgeographien : Beobachtungen zum Verhältnis von Internet, Raum und Gesellschaft / hrsg. von Alexandra Budke ... - Stuttgart : Steiner, 2004. - 192 S. : Ill., graph. Darst., Kt. - (Erdkundliches Wissen ; 136) ISBN 3-515-08506-8

Erfahrungen an der Schnittstelle von Medienarbeit und Praxisforschung

Directory of Open Access Journals (Sweden)

Peter Holzwarth

2007-11-01

Full Text Available Der Beitrag reflektiert die Verbindung von praktischer Medienarbeit und Forschung am Beispiel eines internationalen EU-Forschungsprojekts zum Thema Medien und Migration. Neben didaktischen Prinzipien und Konzepten für die aktive Medienarbeit im Forschungskontext geht es um die Kooperation von medienpädagogischer Begleitung (MB und wissenschaftlicher Begleitung (WB sowie um deren spezifische Kompetenzen.

Integration von 3D-Kamerasystemen am Gabelstapler

OpenAIRE

Kleinert, Steffen; Overmeyer, Ludger

2013-01-01

Dieser Beitrag beschreibt die Integration von laufzeitmessenden 3D Kamerasystemen in die Gabelzinkenspitzen eines Flurförderzeugs. Mit Hilfe der integrierten Kameras und deren ausgewerteter Aufnahmen wurde ein Assistenzsystem für die Handhabung von Ladungsträgern realisiert, das dem Fahrer des Flurförderzeugs Verfahrempfehlungen für die Optimierung der Relativposition zwischen Gabelzinken und Ladungsträger bzw. Lagerplatz ausgibt. Neben der Vorstellung der verwendeten Kamera-Hardware und der ...

Kerttu Wagner. Die historischen romane von Jaan Kross / Wolfgang Drechsler

Index Scriptorium Estoniae

Drechsler, Wolfgang, 1963-

2001-01-01

Arvustus: Wagner, Kerttu. Die historischen Romane von Jaan Kross : am Beispiel einer Untersuchung der deutschen und englischen Übersetzungen von "Professor Martensi ärasõit" (1984). Frankfurt am Main [etc.] : P. Lang, 2001.

Neuere Untersuchungen zur Prädiktion von EEG-Signalen bei Epilepsie

Directory of Open Access Journals (Sweden)

C. Niederhöfer

2007-06-01

Full Text Available Seit einigen Jahren ist die Analyse von EEG-Signalen bei Epilepsie Gegenstand zahlreicher wissenschaftlicher Arbeiten; Zielvorstellung ist dabei die Entwicklung von Verfahren zur Erkennung eines möglichen Voranfallszustandes. Im Vordergrund steht beispielsweise die Approximation einer so genannten effektiven Korrelationsdimension, die Bestimmung der maximalen Lyapunov-Exponenten, Detektionsverfahren für Muster bei Zellularen Nichtlinearen Netzwerken, die Bestimmung der mittleren Phasenkohärenz und Verfahren zur nichtlinearen Prädiktion von EEG-Signalen. Trotz umfangreicher Bemühungen kann bis heute eine Erkennung von Anfallsvorboten mit einer Sensitivität und Spezifität, die eine automatisierte Anfallsvorhersage ermöglichen würde, noch nicht durchgeführt werden. In diesem Beitrag werden neue Ergebnisse zur Prädiktion von EEG-Signalen bei Epilepsie vorgestellt. Dabei werden Signale, welche mittels intrakranieller electrocorticographischer (ECoG und stereoelectroencephalographischer (SEEG Ableitungen registriert wurden, segmentweise analysiert. Unter der Annahme, dass sich Änderungen des Systems ,,Gehirn" als Änderungen im Prädiktor, d.h. in seinen Systemparametern widerspiegeln, könnte eine nähere Betrachtung der Prädiktoreigenschaften zu einer Erkennung von Anfallsvorboten führen.

Gasification of liquid manure; Vergasung von Guelle

Energy Technology Data Exchange (ETDEWEB)

Gudenau, H W; Hoberg, H; Hirsch, U [Technische Hochschule Aachen (Germany). Inst. fuer Eisenhuettenkunde

1997-12-31

The potential of thermal use of liquid manure is investigated. It is recommended to separate the liquid and solid fraction. While the liquid fraction can be used as fertilizer, the solid fraction can be used for generating a fuel gas for combined heat and power generation. (orig) [Deutsch] Die Untersuchungen haben ergeben, dass in der thermischen Verwertung von Guelle ein bisher nur wenig genutztes Potential vorliegt. Die zum Anbau von Getreide notwendige Duengung kann durch Separation von Guelle in Fest- und Duennfraktion effektiver und kostenguenstiger durchgefuehrt werden. Der Naehrstoffgehalt des Guellefeststoffs sollte durch thermische Aufbereitung aufkonzentriert werden, so dass eine Vermarktung auch mit laengeren Transpoertwegen darstellbar ist. Die bei der thermischen Behandlung gewonnene Waerme kann prozessintern genutzt und ueberschuessige Waerme an Abnehmer in der naeheren Umgebung geliefert werden. Genauso besteht die Moeglichkeit, ein Brenngas zu erzeugen und die Energie mit Kraft-Waerme-Kopplung zu nutzen. (orig)

Gasification of liquid manure; Vergasung von Guelle

Energy Technology Data Exchange (ETDEWEB)

Gudenau, H.W.; Hoberg, H.; Hirsch, U. [Technische Hochschule Aachen (Germany). Inst. fuer Eisenhuettenkunde

1996-12-31

The potential of thermal use of liquid manure is investigated. It is recommended to separate the liquid and solid fraction. While the liquid fraction can be used as fertilizer, the solid fraction can be used for generating a fuel gas for combined heat and power generation. (orig) [Deutsch] Die Untersuchungen haben ergeben, dass in der thermischen Verwertung von Guelle ein bisher nur wenig genutztes Potential vorliegt. Die zum Anbau von Getreide notwendige Duengung kann durch Separation von Guelle in Fest- und Duennfraktion effektiver und kostenguenstiger durchgefuehrt werden. Der Naehrstoffgehalt des Guellefeststoffs sollte durch thermische Aufbereitung aufkonzentriert werden, so dass eine Vermarktung auch mit laengeren Transpoertwegen darstellbar ist. Die bei der thermischen Behandlung gewonnene Waerme kann prozessintern genutzt und ueberschuessige Waerme an Abnehmer in der naeheren Umgebung geliefert werden. Genauso besteht die Moeglichkeit, ein Brenngas zu erzeugen und die Energie mit Kraft-Waerme-Kopplung zu nutzen. (orig)

Von Kármán between Aachen and Pasadena

Science.gov (United States)

Krause, Egon; Kalkmann, Ulrich

2013-05-01

In the Introduction the reader is referred back to the academic ceremonials held after Theodore von Kármán's death in Aachen in May 1963. His work as the first director of the Aerodynamisches Institut (Institute of Aerodynamics) of the RWTH Aachen University of Technology from 1913 on and his initiative to re-establish international cooperation after World War I, resulting in the International Union of Theoretical and Applied Mechanics (IUTAM), are commented on. The following chapter describes von Kármán's relation to his former teacher Ludwig Prandtl. Some of von Kármán's scientific contributions during his time in Aachen are briefly reviewed. Thereafter, his first contacts to the California Institute of Technology are covered. Finally, the scientific and political circumstances, which led to von Kármán's decision to leave Germany in the early thirties, are elucidated in some detail. The English translation of the titles of the Aachen papers is given in Appendix I.

Neuro- und Gliotoxizität von Wolframcarbid-basierten Nanopartikeln in vitro

OpenAIRE

Bastian, Susanne

2011-01-01

Die Anzahl neurodegenerativer Erkrankungen nimmt in unserer Gesellschaft stetig zu. Obwohl inzwischen eine Reihe genetischer Ursachen identifiziert worden sind, wird auch der Einfluss von Umweltfaktoren bei der Pathogenese dieser Erkrankungen zunehmend in Betracht gezogen. Der Beitrag von ultrafeinen Partikeln aus Industrie und Umwelt auf neurodegenerative Erkrankungen steht daher zunehmend im Fokus der Forschung. Die Translokation von ultrafeinen Partikeln bzw. Nanopartikeln ins Gehirn ist b...

Gesamtfahrzeugsimulation betriebsfestigkeitsrelevanter Manöver unter Berücksichtigung von Fahrwerkregelsystemen

OpenAIRE

Brandes, Sebastian Jürgen

2016-01-01

In der Automobilbranche dient im Bereich der betriebsfesten Bemessung des Fahrwerks die Methode der Mehrkörpersysteme als Analyseverfahren zur Ermittlung von Bewegungen und Schnittgrößen an den Fahrwerksbauteilen. Eine der aktuellen Herausforderungen hierbei ist der zunehmende interdisziplinäre Charakter in Form von mechatronischen Fahrwerkssystemen. In rein virtuellen Entwicklungsphasen kann deren Einfluss auf die Fahrwerksbelastungen einzig anhand von Gesamtfahrzeugsimulationen ermittelt we...

Die filmstilistische Darstellung von Klaras Gehbehinderung im Kinderfilm "Heidi"

Directory of Open Access Journals (Sweden)

Maria Ohrfandl

2016-09-01

Full Text Available Dieser Beitrag soll die Forschungslücke zur Darstellung von Behinderungen speziell im Kinderfilm im deutschsprachigen Raum füllen. Auf Basis einer neoformalistisch orientierten Filmanalyse nach Bordwell und Thompson (2008, wird anhand von drei Filmsequenzen eine mögliche Lesart des Kinderfilms "Heidi" (Marcus 2005 entwickelt, um die filmstilistische Darstellung der Gehbehinderung des Mädchens Klara zu untersuchen. Die Ergebnisse werden mit theoretischen Überlegungen zur Problematik der Begriffsbestimmung von Körperbehinderung sowie zur Mobilität und Selbstbestimmung von Menschen mit Körperbehinderungen in Bezug gesetzt. Dabei zeigt sich im Wesentlichen, dass im Kinderfilm "Heidi" (Marcus 2005 Klaras Gehbehinderung als 'heilbare Krankheit' und der Rollstuhl als Einschränkung von Mobilität begriffen wird. Außerdem unterliegt Klara aufgrund ihrer Körperbehinderung überwiegend der Fremdbestimmung von Erwachsenen. Zur Klärung wahrscheinlicher filmischer Bildungspotenziale werden die Ergebnisse schließlich anhand der von Jörissen und Marotzki (2009 entwickelten Orientierungsdimensionen "Wissens-, Handlungs-, Grenz- und Biographiebezug" diskutiert. This article aims to bridge a knowledge gap by showing ways of representing disabilities in the German children film genre. Using Bordwell and Thomson's (2008 neoformalistically orientated film analysis approach, the movie "Heidi" (Marcus 2005 is analysed. Bordwell and Thompson's (2008 method is applied to three sequences of "Heidi" in order to present an interpretation and to discuss the representation of Clara's walking impediment. The results are then associated with theoretical considerations regarding the mobility and self-determination of people with disabilities and problematic definitions of the term 'physical disability'. It is shown that characters in the children's film "Heidi" (Marcus 2005 regard Clara's walking impediment as a 'curable disease' and the wheelchair as a limitation

Aino Lepik von Wiren / Aino Lepik von Wiren ; interv. Kadi Alatalu

Index Scriptorium Estoniae

Lepik von Wirén, Aino, 1961-

2007-01-01

Heinrich Marga eksiilvalitsuse (20.06.1990-7.10.1992) kohtuminister Aino Lepik von Wiren pagulaslapse elust Rootsis, haridusest ja elukutse valikust, tööst eksiilvalitsuses, tööleasumisest Eestisse 1992. aastal, seadusandlikust tegevusest ning aluse panekust välismaalaste- ja kodakondsuspoliitikale, naiste võimalustest poliitilisse tippu tõusmiseks, kodu- ja väliseestlaste vastandamisest

Investigation of partial oxidation of hydrogen sulfide for dry desulfurisation of fuel gases; Untersuchung der Partialoxidation von Schwefelwasserstoff zur Trockenentschwefelung von Brenngasen

Energy Technology Data Exchange (ETDEWEB)

Kliemczak, U.

2002-07-01

Three process variants for direct desulfurisation in the dry state of coal gasification gases by partial oxidation of H{sub 2}S were investigated in Prenflo conditions: 1. Heterogeneously catalyzed partial oxidation of H{sub 2}S on fly dust followed by sulfur deposition on the dust; 2. Non-catalyzed partial oxidation of H{sub 2}S in a homogeneous gaseous phase followed by sulfur deposition in a spray separator; 3. Heterogeneously catalyzed partial oxidation of H{sub 2}S in a fixed bed. The experiments were carried out in conditions similar to the crude gas conditions of slag bath gasification at SVZ Schwarze Pumpe. The fixed bed materials investigated were hearth furnace coke, Berl saddles, and an activated carbon developed specially for the investigations, Oxorbon CJ. The focus of the investigations was on the envisaged continuous operation of the process. [German] Im Rahmen der vorliegenden Arbeit wurde an einer zu diesem Zweck modifizierten Technikumsanlage die trockene Direktentschwefelung von Brenngasen aus der Kohlevergasung durch partielle Oxidation von H{sub 2}S untersucht. Im Vordergrund standen zwei Verfahrensvarianten, deren Eignung fuer die Bedingungen der Prenflo-Vergasung ueberprueft werden sollte: Variante 1: die heterogen katalysierte Partialoxidation von H{sub 2}S an Flugstaub mit anschliessender Schwefelabscheidung auf dem Staub und, Variante 2: die nichtkatalysierte Partialoxidation von H{sub 2}S in homogener Gasphase mit anschliessender Schwefelabscheidung in einem Spruehabscheider. Ausgehend von den Versuchsergebnissen der Verfahrensvarianten 1 und 2 wurde zusaetzlich als Verfahrensvariante 3 die heterogen katalysierte Partialoxidation von H{sub 2}S am Festbett untersucht. Diese Versuche orientierten sich an den Rohgasbedingungen der Schlackebadvergasung des SVZ Schwarze Pumpe. Als Festbettmaterialien kamen Herdofenkoks, Berlsaettel und eine, speziell fuer diese Verfahrensvariante entwickelte Aktivkohle Oxorbon CJ, zum Einsatz. Die Eignung des

Von Roll RCP method - first experiences; Von Roll RCP - Verfahren. Erste Erfahrungen

Energy Technology Data Exchange (ETDEWEB)

Capitaine, P.; Engweiler, J. [Roll Umwelttechnik AG, Zuerich (Switzerland)

1998-09-01

The RCP method was designed as a residue-optimised alternative to the thermally optimised grate firing of residual wastes. Its technical realisation and development to market maturity took no more than 5 years. In the first process stage the waste is converted to high-carbon pyrolysis charcoal and high-rank gas in the absence of oxygen. In the second stage these substances are oxidised by addition of oxygen. The resulting temperature causes the non-combustible constituents of the slag to melt. In a third, optional, stage this molten slag can be liberated of (heavy) metals to such an extent that it can subsequently be used directly as additive for grinding. Further exhaust gas treatment is facilitated by the use of a circulatory fluidised-bed secondary combustion chamber. Despite the reduced flue gas volume and resultant higher pollutant concentrations in the crude gas, overall emissions are lower than in conventional plants. [Deutsch] Das reststoffoptimierte RCP Verfahren ist als Alternative zur thermisch optimierten Rostverbrennung von Restabfaellen konzipiert. In nur fuenf Jahren wurde das Verfahren technisch umgesetzt und zur Marktreife entwickelt. In einer ersten Stufe des Verfahrens wird der Abfall unter Luftabschluss in einen kohlenstoffreichen Pyrolysekoks und eine heizwertreiches Gas umgesetzt. Im zweiten Schritt werden diese Stoffe unter Zugabe von Sauerstoff oxidiert. Dabei treten Temperaturen auf, bei denen die nichtbrennbaren Bestandteile der Schlacke schmelzen. Optional wird diese Schmelzschlacke in einem dritten Schritt derart von (Schwer-) Metallen befreit, dass sie anschliessend direkt als Zement-Zumahlstoff eingesetzt werden kann. Die Nutzung der zirkulierenden Wirbelschicht - Nachbrennkammer zur Abgasbehandlung vereinfacht die weitergehende Abgasbehandlung. Trotz verringertem Rauchgasvolumen und damit hoeheren Schadstoffkonzentrationen im Rohgas werden die Gesamtemissionen gegenueber konventionellen Anlagen verringert. (orig./SR)

Eine selbstkonsistente Carleman Linearisierung zur Analyse von Oszillatoren

Directory of Open Access Journals (Sweden)

H. Weber

2017-09-01

Full Text Available Die Analyse nichtlinearer dynamischer Schaltungen ist bis heute eine herausfordernde Aufgabe, da nur selten analytische Lösungen angegeben werden können. Daher wurden eine Vielzahl von Methoden entwickelt, um eine qualitative oder quantitative Näherung für die Lösungen der Netzwerkgleichung zu erhalten. Oftmals wird beispielsweise eine Kleinsignalanalyse mit Hilfe einer Taylorreihe in einem Arbeitspunkt durchgeführt, die nach den Gliedern erster Ordnung abgebrochen wird. Allerdings ist diese Linearisierung nur in der Nähe des stabilen Arbeitspunktes für hyperbolische Systeme gültig. Besonders für die Analyse des dynamischen Verhaltens von Oszillatoren treten jedoch nicht-hyperbolische Systeme auf, sodass diese Methode nicht angewendet werden kann Mathis(2000. Carleman hat gezeigt, dass nichtlineare Differentialgleichungen mit polynomiellen Nichtlinearitäten in ein unendliches System von linearen Differentialgleichungen transformiert werden können Carleman(1932. Wird das unendlichdimensionale Gleichungssystem für numerische Zwecke abgebrochen, kann bei Oszillatoren der Übergang in eine stationäre Schwingung (Grenzzyklus nicht wiedergegeben werden.In diesem Beitrag wird eine selbstkonsistente Carleman Linearisierung zur Untersuchung von Oszillatoren vorgestellt, die auch dann anwendbar ist, wenn die Nichtlinearitäten keinen Polynomen entsprechen. Anstelle einer linearen Näherung um einen Arbeitspunkt, erfolgt mit Hilfe der Carleman Linearisierung eine Approximation auf einem vorgegebenen Gebiet. Da es jedoch mit der selbstkonsistenten Technik nicht möglich ist, das stationäre Verhalten von Oszillatoren zu beschreiben, wird die Berechnung einer Poincaré-Abbildung durchgeführt. Mit dieser ist eine anschließende Analyse des Oszillators möglich.

Eine selbstkonsistente Carleman Linearisierung zur Analyse von Oszillatoren

Science.gov (United States)

Weber, Harry; Mathis, Wolfgang

2017-09-01

Die Analyse nichtlinearer dynamischer Schaltungen ist bis heute eine herausfordernde Aufgabe, da nur selten analytische Lösungen angegeben werden können. Daher wurden eine Vielzahl von Methoden entwickelt, um eine qualitative oder quantitative Näherung für die Lösungen der Netzwerkgleichung zu erhalten. Oftmals wird beispielsweise eine Kleinsignalanalyse mit Hilfe einer Taylorreihe in einem Arbeitspunkt durchgeführt, die nach den Gliedern erster Ordnung abgebrochen wird. Allerdings ist diese Linearisierung nur in der Nähe des stabilen Arbeitspunktes für hyperbolische Systeme gültig. Besonders für die Analyse des dynamischen Verhaltens von Oszillatoren treten jedoch nicht-hyperbolische Systeme auf, sodass diese Methode nicht angewendet werden kann Mathis (2000). Carleman hat gezeigt, dass nichtlineare Differentialgleichungen mit polynomiellen Nichtlinearitäten in ein unendliches System von linearen Differentialgleichungen transformiert werden können Carleman (1932). Wird das unendlichdimensionale Gleichungssystem für numerische Zwecke abgebrochen, kann bei Oszillatoren der Übergang in eine stationäre Schwingung (Grenzzyklus) nicht wiedergegeben werden. In diesem Beitrag wird eine selbstkonsistente Carleman Linearisierung zur Untersuchung von Oszillatoren vorgestellt, die auch dann anwendbar ist, wenn die Nichtlinearitäten keinen Polynomen entsprechen. Anstelle einer linearen Näherung um einen Arbeitspunkt, erfolgt mit Hilfe der Carleman Linearisierung eine Approximation auf einem vorgegebenen Gebiet. Da es jedoch mit der selbstkonsistenten Technik nicht möglich ist, das stationäre Verhalten von Oszillatoren zu beschreiben, wird die Berechnung einer Poincaré-Abbildung durchgeführt. Mit dieser ist eine anschließende Analyse des Oszillators möglich.

Ecobalance of natural gas vehicles; Oekobilanz von Erdgasfahrzeugen

Energy Technology Data Exchange (ETDEWEB)

Nigge, K.M. [Simon, Kucher und Partners Strategy und Marketing Consultants GmbH, Bonn (Germany)

2000-07-01

The impacts on human health and the natural environment of using natural gas, Diesel and petrol as fuels for city buses and passenger cars are compared in a Life Cycle Assessment. In addition to the burning of the fuels in the engines, this assessment also comprises the upstream processes of the fuel supply chain. Despite the increased energy demand of the vehicles, natural gas is associated with the lowest impacts overall for both city buses and passenger cars. The health impacts that can be avoided through the use of natural gas instead of Diesel or petrol thereby differ only weakly between the use of the vehicles in cities of various sizes within Germany. From the perspective of environmental protection, the market introduction of natural gas vehicles therefore does not need remain limited to large cities within agglomerated regions. (orig.) [German] Die Auswirkungen der Verwendung von Erdgas, Diesel und Benzin als Kraftstoffe fuer Stadtbusse und Pkw auf die menschliche Gesundheit und die natuerliche Umwelt werden in einer Oekobilanz verglichen. Diese umfasst neben der motorischen Verbrennung der Kraftstoffe auch die vorgelagerten Prozessketten der Kraftstoffbereitstellung. Sowohl fuer Stadtbusse als auch fuer Pkw schneidet Erdgas trotz eines energetischen Mehrbedarfes der Fahrzeuge insgesamt am guenstigsten ab. Die durch den Einsatz von Erdgas anstelle von Diesel oder Benzin vermeidbaren Gesundheitsschaeden unterscheiden sich dabei zwischen einem Einsatz der Fahrzeuge in Staedten verschiedener Groesse innerhalb von Deutschland nur wenig. Die Markteinfuehrung von Erdgasfahrzeugen muss also aus Sicht des Umweltschutzes nicht auf grosse Staedte in Ballungsgebieten beschraenkt bleiben. (orig.)

Analytische und Effektor-Studien von N-Acyl-Ethanolaminphosphaten

OpenAIRE

Ates, Ebru

2011-01-01

Bei N-Acyl-Ethanolaminphosphaten handelt es sich um eine bislang wenig untersuchte Klasse polarer Substanzen, deren Erforschung aufgrund ihrer strukturellen Analogie zu apolaren, physiologisch wirksamen N-Acyl-Ethanolaminen von Interesse ist. Zu bear-beiten waren analytische Fragestellungen, die auch synthetische Aufgaben beinhalteten, wie Methodenentwicklung und Versuche zur Erfassung von N-Acyl-Ethanolamin-phosphaten in ausgewählten Lebensmitteln sowie strukturelle Studien zur „Bioaktivität...

Räumliche Aspekte von Transformationsproblemen aus systemtheoretischer Perspektive

OpenAIRE

Klüter, Helmut

2000-01-01

Der mit dem Topos "Transformation von Wirtschafts- und Gesellschaftssystemen" axiomatisch angenommene Unvereinbarkeit sozialistischer und marktwirtschaftlicher Strukturen ist aus raumwissenschaftlicher Sicht nicht nachvollziehbar. Zum einen gibt es in Wirtschaftsgeographie und Infrastrukturtheorie eine ganze Reihe von Gemeinsamkeiten und Berührungspunkten, die man für den konstruktiven Systemumbau nutzen kann. Zum andern benötigt der Umbau selbst eine räumliche Infrastruktur. Und zum dritten ...

Zur Dialektik von Soft Skills und fachlicher Kompetenz

OpenAIRE

Jendrowiak, Hans-Werner

2010-01-01

[Der Autor stellt folgende Thesen zur Dialektik von Soft Skills und fachlicher Bildung auf:] 1. Soft Skills sind normale Bildungskategorien und Teil einer Allgemeinen Bildung. […] 2. Soft Skills sind als personalgebundene Kriterien auch immer schon Gegenstand bildungstheoretischer Debatten. […] 3. Soft Skills ist eine trendorientierte Bezeichnung für Bildung. […] 4. Soft Skills sind Ausdruck von Vorstellungen, Ideen und Theorien (Schulkultur, Unternehmenskultur, Unternehmensphilosophie). 5. S...

Entwicklung von Cysteinproteaseinhibitoren - ein klassischer und ein kombinatorischer Ansatz zur Inhibitoroptimierung

OpenAIRE

Machon, Uwe Rainer

2009-01-01

Ziel der Dissertation „Entwicklung von Cysteinproteaseinhibitoren – ein klassischer und ein kombinatorischer Ansatz zur Inhibitoroptimierung“ war die Optimierung von neuen Inhibitoren von Falcipain-2 und Rhodesain als neue potentielle Wirkstoffe gegen Malaria bzw. die Schlafkrankheit über zwei verschiedene Methoden. Es handelt sich hierbei um einen klassischen und einen kombinatorischen Ansatz. Der klassische Ansatz basiert auf einer Struktur, deren Aktivität per Zufall entdeckt wurde. In Scr...

Entwicklung der Reglementierung von 10 MEM-Berufen im Kontext von Bildungsreformen und dem Wandel in der Arbeitswelt: Eine Kurzstudie im Auftrag von LIBS: Eine Kurzstudie im Auftrag von LIBS Industrielle Berufslehren Schweiz, Baden

OpenAIRE

Egg, Maria Esther; Renold, Ursula

2015-01-01

Im Auftrag der LIBS Industrielle Berufslehren Schweiz, hat die KOF die Entwicklung von 10 MEM1-Berufsbildern seit dem ersten Berufsbildungsgesetz dargestellt und diese eingebettet in eine kurze Zusammenfassung der wichtigsten Etappenschritte des Schweizer Berufsbildungssystems.

miR-18a promotes cell proliferation of esophageal squamous cell carcinoma cells by increasing cylin D1 via regulating PTEN-PI3K-AKT-mTOR signaling axis

Energy Technology Data Exchange (ETDEWEB)

Zhang, Weiguo, E-mail: weiguozhangHU@gmail.com; Lei, Caipeng; Fan, Junli; Wang, Jing

2016-08-12

Esophageal squamous cell carcinoma (ESCC) is one of the lethal cancers with a high incidence rate in Asia. Cyclin D1 is overexpressed and plays an important role in the carcinogenesis of ESCC; however the mechanism of the deregulation of Cyclin D1 in ESCC remains to be determined. In the study, we found that miR-18a promotes the expression Cyclin D1 by targeting PTEN in eophageal squamous cell carcinoma TE13 and Eca109 cells. Transfection of miR-18a mimetics increased cyclin D1, while transfection of miR-18a antagomir decreased D1. Moreover, miR-18a-mediated upregulation of cyclin D1 was accompanied with downregulation of PTEN, which is a direct target of miR-18a, and increase of the phosphorylation of AKT and S6K1. In addition, pharmacologic inhibition of AKT or mTOR kinases abolished the increase of cyclinD1 by miR-18a, which was accompanied with decreased phosphorylation of Rb−S780 and inhibition of cell proliferation. Our results demonstrated the upregulation of miR-18a promoted cell proliferation by increasing cylin D1 via regulating PTEN-PI3K-AKT-mTOR signaling axis, suggesting that small molecule inhibitors of AKT-mTOR signaling are potential agents for the treatment of ESCC patients with upregulation of miR-17-92 cluster. - Highlights: • miR-18a promotes the proliferation of ESCC cells. • miR-18a increase cyclin D1 expression in ESCC cells. • miR-18a directly targets PTEN in ESCC cells. • Inhibition of AKT-mTOR prevents miR-18a-induced cyclin D1 in ESCC cells. • miR-18a antagomir sensitizes ESCC cells to cisplatin.

Kleben von Kunststoff mit Metall

CERN Document Server

Brockmann, W; Käufer, H

1989-01-01

Das Buch behandelt das Kleben von Kunststoffen mit Metallen in einer fur den Praktiker verstandlichen und umsetzbaren Form. Es leitet zu Klebeverfahren an, die optimale Ergebnisse hinsichtlich Qualitat, Dauerhaftigkeit und Wirtschaftlichkeit liefern.

DNA甲基化抑制剂对涎腺腺样囊性癌中PTEN基因表达的影响%Effects of DNA methylation inhibitor on the expression of PTEN in adenoid cystic carcinoma cells

Institute of Scientific and Technical Information of China (English)

张华昌; 向学熔; 范小平; 徐军; 杨明聪; 吴静

2011-01-01

目的：研究5-氮杂-2′-脱氧胞苷（5-aza-2,-deoxycytidine,5-Aza-dc）对涎腺腺样囊性癌（adenoid cystic carcinoma,ACC）细胞中抑癌基因第10号染色体同源丢失性磷酸酶张力蛋白基因（phosphatase and tensin homology deleted on chromosome ten,PTEN）的影响及可能的机制。方法：利用RT-PCR检测正常涎腺细胞和涎腺腺样囊性癌细胞中PTEN基因mRNA的表达水平,后运用＂Methprimer＂软件对PTEN基因启动子区进行分析,预测CpG岛,通过甲基化特异性PCR（methylation-specific PCR,MSP）检测PTEN启动子区CpG岛的甲基化状态;利用RT-PCR检测涎腺腺样囊性癌细胞经甲基转移酶抑制剂5-Aza-dc作用后,PTEN基因mRNA的表达水平;western blot检测5-Aza-dc干预对PTEN蛋白表达的影响。结果：涎腺腺样囊性癌细胞中PTEN基因的表达明显低于正常涎腺细胞中的表达,存在统计学意义（p〈0.05）,通过＂Methprimer＂软件表明：涎腺腺样囊性癌细胞PTEN基因启动子区存在CpG岛,同时,通过甲基化特异性PCR（methylation-specific PCR,MSP）检测发现,涎腺腺样囊性癌细胞中PTEN基因启动子甲基化水平呈高表达;而在一定时间内,经5-Aza-dc作用后,涎腺腺样囊性癌细胞中PTEN基因mRNA及蛋白表达水平逐渐增加,且存在统计学意义（p〈0.05）,PTEN mRNA表达水平改变与PTEN蛋白的表达基本一致。结论：涎腺腺样囊性癌细胞系中PTEN的低表达可能与PTEN基因启动子区高水平的甲基化状态相关。%Objective：To detect the effects and mechanism of 5-aza-2＇-deoxycytidine on the expression of PTEN in adenoid cystic carcinoma.Methods：Using the expression of mRNA of PTEN in the normal salivary gland epithelial cells and ACC-2 cells were analyzed by RT-PCR,after using ＂Methprimer＂software,prediction of CpG island in promoter of＇ PTEN gene,the status of methylation of CpG island in promoter of PTEN gene was analyed methylation-specific PCR�

Zwei Briefe auf Guaraní in Alexander von Humboldts Handschrift

Directory of Open Access Journals (Sweden)

Manfred Ringmacher

2014-12-01

Full Text Available Gegenstand des Aufsatzes von Manfred Ringmacher sind zwei Briefe auf Guaraní in Alexander von Humboldts Handschrift. Die Originale der Abschriften wurden im Jahr 1800 in der ehemals jesuitisch betreuten Indianersiedlung Santa María la Mayor am Río Uruguay geschrieben und an den Vizekönig des spanischen Vizekönigreichs La Plata gesandt. Sie sind mit einer zeitgenössischen spanischen Übersetzung versehen; außerdem hat Alexander von Humboldt in französischer Sprache noch einige Erläuterungen gegeben.

Die baltischen Kapitulationen von 1710 : Kontext, Wirkungen, Interpretationen / Marten Seppel

Index Scriptorium Estoniae

Seppel, Marten, 1979-

2015-01-01

Arvustus: Die baltischen Kapitulationen von 1710 : Kontext, Wirkungen, Interpretationen, hrsg. von Karsten Brüggemann, Mati Laur und Pärtel Piirimäe, Queleln und Studien zur baltischen Geschichte, Bd 23 (Köln u.a: Böhlau Verlag, 2014)

La Medea de Lars von Trier

Directory of Open Access Journals (Sweden)

Iratxe Fresneda Delgado

2013-04-01

Full Text Available El presente artículo analiza el modo en el que Lars von Trier recrea para el cine el estereotipo de Medea. Mediante el análisis fílmico de la película y apoyándose en los estudios culturales, el texto se interroga acerca de la importancia y el poder potencial del cine a la hora recuperar el antiguo mito y demostrar su vigencia. El análisis amplía horizontes para la compresión de los mecanismos que articulan el entramado de significados de la película, donde Von Trier aporta una nueva visión del arquetipo de Medea uniéndola, a la tradición pictórica del Romanticismo. Una influencia que habita en las posteriores obras del director danés, donde el paisaje, la naturaleza, se erige en elemento catalizador de las pulsiones humanas, en su cómplice y testigo.This paper explores the way that Lars von Trier’s film recreates the stereotype of Medea. Using film analysis and based on cultural studies the article asks about the importance and potential power of cinema to recover the ancient myth and show their effects. The analysis expands horizons for the understanding of the mechanisms that link the network of meanings of the film, where the author offers a new vision of Medea's archetype attaching it to the pictorial tradition tied to the Romanticism. An influence that can be seen in the later works of Lars von Trier, where the landscape, the nature, stands as a catalyst of human drives, as his accomplice and witness.

Auftreten von Falschem Mehltau bei Gartenkresse (Lepidium sativum L. in der Saatgutvermehrung – Evaluierung von Saatgutbehandlung und Wachstumsbedingungen in einem Gefäßversuch

Directory of Open Access Journals (Sweden)

Zeller, Stefanie

2014-09-01

Full Text Available Die zur Familie der Brassicaceae gehörende Gartenkresse wird in Deutschland überwiegend im biologischen Anbau vermehrt. Seit einigen Jahren werden diese Gartenkressebestände von Erregern des Falschen Mehltaus (Hyaloperonospora parasitica, Perofascia lepidii befallen, was zu einem Totalausfall des Pflanzenbestandes führen kann. Daher ist die biologische Saatgutproduktion von Gartenkresse gefährdet, was eine Beeinträchtigung der Saatgutversorgung für die Keimsprossenerzeugung zur Folge hat. In den laufenden Untersuchungen wird der Einfluss von nicht chemischen Saatgutbehandlungsmaßnahmen (Wasserdampf, Elektronen, sowie Wachstumsbedingungen (Feuchte, Boden auf die Infektion mit Falschem Mehltau untersucht.

Kaks maastikuvaadet Karl Otto Gerhard von Kügelgenilt: romantismi kaja biidermeierlikus sarmis = Two Landscape Views by Otto Gerhard von Kügelgen: Echo of Romanticism in Biedermeier Charm / Kadi Polli

Index Scriptorium Estoniae

Polli, Kadi, 1973-

2011-01-01

2010. aastal Frankfurdis H. W. Fichteri kunstigaleriis müüki tulnud kümnest kunstiteosest, sh. Eesti Kunstimuuseumi poolt omandatud kahest Karl Otto Gerhard von Kügelgeni tööst. Franz Gerhard von Kügelgeni noorema poja Karl Otto Gerhard von Kügelgeni elust, loomingust ja tema akvarellidest "Perekond Vinni mõisas" ja "Rändur metsas"

An accurate von Neumann's law for three-dimensional foams

NARCIS (Netherlands)

Hilgenfeldt, Sascha; Kraynik, Andrew M.; Koehler, Stephan A.; Stone, Howard A.

2001-01-01

The diffusive coarsening of 2D soap froths is governed by von Neumann's law. A statistical version of this law for dry 3D foams has long been conjectured. A new derivation, based on a theorem by Minkowski, yields an explicit analytical von Neumann's law in 3D which is in very good agreement with

Skin Aging-Dependent Activation of the PI3K Signaling Pathway via Downregulation of PTEN Increases Intracellular ROS in Human Dermal Fibroblasts

Directory of Open Access Journals (Sweden)

Eun-Mi Noh

2016-01-01

Full Text Available Reactive oxygen species (ROS play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3 metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts.

Challenge the science-stereotype. Der Einfluss von Technik-Freizeitkursen auf das Naturwissenschaften-Stereotyp von Schülerinnen und Schülern

OpenAIRE

Hannover, Bettina; Kessels, Ursula

2002-01-01

Der Aufsatz untersucht Aspekte von Kultur, die die individuelle Interessen- und Leistungsentwicklung von Schülerinnen und Schülern prägen ... . Es stehen die Kulturen spezifischer Schulfächer im Vordergrund. Im Aufsatz werden kulturell geteilte Annahmen über mathematisch- naturwissenschaftliche Schulfächer im Unterschied zu geistes- und sozialwissenschaftlichen Disziplinen untersucht; nämlich stereotype Vorstellungen über den Gegenstandsbereich, über Unterrichtsscripts, über typische Lehrpers...

Optimierung der Gesichtsklassifikation bei der Erkennung von Akromegalie

Directory of Open Access Journals (Sweden)

Frohner R

2013-01-01

Full Text Available In vorausgegangenen Studien konnte gezeigt werden, dass eine Gesichtsklassifikation mittels Gesichtsphotographien zur Diagnostik von Akromegalie mit guten Ergebnissen eingesetzt werden kann. In diesem Artikel werden die grundlegende Vorgehensweise der Klassifikation mittels der Software FIDA erläutert sowie Optimierungsansätze mit dem Ziel diskutiert, diese Methode näher an den klinischen Einsatz zu bringen. Die Gesichtsklassifikation basiert auf „Knotenpunkten“, die verteilt über die jeweilige Frontal- und/oder Seitenansicht des Gesichts platziert werden und den so genannten „Graphen“ bilden. Mittels mathematischer Verfahren erfolgt eine Analyse der zugrunde liegenden Textur des Bildes sowie die Auswertung geometrischer Informationen. Untersucht wird, wie sich die Reduktion von als irrelevant eingestuften Knoten auf das Klassifikationsergebnis auswirkt. Ebenso wird untersucht, wie sich neu definierte Knoten, die die typischen morphologischen Veränderungen der akromegalen Erkrankung im Gesicht berücksichtigen, auf die Klassifizierungsergebnisse auswirken. Die interne Validierung erfolgt an einem Datenset bestehend aus 57 an Akromegalie erkrankten Probanden (29 weiblich, 28 männlich sowie 59 Kontrollen (29 weiblich, 30 männlich. Die externe Validierung wird an einer weiteren Stichprobe gemessen, die zum Zeitpunkt der Präsentation auf der Tagung der European Neuroendocrine Association 2012 in Wien 13 akromegale Patienten (7 weiblich, 6 männlich sowie 45 Kontrollen (25 weiblich, 20 männlich umfasste. Die Datenbank wird ständig durch neue Probanden aus verschiedenen Quellen erweitert. Erste Ergebnisse zeigen, dass die Verwendung von Graphen mit reduzierten Knoten und von neuen Sets von Knoten unter Einbeziehung typischer morphologischer Veränderungen des Gesichts die Klassifizierung weiter verbessert. Diese Ergebnisse ermutigen zu weiteren Untersuchungen an einer erweiterten Datenbank.

von Hippel-Lindau disease

DEFF Research Database (Denmark)

Binderup, Marie Louise Mølgaard; Gimsing, Steen; Kosteljanetz, Michael

2013-01-01

Endolymphatic sac tumours (ELSTs) of the inner ear occur in 16% of patients with the hereditary tumor syndrome von Hippel-Lindau disease (vHL). ELSTs of all sizes can cause irreversible hearing loss which can, however, be prevented through early diagnosis and treatment. We aim to emphasize the ch...

Ueber den begriff "Kinoplasma" in der spermiogenese von Australorbis Glabratus Olivaceus (Mollusca, Pulmonata, Planorbidae

Directory of Open Access Journals (Sweden)

Rudolf Barth

1960-11-01

Full Text Available Zur Klaerung der Frage, ob der Begriff "Kinoplasma" fuer gewisse, von MERTON (1924,1926, 1930 beobachtete Bildungen an den reifenden Spermiden von pulmonaten Mollusken oder fuer Bestandteile des Cytoplasmas im Sinne von STRASBURGER und SCARTH zu verwenden ist, werden in der vorliegenden Mitteilung die Vorgaenge bei der Spermiohistogenese von Australorbis glabratus olivaceus untersucht. Es ergibt sich: 1. Das von MERTON bezeichnete "Kinoplasma" existiert nicht als solches, es handelt sich bei den von ihm dargestellten Protoplasmabildungen um kugelige, von den Spermiden abgeschnuerte Restkoerper nicht verwendeten Baumaterials, bestehend aus Protoplasma und einigen Mitochondrien. Sie werden von den Naehr- oder Bazalzellen phagozytiert. Der Ausdruck "Kinoplasma" kann nur fuer die submikroskopischen, geformten, faedigen Elemente des Cytoplasmas reserviert bleiben, die den geradlinigen Fall der uebrigen nicht geformten Komponenten bremst oder ablenkt; damit muss das Kinoplasma aber aus dem Begriff des Cytoplasmas herausgenommen werden, da es, wenn auch vermutlich reversibel, eine Differenzierung darstellt. 2. Der Spermienfaden wird von den Centriolen (Axialfilament und den Mitochondrien (zwei peripher gelegene Spiralfilamente, sowie einem Plasmamantel gebildet. 3. Nach Beendigung des Auswachsens der Spermiengeissel, die zu diesem Zeitpunkt nur aus dem Achsenfaden und dem Protoplasmazylinder besteht, setzt sich eine Protoplasmamasse vom Kopf in Richtung zum Geisselende in Bewegung. Sie fuehrt den Golgi-Koerper und sehr viele Mitochondrien mit sich. Aus diesen entwickeln sich Fibrillen, die sich zu den beiden Spiralfilamenten zusammenfuegen. Diese Masse entspricht der von MERTON in seiner Theorie als Kinoplasma bezeichneten Komponente. 4. Die Bewegung dieses Protoplasmateils wird auf den Schub zurueckgefuehrt, den die sich bildenden Fibrillen auf die Mitochondrien ausueben. 5. Die Rueckwaertsbewegung dieses Protoplasmakoerpers beruht wahrscheinlich auf

Asymptotic analysis of a von Koch beam

International Nuclear Information System (INIS)

Carpinteri, Alberto; Pugno, Nicola; Sapora, Alberto

2009-01-01

Fractal geometry is used in diverse research areas, being an useful tool in describing the mechanical behaviour of natural and man-made structures. In this paper, the structural behaviour of a von Koch cantilever beam is analyzed in the small deformations regime. Analytical recursive formulae for the strain energy scaling are derived, which have been found in good agreement with numerical simulations. Energy considerations suggest a peculiar scaling for the beam rigidity in order to prevent compliance divergence. The results are then extended to evaluate the stiffness matrix of a von Koch beam.

Cytotoxic activities of amentoflavone against human breast and cervical cancers are mediated by increasing of PTEN expression levels due to peroxisomes proliferate-activated receptor {gamma} activation

Energy Technology Data Exchange (ETDEWEB)

Lee, Eunjung; Shin, Soyoung; Lee, Jeeyoung; Lee, So Jung; Kim, Jinkyoung; Yoon, Doyoung; Kim, Yangmee [Konkuk Univ., Seoul (Korea, Republic of); Woo, Eunrhan [Chosun Univ., Gwangju (Korea, Republic of)

2012-07-15

Human peroxisomes proliferate-activated receptor gamma (hPPAR{gamma}) has been implicated in numerous pathologies, including obesity, diabetes, and cancer. Previously, we verified that amentoflavone is an activator of hPPAR{gamma} and probed the molecular basis of its action. In this study, we investigated the mechanism of action of amentoflavone in cancer cells and demonstrated that amentoflavone showed strong cytotoxicity against MCF-7 and HeLa cancer cell lines. We showed that hPPAR{gamma} expression in MCF-7 and HeLa cells is specifically stimulated by amentoflavone, and suggested that amentoflavone-induced cytotoxic activities are mediated by activation of hPPAR{gamma} in these two cancer cell lines. Moreover, amentoflavone increased PTEN levels in these two cancer cell lines, indicating that the cytotoxic activities of amentoflavone are mediated by increasing of PTEN expression levels due to hPPAR{gamma} activation.

Biphasic Estradiol-induced AKT Phosphorylation Is Modulated by PTEN via MAP Kinase in HepG2 Cells

Science.gov (United States)

Marino, Maria; Acconcia, Filippo; Trentalance, Anna

2003-01-01

We reported previously in HepG2 cells that estradiol induces cell cycle progression throughout the G1–S transition by the parallel stimulation of both PKC-α and ERK signaling molecules. The analysis of the cyclin D1 gene expression showed that only the MAP kinase pathway was involved. Here, the presence of rapid/nongenomic, estradiol-regulated, PI3K/AKT signal transduction pathway, its modulation by the levels of the tumor suppressor PTEN, its cross-talk with the ERK pathway, and its involvement in DNA synthesis and cyclin D1 gene promoter activity have all been studied in HepG2 cells. 17β-Estradiol induced the rapid and biphasic phosphorylation of AKT. These phosphorylations were independent of each other, being the first wave of activation independent of the estrogen receptor (ER), whereas the second was dependent on ER. Both activations were dependent on PI3K activity; furthermore, the ERK pathway modulated AKT phosphorylation by acting on the PTEN levels. The results showed that the PI3K pathway, as well as ER, were strongly involved in both G1–S progression and cyclin D1 promoter activity by acting on its proximal region (-254 base pairs). These data indicate that in HepG2 cells, different rapid/nongenomic estradiol-induced signal transduction pathways modulate the multiple steps of G1–S phase transition. PMID:12808053

Zur Makrostruktur von Finanzmärkten: Börsen als Finanzintermediäre im Wettbewerb

OpenAIRE

Oehler, Andreas

2003-01-01

Die Analyse der so genannten Mikrostruktur von Finanzmärkten und ihr Einfluss auf das Marktergebnis haben in den letzten Jahren im Fokus der Finanzmarktforschung gestanden. Hinsichtlich der Entwicklung, Gestaltung und Regulierung von Finanzsystemen ist jedoch eine Erweiterung des Blickfeldes gewissermaßen in der Gegenrichtung ebenfalls zu forcieren, also die theoretische wie empirische Analyse der Makrostruktur von Finanzmärkten, die insbesondere Wettbewerb und Fragmentierung von Finanzmärkte...

CD31-Expression am Primärtumor und Nachweis hämatogen disseminierter Tumorzellen im Knochenmark von Brustkrebspatientinnen

OpenAIRE

Eisenmann, Petra

2005-01-01

Der Nachweis von disseminierten Tumorzellen im Knochenmark von Patientinnen mit primärem Mammakarzinom ist ein wichtiger prognostischer Parameter. In der vorliegenden Arbeit wurde der Nachweis von CD31 am Primärtumor Mammakarzinom mit dem Auftreten von Mikrometastasen im Knochenmark korreliert. Ferner wurde die prognostische Bedeutung von disseminierten Tumorzellen im Knochenmark und die prognostische Bedeutung von CD31 evaluiert. Bei 50 Patientinnen des Gesamtkollektivs von 195 (25,6%) wu...

Strukturbasierte Entwicklung von Assaysystemen und Charakterisierung von orthosterischen und allosterischen Kinaseinhibitoren

OpenAIRE

Klüter, Sabine

2010-01-01

Die Proteinkinasen stellen eine wichtige Enzymklasse für die Regulation der Signaltransduktion dar. Sie steuern diese diffizil regulierten, intrazellulären Signalkaskaden durch Übertragung der ?-Phosphatgruppe von ATP auf andere Proteine. Fehlregulationen dieser komplexen Stoffwechselwege können Krankheiten wie Krebs, Diabetes oder Autoimunkrankheiten verursachen. Somit gehören die Kinasen in den letzten Jahren zu den wichtigsten Zielproteinen der Pharmaindustrie. Die klassi...

Die räumliche Dimension von Herrschaftsverhältnissen

Directory of Open Access Journals (Sweden)

Ruben Marc Hackler

2006-11-01

Full Text Available Sara Mills stellt in klarer Sprache ein Konzept vor, sexistische, rassistische und klassenbezogene Herrschaftspraxen in den Kolonien des British Empire hinsichtlich ihrer räumlichen Dimension zu analysieren. Ihr Ansatz soll möglichst viele Formen von Herrschaft integrieren, offen bleibt aber die Frage, ob dabei das von ihr verwendete Habituskonzept Bourdieus die passende Erklärung hierzu liefert.

Von Neumann algebras as complemented subspaces of B(H)

DEFF Research Database (Denmark)

Christensen, Erik; Wang, Liguang

2014-01-01

Let M be a von Neumann algebra of type II1 which is also a complemented subspace of B( H). We establish an algebraic criterion, which ensures that M is an injective von Neumann algebra. As a corollary we show that if M is a complemented factor of type II1 on a Hilbert space H, then M is injective...

DAF-18/PTEN signals through AAK-1/AMPK to inhibit MPK-1/MAPK in feedback control of germline stem cell proliferation.

Directory of Open Access Journals (Sweden)

Patrick Narbonne

2017-04-01

Full Text Available Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems. Stem cell proliferation rates can further be locally refined to meet the resident tissue's need for differentiated progeny. We have recently shown that the accumulation of mature oocytes in the C. elegans germ line, through DAF-18/PTEN, inhibits adult germline stem cell (GSC proliferation, despite high systemic IIS activation. We show here that this feedback occurs through a novel cryptic signalling pathway that requires PAR-4/LKB1, AAK-1/AMPK and PAR-5/14-3-3 to inhibit the activity of MPK-1/MAPK, antagonize IIS, and inhibit both GSC proliferation and the production of additional oocytes. Interestingly, our results imply that DAF-18/PTEN, through PAR-4/LKB1, can activate AAK-1/AMPK in the absence of apparent energy stress. As all components are conserved, similar signalling cascades may regulate stem cell activities in other organisms and be widely implicated in cancer.

Polychaeten aus den Zoologischen Museen von Leiden und Amsterdam I

NARCIS (Netherlands)

Augener, H.

1933-01-01

In der vorliegenden Arbeit ist die Untersuchung eines sehr umfangreichen Polychaeten-Materials niedergelegt, das mir von Herrn Prof. Dr. E. D. van Oort in Leiden und Herrn Prof. Dr. L. F. de Beaufort in Amsterdam zur Bearbeitung übergeben wurde. Von diesem Material ist der dem Museum in Leiden

Physikalische Grundlagen von chemischen Raman-Sensoren mit Schwerpunkt auf faseroptischen SERS-Sonden

OpenAIRE

Viets, Carmen

2001-01-01

Faseroptische SERS-Sensoren wurden durch die Beschichtung der Endflächen von optischen Fasern mit rauhen Metallfilmen erzeugt. Zu den verschiedenen Präparationstechniken, die angewendet und verglichen wurden, gehörten das langsame Aufdampfen von Metall-Inselfilmen und das Bedampfen von Nanopartikeln, aufgerauhten oder elektronenlithographisch strukturierten Oberflächen mit Metallfilmen. Der Einfluß der Laserleistung auf die Messungen mit SERS-Sensoren wurde untersucht, und es wurden maximale ...

Philologie im Horizont der Geschichtlichkeit von Sprache und Text: zum Tagungsband von Wulf Oesterreicher und Maria Selig

Directory of Open Access Journals (Sweden)

Olaf Müller

2016-03-01

Full Text Available Wulf Oesterreicher und Maria Selig, Hrsg., Geschichtlichkeit von Sprache und Text: Philologien – Disziplingenese – Wissenschaftshistoriographie (Paderborn: Wilhelm Fink, 2014, 332 S.

Alternative Regulierungsansätze im Kontext der Better Regulation Agenda : eine Analyse von Konzepten, Potenzialen und Erfolgsfaktoren von Regulierung im Schatten staatlicher Hierarchie

OpenAIRE

Denker, Philipp

2008-01-01

Der vorliegende Beitrag untersucht das Potential und die Bedingungen alternativer Regulierungsformen vor dem Hintergrund von Better Regulation in Deutschland. Nahezu alle EU- und OECD-Staaten betreiben heute umfassende politische Reformprogramme zur Modernisierung der Regulierungsarchitekturen, die unter dem Label Better Regulation subsumiert werden. Die Zielsetzung dieser Programme besteht zum einen in der wirtschaftsfreundlichen Reduktion von Regulierungskosten und zum anderen in der Effekt...

[Peter von Brackel. Christlich Gesprech von der grawsamen Zerstörung in Lifland durch den Muscowiter vom 58. Jar her geschehenn...] / Stefan Donecker

Index Scriptorium Estoniae

Donecker, Stefan, 1977-

2015-01-01

Arvustus: Christlich Gesprech von der grawsamen Zerstörung in Lifland durch den Muscowiter vom 58. Jar her geschehenn: auch ihren Ursachen mit einer kurtzen Predig und Vermanung, wie beid, Gotlosenn unnd Frommen, diese schreckliche Mutation fruchtbarlich behertzigen und ihnen zu Nutz machen sollen: durch Timannum Brakel Livoniensem, der Gemeine Christi vonn der Augsburgischen Confession Prediger zu Anttorf einfeltig gestellet unnd inn Druck verfertiget = Darstellung der Geschichte Livlands vor und während des "Livländischen Krieges" bis 1578 in gereimter Dialogform und Prosa von dem Prediger und Geschichtsschreiber Timann Brakel : Originaltext und Übersetzung ins Hochdeutsche mit Kommentaren, Ergänzungen, Bildern und dem Lebenslauf des Timann Brakel. (Beiträge zur baltischen Geschichte, 19). Verlag Harro von Hirschheydt. Wedemark 2012

Properties of von Neumann entropy

Indian Academy of Sciences (India)

disentangled) as seen by moving observers, is used to investigate the properties of von Neumann entropy, as a measure of spin–momentum entanglement. To do so, we partition the total Hilbert space into momentum and spin subspaces so that the ...

Herstellung von Convenience-Erzeugnissen aus Süß- und Salzwasserfischen

OpenAIRE

Strebl-Schneider, Scarlett

2010-01-01

Die vorhandenen Kapazitäten der nationalen Teichwirtschaft werden aufgrund der begrenzten Absatzmöglichkeiten des einheimischen Speisekarpfens nicht ausgeschöpft. Im Hinblick auf die Überfischung zahlreicher Salzwasserfischbestände und die zunehmende Tendenz zu einer nachhaltigen Fischerei, entstand seitens eines Fisch verarbeitenden Unternehmens die Intention, die nationalen Ressourcen durch die Entwicklung von neuartigen Convenience-Erzeugnissen auf der Basis von Karpfen effizienter zu nutz...

DEEP VEIN THROMBOSIS IN PATIENT WITH VON WILLEBRAND DISEASE

Directory of Open Access Journals (Sweden)

V. A. Elykomov

2016-01-01

Full Text Available Objective: to identify the possible factors of thrombogenic risk and ways of its prevention in patients with von Willebrand disease.Case description. Patient X., 42 years old, who suffers from von Willebrand disease type 3 with 5-years of age. Asked on reception to the traumatologist in the polyclinic of the Regional Hospital with pain in the left hip joint. Recommended planned operative treatment in the Altai Regional Clinical Hospital. Preoperative preparation included the infusion of concentrate of von Willebrand factor and coagulation factor VIII. Operation – cement total arthroplasty of the left hip joint. In the postoperative period analgesic treatment, elastic compression of the lower extremities, iron supplements, also conducted infusion of concentrate of von Willebrand factor and coagulation factor VIII for 20 days and thromboprophylactic with dabigatran. On the 3rd day after the operation the patient revealed deep vein thrombosis of the femoral segment (floating clot.Results. The patient was operated for emergency indications in the Department of endovascular surgery – installation of venous cava filter “Volan”. Dabigatran is cancelled, appointed clexane for 3 months. In our clinical example the patient lacked risk factors of pulmonary embolism as obesity, age, smoking, prolonged immobilization, estrogen therapy. Overdose of factor VIII were not observed – the level of factor did not exceed 135 % on transfusions. At the same time, the patient was found polymorphisms in the genes ITGA2, FGB, MTHFR, MTR – heterozygote, MTRR – mutant homozygote, which may indicate the genetic factors of thrombogenic risk. Also a significant risk factor was massive surgical intervention (total hip replacement. Despite preventive measures (elastic compression, thromboprophylactic dabigatran, early activation we cannot to avoid thrombotic complications.Conclusion. This article presents a case demonstrating a thrombotic complication in patients

Analyse kognitiver Benutzermodelle für die Evaluation von Mensch-Maschine-Systemen

OpenAIRE

Dzaack, Jeronimo

2008-01-01

Die Entwicklung und Gestaltung von Schnittstellen für Mensch-Maschine-Systeme erfordern, neben der Kenntnis der Aufgabe und der Arbeitsumgebung, auch eine Vorstellung über die kognitiven Anforderungen an zukünftige Benutzer. Ein Grund dafür liegt in der zunehmenden Informationsdichte und dem ansteigenden Automatisierungsgrad von technischen Systemen. Daraus ergibt sich die Frage, welche Art von Schnittstelle die kognitiven Prozesse bei der Interaktion am besten unterstützt und wie diese prosp...

Kodierung von Metadaten digitaler Briefeditionen in TEI-XML

OpenAIRE

Dumont, Stefan

2017-01-01

Folien zu einem Vortrag im Rahmen des Digital-Humanities-Kolloquium an der BBAW am 7.7.2017. Der Vortrag erläutert, ausgehend von editionswissenschaftlichen Entwicklungen der 1980er und 1990er Jahre, wie die "Kopfdaten" eines Briefes nach den Richtlinien der Text Encoding Initiative (TEI) kodiert werden können. Insbesondere wird auf das TEI-Element correspDesc eingegangen und die Kodierung anhand eines Beispiels veranschaulicht. Darüber hinaus wird der Mehrwert von Briefmetadaten sowohl für d...

Biologischer Anbau von Strauchbeeren

OpenAIRE

Schmid, Andi

2004-01-01

Das Merkblatt enthält auf Österreich angepasste, praxisnahe Informationen zur Produktion von hochwertigen Strauchbeeren wie Himbeeren, Brombeeren, Johannisbeeren, Stachelbeeren und Heidelbeeren. Weiterhin: übersichtliche Hinweise zur Planung, Standortwahl, Sortenauswahl, Bodenvorbereitung und Pflanzung, Bewässerung, Nährstoffversorgung, Witterungsschutz, Beikrautregulierung, Ernte und Lagerung. (Diese Publikation enthält spezifische Informationen für Österreich)

Interpretation of ultrasonic images; Interpretation von Ultraschall-Abbildungen

Energy Technology Data Exchange (ETDEWEB)

Mueller, W; Schmitz, V; Kroening, M [Fraunhofer-Institut fuer Zerstoerungsfreie Pruefverfahren, Saarbruecken (Germany)

1998-11-01

During the evaluation of ultrasonic images, e.g. SAFT-reconstructed B-scan images (SAFT=Synthetic Aperture Focusing Technique) it is often difficult to decide, what is the origin of reconstructed image points: were they caused by defects, specimens geometry or mode-conversions. To facilitate this evaluation a tool based on the comparison of data was developed. Different kinds of data comparison are possible: identification of that RF-signals, which caused the reconstructed image point. This is the comparison of a reconstructed image with the corresponding RF-data. Comparison of two reconstructed images performing a superposition using logical operators. In this case e.g. the reconstruction of an unknown reflector is compared with that of a known one. Comparison of raw-RF-data by simultaneous scanning through two data sets. Here the echoes of an unknown reflector are compared with the echoes of a known one. The necessary datasets of known reflectors may be generated experimentally on reference reflectors or modelled. The aim is the identification of the reflector type, e.g. cracklike or not, the determination of position, size and orientation as well as the identification of accompanying satellite echoes. The interpretation of the SAFT-reconstructed B-scan image is carried out by a complete description of the reflector. In addition to the aim of interpretation the tool described is well suited to educate and train ultrasonic testers. (orig./MM) [Deutsch] Bei der Auswertung von Ultraschall-Abbildungen, z.B. SAFT-rekonstruierten B-Bildern (SAFT=Synthetische Apertur Fokus Technik), ist es oft schwierig zu entscheiden, wo rekonstruierte Bildpunkte herruehren: wurden sie durch Materialfehler, Bauteilgeometrie oder durch Wellenumwandlungen versursacht. Um diese Auswertung zu erleichtern, wurde ein Werkzeug entwickelt, welches auf dem Vergleich von Datensaetzen basiert. Es koennen verschiedene Arten des Datenvergleichs durchgefuehrt werden: Identifikation der HF

Molekulare Charakterisierung von Glykosyltransferasen in Vitis vinifera

OpenAIRE

Frotscher, Johanna

2014-01-01

Terpenoide spielen eine wichtige Rolle für das Aroma von Weinbeeren (Vitis vinifera). Glykosyltransferasen katalysieren die Übertragung von Zuckerresten auf Terpenoide, was diese geruchlos werden lässt. Um die verantwortlichen Enzyme zu identifizieren wurde deren Genfamilie in silico untersucht, 15 Kandidatengene ausgewählt, deren Transkription analysiert und die Ergebnisse mit Terpenoidprofilen verglichen. Dadurch konnten fünf Gene ausgewählt werden, deren offener Leserahmen sequenziert wurd...

Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.

Science.gov (United States)

Liu, Tiantian; Chen, Xiaoxu; Li, Tianjiao; Li, Xueliang; Lyu, Yinghua; Fan, Xiaoteng; Zhang, Pengfei; Zeng, Wenxian

2017-10-01

Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

A study of the effect of ethamsylate (Dicynene) on the bleeding time, von Willebrand factor level and fibrinolysis in patients with von Willebrand's disease.

Science.gov (United States)

Hutton, R A; Hales, M; Kernoff, P B

1988-12-22

Nine patients with clinically moderate or severe Type I von Willebrand's disease were treated for 2 weeks with ethamsylate (2 g/day in four equal doses) and with a matched placebo in a randomised double-blind trial. Template bleeding time, von Willebrand factor activity (ristocetin co-factor) and antigen, euglobulin lysis time and type I tissue plasminogen activator inhibitor were determined before and at the end of each treatment period. None of these parameters showed any significant change attributable to ethamsylate. Thus, despite the fact that five patients thought subjectively that their bleeding symptoms improved during ethamsylate treatment compared to only one while on placebo, we obtained no evidence that the drug was of benefit to patients with von Willebrand's disease.

Die Bedeutung von Musiker- und Komponistenbriefe für die regionale und europäische Kulturgeschichte

Directory of Open Access Journals (Sweden)

Buschmeier Gabriele

2002-01-01

Full Text Available (nemački Die Entwicklung der Musikkultur insbesondere in Mittel- und Osteuropa ist von einem äußerst regen Austausch und lebendigen Beziehungen gekennzeichnet. Die Dokumente dieser Beziehungen sind zum Teil die erhaltene Briefe. Für den Musikwissenschaftler sind dabei alle Arten von Briefen sowohl privaten als auch geschäftlichen Charakters, von Interesse und zwar nicht nur Briefe von den sogenannten "Heroen" der Musikgeschichte, sondern insbesondere auch von nur lokal bekannten Musikern oder Menschen, die sich mit Musik beschäftigen.

[Hans Jakob Christoffel von Grimmelshausen. Saksa Simplicissimuse seiklused] / Meelis Friedenthal

Index Scriptorium Estoniae

Friedenthal, Meelis, 1973-

2011-01-01

Tutvustus: Grimmelshausen, Hans Jakob Christoffel von. Saksa Simplicissimuse seiklused, teisisõnu: ühe veidra vagabundi elulugu, kel Melchior Sternfels von Fuchshaim nimeks, et kus ja mis moel ta siia ilma sündis ning mida siin nägi, õppis, oma nahal tunda sai ja kannatas, nagu sellestki, miks ta siinsest ilmast vabatahtlikult loobub. [Tallinn] : Pegasus, c2010

Von Krahli teater kolib mõneks ajaks Saksamaale / Rain Tolk

Index Scriptorium Estoniae

Tolk, Rain, 1977-

2006-01-01

Von Krahli Teatri selle hooaja eelviimane esietendus "Europiraadid" on 17. mail Düsseldorfis, koostöös Saksamaa teatrirühmaga Showcase Beat Le Mot. Eesti poole pealt teevad kaasa Juhan Ulfsak, Taavi Eelmaa, Maarja Jakobson ja üllatusmängijana filmimees Rain Tolk, kes räägib oma suhtumisest teatrisse ja suhetest Von Krahli Teatriga

VON WISPR Family Processors: Volume 1

National Research Council Canada - National Science Library

Wagstaff, Ronald

1997-01-01

...) and the background noise they are embedded in. Processors utilizing those fluctuations such as the von WISPR Family Processors discussed herein, are methods or algorithms that preferentially attenuate the fluctuating signals and noise...

Acquired von Willebrand syndrome: A rare disorder of heterogeneous etiology

Directory of Open Access Journals (Sweden)

P Kasatkar

2013-01-01

Full Text Available Context: Acquired von Willebrand syndrome (AVWS is a rare bleeding disorder that mimics the inherited form of von Willebrand disease (VWD in terms of laboratory findings and clinical presentation. Aims: To study the etiology of acquired VWD. Settings and Design: The patients referred from various hospitals in and out of Mumbai were included in the study. Materials and Methods: Six patients with AVWS diagnosed at this center over the last 10 years were analyzed against 171 patients with inherited VWD. The differential diagnosis of AVWS was made based on reduced levels of von Willebrand antigen and von Willebrand ristocetin cofactor, decrease in ristocetin induced platelet aggregation, absence of correction in mixing studies with no prior history of bleeding problems and a negative family history for bleeding disorders. Results: In three patients, the disease was associated with systematic lupus erythematosus, out of which one was also associated with Kikuchi lymphadenitis and second with autoimmune hemolytic anemia. Fourth case was associated with hypothyroidism and fifth was a case of dermatitis and vitiligo. The last patient was a case of hemophilia A with Burkitts lymphoma, who developed autoantibodies to von Willebrand factor. Except two patients, all other patients responded to immune suppressive therapy with corticosteroids, while the patient with hypothyroidism responded to oral thyroxine. Conclusion: AVWS is a rare condition and may often be missed or diagnosed as inherited disease associated with heterogeneous disease conditions.

Kostenorientiertes Controlling von E-Learning-Plattformen mit dem TCO-Konzept - Methodische Grundlagen, Softwareunterstützung und Entwicklungsperspektiven

Directory of Open Access Journals (Sweden)

Jan vom Brocke

2007-07-01

Full Text Available Zur administrativen Unterstützung von Lehr- und Lernprozessen werden E-Learning-Plattformen eingesetzt, die auf der Grundlage des Internet Funktionen zur Distribution von Lehr- und Lernmaterialien und zur Kommunikation zwischen Lehrenden und Lernenden anbieten. Zahlreiche wissenschaftliche Beiträge und Marktstudien beschäftigen sich mit der multikriteriellen Evaluation dieser Softwareprodukte zur informatorischen Fundierung strategischer Investitionsentscheidungen. Demgegenüber werden Instrumente zum kostenorientierten Controlling von E-Learning-Plattformen allenfalls marginal thematisiert. Dieser Beitrag greift daher das Konzept der Total Cost of Ownership (TCO auf, das einen methodischen Ansatzpunkt zur Schaffung von Kostentransparenz von E-Learning-Plattformen bildet. Aufbauend auf den konzeptionellen Grundlagen werden Problembereiche und Anwendungspotenziale für das kostenorientierte Controlling von LMS identifiziert. Zur softwaregestützten Konstruktion und Analyse von TCO-Modellen wird das Open Source-Werkzeug TCO-Tool eingeführt und seine Anwendung anhand eines synthetischen Fallbeispiels erörtert. Abschließend erfolgt die Identifikation weiterführender Entwicklungsperspektiven des TCO-Konzepts im Kontext des E-Learning. Die dargestellte Thematik ist nicht nur von theoretischem Interesse, sondern adressiert auch den steigenden Bedarf von Akteuren aus der Bildungspraxis nach Instrumenten zur informatorischen Fundierung von Investitions- und Desinvestitionsentscheidungen im Umfeld des E-Learning.

Rezension von: Karen Ellwanger, Heidi Helmhold, Traute Helmers, Barbara Schrödl (Hg.: Das ‚letzte Hemd‘. Zur Konstruktion von Tod und Geschlecht in der materiellen und visuellen Kultur. Bielefeld: transcript Verlag 2010.

Directory of Open Access Journals (Sweden)

Ulrike Vedder

2010-10-01

Full Text Available Die Einkleidung und Zur-Schau-Stellung von Leichnamen prägt seit jeher den religiösen, kulturellen, sozialen und individuellen Umgang mit dem Tod. Für historische und gegenwärtige Inszenierungen von Tod und Toten ist deren vestimentäre, materielle und visuelle Codierung also von besonderer Bedeutung, wie in dem hier empfohlenen Aufsatzband eindrücklich erforscht wird. Darüber hinaus machen die Beiträge in präzisen Einzelanalysen deutlich, auf welche Weise jeder Inszenierung von toten Körpern immer auch Geschlechterkonstruktionen inhärent sind.

Die Krakauer Kirche von Karmeliten und Karmelitaninnen

Directory of Open Access Journals (Sweden)

Józef Szymon Wronski

2004-12-01

Full Text Available 1. Die Klosterkirche der unbeschuhten Karmelitinnen Zum Heiligen Josef. Ein glücklicher Auftakt und somit die charakteristische Einführung in das 20. Jh. für den Kirchenbau von Krakau war die Errichtung der Karmeliterinnen St. Josephs-Kirche an der Lobzowska-Straße 40, in der die Architekten (Tadeusz Stryjeński (1849-1943 - Projektant der Kirche und Franciszek Mączyński (1874-1947 - Ausführer des Bauprojektes mit eigenen Verbesserungen die historisch- eklektizistischen Formen d.h. die mittelalterlichen Formen vor allem des sog. Übergangsstils vereinfachten. Die Kirche, die in den Jahren 1903-1905 errichtet wurde, steht inmitten vom Baukomplex des Klosters, dessen Grundriss das Quadrat ist49. Der Kirchenbau ist ein dem Gesamtbau des Klosters eingefügter Längsraum. Hinter dem Chor liegt das Oratorium des Konvents. Das Material Backstein (mit Verwendung von Stein erinnert an die Baukunst eines der besten Architekten jener Zeit, nämlich Teodor Talowskis (1857-1910, der viele Kirchen in Südpolen, aber auch viele Bürgerhäuser nicht nur in Krakau im ausgehenden 19. Jh. baute. Die Architektur der Karmeliterinnen St. Josephs-Kirche ist immer noch im Malerischen begriffen. Aber die Vereinfachung der historischen Formen führt zu ihrer „Beruhigung” und dadurch zur Wuchtigkeit des Ausdrucks. Bemerkenswert ist die in dieser Zeit (in der Anlage noch seltene ausgewogene Proportionierung des Baukörpers. Das methodische Prinzip jener Zeit ist der Kontrast. Im Kontrast zu den gedrungenen und wuchtigen Formen des Baukörpers stehen z.B. die sich verjüngenden obeliskenförmigen und pylonenartigen Türmchen, die nicht nur die Eingangsfassade der Kirche flankieren, sondern auch an den Ecken des Querhauses der Kirche stehen. Die ingravierten weißen Steine an der Fassade in der Zahl von Zehn erinnern an das Gebot des Karmelterinnenordens: Bete täglich den Rosenkranz und sind zugleich ein Vanitativmotiv. 2. Die Klosterkirche der unbeschuhten

Ludwig Leichhardt und Alexander von Humboldt

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Aliya-Katarina Südfels

2012-10-01

Full Text Available Zusammenfassung Im Juli des Jahres 1841 kommt es zu einem Treffen zwischen zwei Männern, das zunächst belanglos erscheint, sich aber Jahre später als wichtige historische Begebenheit herausstellen wird. In seinem Pariser Büro empfängt der 71jährige Naturforscher Alexander von Humboldt den jungen Preußen Ludwig Leichhardt. Der angehende Naturwissenschaftler erhofft sich Zuspruch und Empfehlung des berühmten Alexander von Humboldts. Die Unterredung ist kurz und verläuft für Leichhardt ergebnislos. Es wird das einzige Treffen der beiden Naturwissenschaftler bleiben. Aus heutiger Sicht unverständlich, da Ludwig Leichhardt und Alexander von Humboldt mehr verband, als ihre Leidenschaft für die Naturwissenschaften. Viel zu wenig ist sich bis jetzt den biographischen Analogien und den vergleichbaren geographischen Leistungen der beiden Preußen gewidmet worden. Abstract During July 1841 a meeting between two men takes place, which seems to have been extraneous, but turns out to be a significant historical incident. 71 year old natural scientist Alexander von Humboldt welcomes young Ludwig Leichhardt from Prussia in his office in Paris. The prospective young scientist expects help and references from famous Alexander von Humboldt. The conversation is short and ends from Leichhardt’s point of view without results. Unfortunately this is going to be the only meeting between the two scientists even though the two Prussians have more in common than their passion for the natural sciences. Way too seldomly have biographical analogy and geographical productivity of the two men been compared. Résumé En juillet 1841 une rencontre entre deux hommes a lieu, qui au premier abord semble sans importance, mais qui des années plus tard est considéré comme un événement historique majeur. Dans son bureau parisien, le naturaliste Alexandre de Humboldt, alors âgé de 71 ans, reçoit le jeune Prussien Ludwig Leichhardt. Le jeune scientifique en devenir

Shock, diaschisis and von Monakow

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Eliasz Engelhardt

2013-07-01

Full Text Available The concept of shock apparently emerged in the middle of the 18th century (Whyett as an occurrence observed experimentally after spinal cord transection, and identified as "shock" phenomenon one century later (Hall. The concept was extended (Brown-Séquard and it was suggested that brain lesions caused functional rupture in regions distant from the injured one ("action à distance". The term "diaschisis" (von Monakow, proposed as a new modality of shock, had its concept broadened, underpinned by observations of patients, aiming at distinguishing between symptoms of focal brain lesions and transitory effects they produced, attributable to depression of distant parts of the brain connected to the injured area. Presently, diaschisis is related mainly to cerebrovascular lesions and classified according to the connection fibers involved, as proposed by von Monakow. Depression of metabolism and blood flow in regions anatomically separated, but related by connections with the lesion, allows observing diaschisis with neuroimaging.

Guy von Dardel 1919-2009

CERN Multimedia

2009-01-01

Guy von Dardel, a well-known figure at CERN and in the international particle physics community, passed away on 28 August. Guy von Dardel came to CERN when it was founded in 1954 and was a full-time staff member until 1964, performing several experiments and working on technical developments. These included the first measurement of the neutral pion’s life-time. Called to Lund University in 1964, he became professor there in 1965 and director of the 1.2 GeV electron accelerator. In the late 1960s, he performed an experiment at CERN’s PS that measured the decays of the Λ. Then, in the early 1970s, he involved the Lund group in a series of experiments at the Intersecting Storage Rings (ISR), where he measured the production of various types of particles. In particular, he participated in a series of experiments that observed the production of a high abundance of particles with large transverse momenta. This required an explanation...

von Neumann's hypothesis concerning coherent states

International Nuclear Information System (INIS)

Zak, J

2003-01-01

An orthonormal basis of modified coherent states is constructed. Each member of the basis is an infinite sum of coherent states on a von Neumann lattice. A single state is assigned to each unit cell of area h (Planck constant) in the phase plane. The uncertainties of the coordinate x and the square of the momentum p 2 for these states are shown to be similar to those for the usual coherent states. Expansions in the newly established set are discussed and it is shown that any function in the kq-representation can be written as a sum of two fixed kq-functions. Approximate commuting operators for x and p 2 are defined on a lattice in phase plane according to von Neumann's prescription. (leeter to the editor)

Behaviour of metals during the thermal conversion of Chinese reed; Verhalten von Metallen bei der thermischen Nutzung von Schilfgras

Energy Technology Data Exchange (ETDEWEB)

Klensch, S.; Reimert, R. [Karlsruhe Univ. (T.H.) (Germany). Engler-Bunte-Institut Bereich 1 - Gas, Erdoel und Kohle

1998-12-31

limit values shows that a returning of the fly ash on forest areas is generally possible. Due to the high content of Zn of 1100 mg/kg in the fly ash a returning to agricultural areas is not allowed. (orig.) [Deutsch] Bei den Konversionsverfahren (Vergasung und Verbrennung) zur thermischen Nutzung von Biomasse sollen die anfallenden Rueckstaende (Aschen) moeglichst als Duengemittel auf Forst- oder Agrarflaechen zurueckgefuehrt aber keinesfalls deponiert werden. Hierzu duerfen insbesondere die Schwermetallkonzentrationen in den Aschen gewisse Grenzwerte nicht ueberschreiten. Zur Untersuchung des Schwermetallverhaltens bei der Umwandlung von Biomassen werden Messungen zum Einfluss der Konversionstemperatur (1000-1300 C), der Gasatmosphaere (reduzierend, oxidierend) und der Entstaubungstemperatur (300-750 C) in einer halbtechnischen Anlage bei einem Systemdruck von 1,2 bar durchgefuehrt. Kernstuecke der Anlage sind ein Flugstromreaktor (Reaktionslaenge 2500 mm, Innendruchmesser 70 mm) und ein Kerzenfilter mit 6 Filterelementen vom Typ DIA-Schumalith 10-20 (60/40 x 1500). Der Biomassestrom betraegt 6 kg/h. Die Ergebnisse der Schilfgrasvergasung werden als Mittelwerte ueber den Temperaturbereich von 1000 bis 1160 C bei einer konstanten Filtertemperatur von 550 C in Form von Metallkonzentrationen der Elemente Si, Al, Ca, Fe, Mg, Na, K, Pb, Zn, Cr, Cu und Ni in Schilfgrasasche, Schlacke, Flugasche und Produktgas angegeben. Die Angabe von An- und Abreicherungsfaktoren fuer die verschiedenen Elemente in Flugasche und Schlacke verdeutlichen das Verhalten der Metalle waehrend des Konversionsprozesses. Die Konzentrationen der nichtfluechtigen bzw. schwerfluechtigen Elemente Si, Al, Ca, Fe, Mg und K sind in der Schilfgrasasche, in der Schlacke und in der Flugasche nahezu gleich. Die Konzentrationen der umweltrelevanten Schwermetalle Cr, Pb und Zn sind jeweils in der Schlacke zum Teil deutlich niedriger als in der Schilfgrasasche. Diese Schwermetalle reichern sich in der Flugasche an

Die grossen Physiker und ihre Entdeckungen von den fallenden Körpern zu den Quarks

CERN Document Server

Segrè, Emilio

1998-01-01

Von Galileo Galilei bis zu Richard Feynman und Murray Gell-Mann - von den fallenden Körpern zu den Quarks: Der Physiknobelpreisträger Emilio Segre hat seine ganz persönliche Geschichte der Physik geschrieben. Er erzählt von den großen Gestalten und deren wichtigen Entdeckungen mit großer Anschaulichkeit und Lebendigkeit.

Chancen und Gefahren von Global-Marketing-Konzepten

OpenAIRE

Berndt, Ulrike

1990-01-01

Chancen und Gefahren von Global-Marketing-Konzepten. - Augsburg : Förderges. Marketing, 1990. - 57, XII S. - Zugl: Augsburg, Univ., Diplomarb. - (Arbeitspapiere zur Schriftenreihe Schwerpunkt Marketing ; 29)

Fragmentierungsarten von Nierensteinen unter extrakorporaler Stoßwellenlithotripsie: eine multivariate Analyse

Directory of Open Access Journals (Sweden)

Aeberli D

1999-01-01

Full Text Available Das primäre Ziel dieser retrospektiven Studie war die Evaluation von routinemäßig anwendbaren Kriterien, welche die Fragmentierung von Nierensteinen unter extrakorporaler Stoßwellenlithotripsie (ESWL voraussagen können. Die Serie umfaßte 202 konsekutive Patienten (121 Männer, 81 Frauen mit einem medianen Alter von 48 Jahren (19-81 Jahre, die an der Urologischen Universitätsklinik Bern mit dem originalen Dornier HM-3 behandelt wurden. Einschlußkriterien waren Einzelsteine von 10-30 mm Größe mit Lage im Nierenbeckenkelchsystem. Die Steine wurden im Abdomen-Leerbild nach ihrer Lage, Größe, Form, Dichte (im Vergleich zur 12. Rippe, Struktur und Oberfläche beurteilt. Weiter wurden Alter, Geschlecht und Body-Mass-Index des Patienten berücksichtigt. Die Desintegration wurde am 1. Tag nach ESWL mittels Abdomen-Leerbild dokumentiert. Zielwert der Analyse war die binäre Variable steinfrei versus Restfragmente, gegen die alle präoperativen Parameter mittels multivariater logistischer Regression getestet wurden. Die Erfolgsrate betrug 95,5 %; 42 Patienten (20,8 % waren steinfrei und 151 Patienten (74,7 % hatten sog. klinisch insignifikante Restfragmente (5 mm oder kleiner. Von den Männern waren 14,9 %, von den Frauen 29,6 % steinfrei (p = 0,01. Alle anderen Parameter erreichten keine statistische Signifikanz, möglicherweise aufgrund zu kleiner Subgruppen (fehlende statistische Macht. Die Desintegrationsrate des HM-3 für Nierensteine ist insgesamt ausgezeichnet, bei Frauen noch besser als bei Männern. Gerade wegen dieser hohen Erfolgsrate wären größere Patientenzahlen notwendig, um eventuelle Unterschiede zwischen den präinterventionellen Parametern definieren zu können.

J-GLOBAL MeSH Dictionary: von Willebrand病 [MeCab user dictionary for science technology term[Archive

Lifescience Database Archive (English)

Full Text Available MeCab user dictionary for science technology term von Willebrand病 名詞 一般 * * * * von Willebrand...病 ... MeSH D014842 200906053707829497 C LS51 UNKNOWN_2 von Willebrand 病

Vergleich verschiedener Methoden zur Haftkraftmessung von Dentinadhäsiven

OpenAIRE

Schwertner, Katharina

2010-01-01

Zur Bestimmung der Haftkraft von Adhäsiven stehen verschiedene Methoden zur Verfügung. Ziel dieser Studie war es, vier gebräuchliche in vitro Haftkraftmessmethoden (Tensile Bond Strength Test, Shear Bond Strength Test, Microtensile Bond Strength Test, Push-out Bond Strength Test) an drei unterschiedlichen Adhäsivsystemen (Syntac, Clearfil SE Bond, Adper Scotchbond Multi Purpose) zu testen und die Ergebnisse zu vergleichen. Die Haftkräfte sind abhängig von der verwendeten Messmethode. Viele Pa...

Numerical Analysis Of Buckling Of Von Mises Planar Truss

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Kalina Martin

2015-12-01

Full Text Available A computational algorithm of a discrete model of von Mises planar steel truss is presented. The structure deformation is evaluated by seeking the minimal potential energy. The critical force invented by mathematical solution was compared with solution by computer algorithm. Symmetric and asymmetric effects of initial shape of geometric imperfection of axis of struts are used in model. The shapes of buckling of von Mises planar truss of selected vertical displacement of top joint are shown.

Die Darstellung von guten und schlechten Beziehungen in Kinderzeichnungen

OpenAIRE

Gramel, Sabine

2005-01-01

Nach welchen Kriterien sich Bilder, auf denen Kinder eine positive Beziehung darstellen, von Bildern unterscheiden, auf denen negative Beziehungen dargestellt sind, wurde an einer Stichprobe von 45 Kindern zwischen 4;6 und 11;6 Jahren untersucht. Die Kinder fertigten jeweils ein positives und ein negatives Beziehungsbild an. Es zeigte sich, dass die Kinder in beiden Beziehungskategorien zum großen Teil Gleichaltrige darstellten. Sie benannten für ihre Bilder Kriterien, anhand derer man die po...

Molecular quantum control landscapes in von Neumann time-frequency phase space

Science.gov (United States)

Ruetzel, Stefan; Stolzenberger, Christoph; Fechner, Susanne; Dimler, Frank; Brixner, Tobias; Tannor, David J.

2010-10-01

Recently we introduced the von Neumann representation as a joint time-frequency description for femtosecond laser pulses and suggested its use as a basis for pulse shaping experiments. Here we use the von Neumann basis to represent multidimensional molecular control landscapes, providing insight into the molecular dynamics. We present three kinds of time-frequency phase space scanning procedures based on the von Neumann formalism: variation of intensity, time-frequency phase space position, and/or the relative phase of single subpulses. The shaped pulses produced are characterized via Fourier-transform spectral interferometry. Quantum control is demonstrated on the laser dye IR140 elucidating a time-frequency pump-dump mechanism.

Ausbau der ganztägigen Kindertagesbetreuung kann zur Zufriedenheit von Müttern beitragen

OpenAIRE

Stahl, Juliane F.; Schober, Pia S.

2016-01-01

Eltern mit Kindern, die noch nicht zur Schule gehen, stehen bei der Vereinbarkeit von Familie und Beruf vor besonderen Herausforderungen. Um diese Eltern besser zu unterstützen, hat die Politik sowohl den Ausbau von Plätzen in der öffentlichen Kindertagesbetreuung (Kita) forciert als auch ein bedarfsorientiertes Angebot an Ganztagsplätzen gesetzlich verankert. Der vorliegende Beitrag untersucht auf Basis von Daten des Sozio-oekonomischen Panels (SOEP) und der Stichprobe 'Familien in Deutschla...

[Carl Schirren als Gelehrter im Spannungsfeld von Wissenschaft und politischer Publizistik. 13 Beiträge zum 22. Baltischen Seminar 2010 ; Carl Schirren. Vorlesungen über livländische Geschichte. Nachschrift von Johannes Lossius] / Karsten Brügge

Index Scriptorium Estoniae

Brüggemann, Karsten, 1965-

2015-01-01

Arvustus: Carl Schirren als Gelehrter im Spannungsfeld von Wissenschaft und politischer Publizistik. 13 Beiträge zum 22. Baltischen Seminar 2010 (Baltische Seminare, 20). Hrsg. von Michael Garleff. Verlag Carl-Schirren-Gesellschaft. Lüneburg 2013; Carl Schirren. Vorlesungen über livländische Geschichte. Nachschrift von Johannes Lossius (Baltische Seminare, 20-1). Hrsg. von Carl Schirren und Wilhelm Lenz. Verlag Carl-Schirren-Gesellschaft. Lüneburg 2013

Synthese und Charakterisierung von potenziellen Inhibitoren des „Macrophage infectivity potentiator“ (Mip) Proteins von Legionella pneumophila - Ein neuer Ansatz in der Legionellose-Therapie

OpenAIRE

Juli, Christina

2012-01-01

Die vorliegende Arbeit beschäftigt sich mit der Synthese und Charakterisierung potenzieller Inhibitoren des Oberflächenproteins Mip von Legionella pneumophila. Der gramnegative Mikroorganismus ist der ursächliche Erreger der Legionellose. Die Erkrankung kann in zwei verschiedenen Formen auftreten, dem Pontiac-Fieber, einer Grippe-ähnlichen Atemwegserkrankung, und der Legionärskrankheit, einer schweren Lungenentzündung mit einer Mortalitätsrate von bis zu 30 %. Natürliche und künstlich geschaf...

Ontologie-basierte Definition von Anforderungen an Validierungswerkzeuge in der Fahrzeugtechnik

OpenAIRE

El-Haji, Mohanad

2016-01-01

Die Aktivitäten Validierung und Verifizierung nehmen eine zentrale Rolle in der Produktentwicklung ein. Im Zuge von Validierungs- und Verifizierungsaktivitäten werden Versuche durchgeführt, um eine Prognose hinsichtlich des zukünftigen Verhaltens von Systemen zu erstellen. Die in dieser Arbeit entwickelte Methode leistet einen Beitrag zur Steigerung der Effizienz und Effektivität der Validierung und Verifizierung bei innovativen Fahrzeugentwicklungen.

Nanostrukturierte Thermoelektrika auf Basis von Bi1-xSbx-Legierungen

OpenAIRE

Landschreiber, Bernadette

2013-01-01

Die strukturellen und thermoelektrischen Eigenschaften verschieden synthetisierter Bi1-xSbx-Proben wurden vorgestellt und diskutiert. Dabei wurden neben coreduzierten und kugelgemahlenen Bi1-xSbx-Nanolegierungen auch Einschlussverbindungen von Antimon-Partikeln in einer Bismut-Matrix untersucht. Die strukturellen und thermoelektrischen Eigenschaften coreduzierter und kugelgemahlener wurden in Abhängigkeit von der Zusammensetzung und den Pressbedingungen untersucht. Zudem wurden für die coredu...

Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss

Science.gov (United States)

Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen; Zhao, Jean J; Roberts, Thomas M

2016-01-01

We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110α and p110β. We found that p110β localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110β to rafts alleviated the requirement for p110β-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110α, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110α allowed its EGFR-mediated activation by GPCRs. Notably, p110β dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110β. DOI: http://dx.doi.org/10.7554/eLife.17635.001 PMID:27700986

[Precocious puberty and von Recklinghausen's disease].

Science.gov (United States)

Barg, Ewa; Wikiera, Beata; Basiak, Aleksander; Głab, Ewa

2006-01-01

Von Recklinghausen's disease belongs to a group of neurocutaneous syndromes and is characterised by skin, nerve and bone abnormalities. We present a case of von Recklinghausen's disease and precocious puberty in 7-year-old boy. At the age of three café au lait spots on the skin and an incranial tumour situated near the optic chiasm--qualified as inoperable--were discovered. At the age of 7 first signs of precocious puberty appeared (pubic hair P3 and enlargement of the testes (15 ml) and penis). Laboratory measurements included: LH 7.5 mIU/ml, FSH 1.1 mIU/ml, testosterone 183 ng/ml, assessment of bone age: 9 years. The response to LHRH stimulation was characteristic for true precocious puberty (LH 15.9 mIU/ml and FSH 1.5 mIU/ml after 30 minutes). The MRI of the brain showed a tumour of the suprasellar region with compression of pituitary stalk. True precocious puberty was diagnosed. Treatment with Diphereline was introduced. At present the boy is 9 years old and has been treated with Diphereline for 16 months. The volume of the testicles has decreased to 7 ml and loss of pubic hair was noted. The MRI does not show any progression in tumour growth. The authors would like to underline the need of close observation of children with von Reclinghausen disease with regard to possibility of uncovering true precocious puberty which is critical for rapid diagnosis and introduction of correct treatment.

Johann Friedrich Wilhelm Adolf von Baeyer

Indian Academy of Sciences (India)

Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 6. Johann Friedrich Wilhelm Adolf von Baeyer: A Pioneer of Synthetic Organic Chemistry. Gopalpur Nagendrappa. General Article Volume 19 Issue 6 June 2014 pp 489-522 ...

β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.

Directory of Open Access Journals (Sweden)

Jeffrey C Francis

Full Text Available Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

Monoklonale Antikörper zum Nachweis von 2,4,6-Trichloranisol in Kork

OpenAIRE

Lausterer, Ralph

2005-01-01

Die Verbindung 2,4,6-Trichloranisol (TCA) kann in Kork und Wein vorkommen. TCA entsteht durch mikrobielle Umsetzung von Chlorphenolen. In den betroffenen Industrien führt TCA zu jährlichen Verlusten von mehr als einer Milliarde €. Zur Bestimmung von TCA sollten enzymkoppelte Immunabsorptionstest (ELISAs) mit monoklonalen Antikörpern (mAk) entwickelt werden. Es wurden drei TCA-spezifische mAk-produzierende Zelllinien gewonnen. Mit diesen mAk wurden hochsensitive ELISAs hergstellt, die eine Nac...

Molekulargenetische Studie zur Verbreitung und Interaktion von PCV-2 bei Haus- und Wildschweinen

OpenAIRE

Bronnert, Bastian Balthasar Marcel

2014-01-01

Im Rahmen der vorliegenden Arbeit wurden Wild- und Hausschweingewebeproben aus den Jahren 2005 bis 2008 mittels nested PCR auf das Vorkommen von PCV-2 untersucht und die positiv getesteten Proben mittels Realtime PCR quantifiziert. Zusätzlich wurden die Proben im Institut für Pathologie der Justus-Liebig-Universität histologisch und immunhistologisch untersucht (Dissertation Hohloch). Ziel war es das Vorkommen von PCV-2 und die Häufigkeit von PCV-2 assoziierter Erkankungen bei Haus- und Wilds...

Von Systemkritik zur Anpassung : Wie ein Buch in der Übersetzung die Farbe wechselt / Marianne Vogel

Index Scriptorium Estoniae

Vogel, Marianne

2002-01-01

Arvustus: Vetemaa, Enn. Die Nixen von Estland : ein Bestimmungsbuch / frei nach E. Vetemaa ; bearbeitet und illustriert von Kat Menschik ; nach dem russischen Übersetzungsmanuskript ins Deutsche übertragen von Günter Jäniche. Frankfurt/M : Eichborn Verlag, 2002.

The smooth entropy formalism for von Neumann algebras

International Nuclear Information System (INIS)

Berta, Mario; Furrer, Fabian; Scholz, Volkher B.

2016-01-01

We discuss information-theoretic concepts on infinite-dimensional quantum systems. In particular, we lift the smooth entropy formalism as introduced by Renner and collaborators for finite-dimensional systems to von Neumann algebras. For the smooth conditional min- and max-entropy, we recover similar characterizing properties and information-theoretic operational interpretations as in the finite-dimensional case. We generalize the entropic uncertainty relation with quantum side information of Tomamichel and Renner and discuss applications to quantum cryptography. In particular, we prove the possibility to perform privacy amplification and classical data compression with quantum side information modeled by a von Neumann algebra

Dr. Space the life of Wernher von Braun

CERN Document Server

Ward, Bob

2013-01-01

Written by veteran aerospace journalist Bob Ward, who spent years investigating his subject, this biography presents a revealing but even-handed portrait of the father of modern rocketry. As he chronicles Wernher von Braun's life, Ward explodes many myths and misconceptions about the controversial genius who was a hero to some, a villain to others. The picture of von Braun that emerges is of a brilliant scientist with limitless curiosity and a drive to achieve his goals at almost any price from, developing the world's first ballistic missile used against the Allies in World War II to help

The smooth entropy formalism for von Neumann algebras

Energy Technology Data Exchange (ETDEWEB)

Berta, Mario, E-mail: berta@caltech.edu [Institute for Quantum Information and Matter, California Institute of Technology, Pasadena, California 91125 (United States); Furrer, Fabian, E-mail: furrer@eve.phys.s.u-tokyo.ac.jp [Department of Physics, Graduate School of Science, University of Tokyo, Tokyo, Japan and Institute for Theoretical Physics, Leibniz University Hanover, Hanover (Germany); Scholz, Volkher B., E-mail: scholz@phys.ethz.ch [Institute for Theoretical Physics, ETH Zurich, Zurich (Switzerland)

2016-01-15

We discuss information-theoretic concepts on infinite-dimensional quantum systems. In particular, we lift the smooth entropy formalism as introduced by Renner and collaborators for finite-dimensional systems to von Neumann algebras. For the smooth conditional min- and max-entropy, we recover similar characterizing properties and information-theoretic operational interpretations as in the finite-dimensional case. We generalize the entropic uncertainty relation with quantum side information of Tomamichel and Renner and discuss applications to quantum cryptography. In particular, we prove the possibility to perform privacy amplification and classical data compression with quantum side information modeled by a von Neumann algebra.

Prophylaxis escalation in severe von Willebrand disease: A prospective study from the von Willebrand Disease Prophylaxis Network

NARCIS (Netherlands)

T.C. Abshire (Thomas Calvin); J. Cox-Gill; C.L. Kempton; F.W.G. Leebeek (Frank); M. Carcao (M.); P. Kouides (P.); S. Donfield (S.); E. Berntorp

2015-01-01

textabstractBackground: Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may

Experiences with the use of conservative tracers as an aid in transferring lysimeter results to the open field; Erfahrungen beim Einsatz von konservativen Tracern als Hilfsmittel zur Uebertragung von Lysimeterergebnissen auf Freilandflaechen

Energy Technology Data Exchange (ETDEWEB)

Seeger, J.; Meissner, R.; Rupp, H. [UFZ - Umweltforschungszentrum Leipzig-Halle GmbH, Falkenberg (Germany). Lysimeterstation; Mueller, L.; Eulenstein, F. [Zentrum fuer Agrarlandschafts- und Landnutzungsforschung e.V. (ZALF), Muencheberg (Germany)

1999-02-01

Four lysimeter trials performed on an IS-type soil yielded an almost constant range of displacement of a tracer front (NO{sub 3} front) of 4.0 to 4.5 mm / l of seepage water (referred to a surface area of 1 m-2 and a depth of 1 m). This was experimental confirmation of a tentatively formulated simplified relationship between seepage water volume, vertical tracer displacement, and field capacity. The results were also in very good agreement with those of a control study in the open field carried out under similar hydrological, pedological, and agrotechnical conditions using lysimeters and Cl tracers for determining quantities of seepage water formation. As the present lysimeter trials mirror soil hydrological processes in the open field with sufficient accuracy, they appear well suited to take the place of the so often lacking territorial data as a means of validating mathematical models describing seepage-water-bound material export. [Deutsch] Auf der Basis von 4 Lysimeterversuchen konnte fuer die Bodenart IS ein nahezu konstanter Wertebereich fuer die Verlagerung einer Tracerfront (NO{sub 3}-Front) in Hoehe von 4,0 bis 4,5 mm/l Sickerwasser (bezogen auf eine Oberflaeche von 1 m{sup 2} und eine Tiefe von 1 m) ermittelt werden. Damit konnte die vereinfachte Beziehung zwischen Sickerwassermenge, Tracerverlagerungstiefe und Feldkapazitaet experimentell bestaetigt werden. Ein Vergleich zur Bestimmung der Sickerwassermengenbildung mit Hilfe von Lysimetern und durch Einsatz von Cl-Tracern unter aehnlich hydrologischen, pedologischen und agrotechnischen Bedingungen im Freiland wies eine hohe Uebereinstimmung auf. Da die hier durchgefuehrten Lysimeteruntersuchungen bodenhydrologische Prozesse von Freilandflaechen mit ausreichender Genauigkeit widerspieglen, erscheinen sie anstelle oft fehlender Gebietskenndaten zur Validierung von mathematischen Modellen zur Beschreibung sickerwassergebundener Stoffaustraege gut geeignet. (orig.)

Von Bertalanffy's dynamics under a polynomial correction: Allee effect and big bang bifurcation

Science.gov (United States)

Leonel Rocha, J.; Taha, A. K.; Fournier-Prunaret, D.

2016-02-01

In this work we consider new one-dimensional populational discrete dynamical systems in which the growth of the population is described by a family of von Bertalanffy's functions, as a dynamical approach to von Bertalanffy's growth equation. The purpose of introducing Allee effect in those models is satisfied under a correction factor of polynomial type. We study classes of von Bertalanffy's functions with different types of Allee effect: strong and weak Allee's functions. Dependent on the variation of four parameters, von Bertalanffy's functions also includes another class of important functions: functions with no Allee effect. The complex bifurcation structures of these von Bertalanffy's functions is investigated in detail. We verified that this family of functions has particular bifurcation structures: the big bang bifurcation of the so-called “box-within-a-box” type. The big bang bifurcation is associated to the asymptotic weight or carrying capacity. This work is a contribution to the study of the big bang bifurcation analysis for continuous maps and their relationship with explosion birth and extinction phenomena.

Prospektive, monozentrische, einarmige, randomisierte, kontrollierte Studie über fraktionierte CO₂-Lasertherapie von freien Hauttransplantaten

OpenAIRE

Schönberger, Carmen

2017-01-01

Hintergrund: Nach einer Hauttransplantation ist häufig das ästhetische Ergebnis aufgrund von Pigmentverschiebungen und Narben stark beeinträchtigt und wird von den Patienten als unbefriedigend betrachtet. Bisher gibt es keine prospektive, randomisierte, kontrollierte in vivo Studie, die die Wirksamkeit des fraktionierten CO2-Lasers zur Konturanpassung und Narbenkorrektur von Hauttransplantaten nachgewiesen hat. Da sich allerdings in der Vergangenheit in zahlreichen Studien der fraktionierte C...

Practical event analysis; Durchfuehrung von Ereignisanalysen in der Praxis

Energy Technology Data Exchange (ETDEWEB)

Scheuring, R. [Bayernwerk Kernenergie GmbH - Kernkraftwerk Grafenrheinfeld (Germany)

1999-04-01

The paper explains the systematic approaches and practical aspects of evaluation of NPP operating reports and implementation of identified remedial action for enhancing the safety in terms of human, organisational, and technology factors. The procedures adopted for the Grafenrheinfeld nuclear power station (KKG) serve as an example. (orig./CB) [German] Ein wichtiger Bestandteil zur Erhaltung und Fortentwicklung des Sicherheitsniveaus ist das Lernen aus der Erfahrung. Hierzu wiederum ist ein systematisches Vorgehen zur Vermeidung von Fehlern und Behebung von Schwachstellen menschlicher, technischer und organisatorischer Natur unabdingbare Voraussetzung. Die Anwendung einer umfassenden Auswertemethodik beinhaltet - die Erfassung und Informationsweitergabe externer und interner Vorkommnisse und Erfahrungen - eine systematische Analyse/Auswertung - eine konsequente Umsetzung der Abhilfemassnahmen unter Einbeziehen aller betroffenen Organisationseinheiten. Wie erfolgt die Umsetzung dieser Vorgaben in die Praxis? Im Kernkraftwerk Grafenrheinfeld (KKG) ist die Auswertung von externen und internen Betriebserfahrungen als Aufgabe im Betriebshandbuch (BHB) 'Personelle Betriebsorganisation' vorgegeben und im Detail im Sinne der Ablauforganisation im Qualitaetssicherungshandbuch in Qualitaetssicherungsanweisungen (QSA) beschrieben. (orig.)

Spurenstoffuntersuchungen zur Bildung und Ausbreitung von Wassermassen im subpolaren Nordatlantik

OpenAIRE

Hildebrandt, Hauke

2001-01-01

In der vorliegenden Arbeit wurde ein umfangreicher Spurenstoffdatensatz aus dem subpolaren Nordatlantik erstellt und ausgewertet, der Tritium-, Helium- und Neon- sowie O-18-Messungen umfaßt. Das Hauptaugenmerk galt dabei der Bildung und Ausbreitung der tiefen Wassermassen und deren Variabilität auf Zeitskalen von einigen Jahren. Anhand von Tracermittelwerten, die mit Hilfe eines optimierten Interpolationsverfahrens gewonnen wurden, konnte gezeigt werden, daß die konvektive Neubildung de...

Evolution und Funktionsvariabilität von bunodonten Molaren bei Primaten

OpenAIRE

Menz, Ulrike Maria (Doktor)

2017-01-01

In der vorliegenden Arbeit werden funktionale Details der Okklusion während der Mastikation bei ausgewählten fossilen und rezenten Primaten quantitativ vergleichend untersucht. Dazu wurden die Okklusionsflächen von antagonistischen Molarenpaaren mit modernen virtuellen Verfahren eingescannt und anhand von 3D Kronenmodellen kartiert und funktional ausgewertet. Die in der Forschergruppe DFG FOR 771 entwickelte Software „Occlusal Fingerprint Analyser“ (OFA) kam erstmals bei einer großen Stichpro...

Von Kalifornien nach Taxham / Katri Soe

Index Scriptorium Estoniae

Soe, Katri, 1971-

2005-01-01

Neljas osa magistritööst "Von Kalifornien nach Taxham: Formen und Strukturen der Kommunikation in Peter Handkes Romanen "Der kurze Brief zum langen Abschied" und "In einer dunklen Nacht ging ich aus meinem stillen Haus"" (Tartu, 2000. Juhendaja: Claus Sommerhage)

Differential effects of the loss of intrachain- versus interchain-disulfide bonds in the cystine-knot domain of von Willebrand factor on the clinical phenotype of von Willebrand disease

NARCIS (Netherlands)

Tjernberg, Pernilla; Vos, Hans L.; Spaargaren-van Riel, Caroline C.; Luken, Brenda M.; Voorberg, Jan; Bertina, Rogier M.; Eikenboom, Jeroen C. J.

2006-01-01

Von Willebrand factor (VWF) contains a large number of cysteine residues, which all form disulfide bonds. Mutations of cysteines located in the cystine-knot (CK) domain of VWF have been identified in both qualitative type 2A (IID) and quantitative type 3 von Willebrand disease (VWD). Our objective

Die nuklearen Anlagen von Hanford (1943-1987) Eine Fallstudie über die Schnittstellen von Physik, Biologie und die US-amerikanische Gesellschaft zur Zeit des Kalten Krieges

Science.gov (United States)

Macuglia, Daniele

Die Geschichte des Kalten Krieges eröffnet viele Möglichkeiten, sich näher mit den Schnittstellen von Physik und Biologie während des 20. Jahrhunderts zu befassen. Nicht nur das Unglück in Tschernobyl aus dem Jahr 1986, auch das Beispiel der nuklearen Anlagen in Hanford in den Vereinigten Staaten zeigt die biologischen Folgen von nuklearer Physik.

Von Neumann entropy in a Rashba-Dresselhaus nanodot; dynamical electronic spin-orbit entanglement

Science.gov (United States)

Safaiee, Rosa; Golshan, Mohammad Mehdi

2017-06-01

The main purpose of the present article is to report the characteristics of von Neumann entropy, thereby, the electronic hybrid entanglement, in the heterojunction of two semiconductors, with due attention to the Rashba and Dresselhaus spin-orbit interactions. To this end, we cast the von Neumann entropy in terms of spin polarization and compute its time evolution; with a vast span of applications. It is assumed that gate potentials are applied to the heterojunction, providing a two dimensional parabolic confining potential (forming an isotropic nanodot at the junction), as well as means of controlling the spin-orbit couplings. The spin degeneracy is also removed, even at electronic zero momentum, by the presence of an external magnetic field which, in turn, leads to the appearance of Landau states. We then proceed by computing the time evolution of the corresponding von Neumann entropy from a separable (spin-polarized) initial state. The von Neumann entropy, as we show, indicates that electronic hybrid entanglement does occur between spin and two-dimensional Landau levels. Our results also show that von Neumann entropy, as well as the degree of spin-orbit entanglement, periodically collapses and revives. The characteristics of such behavior; period, amplitude, etc., are shown to be determined from the controllable external agents. Moreover, it is demonstrated that the phenomenon of collapse-revivals' in the behavior of von Neumann entropy, equivalently, electronic hybrid entanglement, is accompanied by plateaus (of great importance in quantum computation schemes) whose durations are, again, controlled by the external elements. Along these lines, we also make a comparison between effects of the two spin-orbit couplings on the entanglement (von Neumann entropy) characteristics. The finer details of the electronic hybrid entanglement, which may be easily verified through spin polarization measurements, are also accreted and discussed. The novel results of the present

Dependence of the wind climate of Ireland on the direction distribution of geostrophic wind; Die Abhaengigkeit des Windklimas von Irland von der Richtungsverteilung des geostrophischen Windes

Energy Technology Data Exchange (ETDEWEB)

Frank, H.P. [Forskningcenter Risoe, Roskilde (Denmark). Afdelingen for Vindenergi og Atmosfaerefysik

1998-01-01

The wind climate of Ireland is calculated using the Karlsruhe Atmospheric Mesoscale Model KAMM. The dependence of the simulated wind energy on the direction distribution of geostrophic wind is studied. As geostrophic winds from the south-west are most frequent, sites on the north-west coast are particularly suited for wind power stations. In addition, geostrophic wind increases from the south-east to the north-west. (orig.) [Deutsch] Das Windklima von Irland wurde mit dem Karlsruher Atmosphaerischen Mesoskaligen Modell KAMM berechnet. Hier wird die Abhaengigkeit der simultierten Windenergie von der Richtungsverteilung des geostrophischen Windes untersucht. Da geostrophische Winde aus Suedwest am haeufigsten vorkommen, eignet sich besonders die Nordwestkueste als Standort fuer Windkraftanlagen. Zusaetzlich nimmt auch der mittlere geostrophische Wind von Suedost nach Nordwest zu. (orig.)

Gewaltenteilung im Rechsstaat und europäische Geschichte. 3 : Vorträge am Staatsgerichtshof und am Historischen Seminar der Universität Tartu (Dorpat)/Estland / Ingo von Münch, Niels von Redecker ; Forum Academicum Inter Nationes ; Roela Uemõisa

Index Scriptorium Estoniae

Münch, Ingo von

1998-01-01

Sisaldab: Die Gewaltenteilung im Rechtstaat = Võimude lahususe printsiip õigusriigis / Ingo von Münch ; Can we have a European history / Niels von Redecker ; The Ostpolitik of Willy Brandt / Niels von Redecker

Nonconventional ergodic averages and multiple recurrence for von Neumann dynamical systems

NARCIS (Netherlands)

Austin, T.; Eisner, T.; Tao, T.

2011-01-01

The Furstenberg recurrence theorem (or equivalently Szemerédi’s theorem) can be formulated in the language of von Neumann algebras as follows: given an integer k ≥ 2, an abelian finite von Neumann algebra (M,τ) with an automorphism α : M→M, and a nonnegative a in M with τ(a) > 0, one has liminf

Pseudo (Platelet-type von Willebrand disease in pregnancy: a case report

Directory of Open Access Journals (Sweden)

Grover Neetu

2013-01-01

Full Text Available Abstract Background Pseudo (platelet-type-von Willebrand disease is a rare autosomal dominant bleeding disorder caused by an abnormal function of the glycoprotein lb protein; the receptor for von Willebrand factor. This leads to an increased removal of VWF multimers from the circulation as well as platelets and this results in a bleeding diathesis. Worldwide, less than 50 patients are reported with platelet type von Willebrand disease (PT-VWD. Case presentation We describe the management of platelet type von Willebrand disease in pregnancy of a 26 year old Caucasian primigravida. The initial diagnosis was made earlier following a significant haemorrhage post tonsillectomy several years prior to pregnancy. The patient was managed under a multidisciplinary team which included obstetricians, haematologists, anaesthetists and neonatologists. Care plans were made for the ante- natal, intra-partum and post-partum periods in partnership with the patient. The patient’s platelet count levels dropped significantly during the antenatal period. This necessitated the active exclusion of other causes of thrombocytopenia in pregnancy. A vaginal delivery was desired and plans were made for induction of labour at 38 weeks of gestation with platelet cover in view of the progressive fall of the platelet count. The patient however went into spontaneous labour on the day of induction. She was transfused two units of platelets before delivery. She had an unassisted vaginal delivery of a healthy baby. The successful antenatal counselling has encouraged the diagnosis of the same condition in her mother and sister. We found this to be a particularly interesting case as well as challenging to manage due to its rarity. Psuedo von Willebrand disease in pregnancy can be confused with a number of other differential diagnoses, such as gestational thrombocutopenia, idiopathatic thrombocytopenia, thrombotic thrombocytopenic purpura and pre-eclampsia; all need consideration

Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease

DEFF Research Database (Denmark)

Lassila, Riitta; Holme, Pål André; Landorph, Andrea

2011-01-01

Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor. The diagno......Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor...... subtyping may also be problematic. This article summarizes the guidelines of the Nordic Haemophilia Council (NHC), which are intended to serve as a practical tool and provide the standards for diagnosing and treating VWD patients. The complete Nordic Guidelines on VWD are available at the NHC Web site (http://nordhemophilia.org)....

The Molecular Genetics of von Willebrand Disease

Directory of Open Access Journals (Sweden)

Ergül Berber

2012-12-01

Full Text Available Quantitative and/or qualitative deficiency of von Willebrand factor (vWF is associated with the most common inherited bleeding disease von Willebrand disease (vWD. vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD.

The molecular genetics of von Willebrand disease.

Science.gov (United States)

Berber, Ergül

2012-12-01

Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.

Investigations of water pollution effects of mining spoil heaps depending on the period of existence. Final report. Part project 2; Untersuchungen gewaesserrelevanter Einfluesse von Bergbauhalden in Abhaengigkeit von der Standzeit. Abschlussbericht. Teilprojekt 2

Energy Technology Data Exchange (ETDEWEB)

Puchelt, H.; Stueben, D.; Berner, Z.; Kappes, B.

1996-12-01

Apart form the main elements, the Wiesloch Ag-Pb-Zn mineralisation contains a series of higly toxic trace elements. The main ore minerals of galena, zinc blende and Menikow pyrites also contain Tl, Cd, As and Sb up to the precent range. The main and trace element contents of ores, flotation residues and slags were examined in detail. Their weathering properties were estimated, depending on the time of existence, from new secondary mineral formations. An element displacement from the spoil heaps reaching several decimetres in the ceiling was shown. Strong contamination can be proved by washing out and dispersion of As and Tl in agriculturally used areas and can be found in plants. Using elution experiments, the metal release of hevy metals and arsenic from ores, flotation wastes and slags was examined for the quantitative estimation of the material transfer. Also, the excellent suitability of synthetic Fe-Mn hydroxides for the decontamination of water containing arsenic and heavy metals was shown. (orig.) [Deutsch] Die Wieslocher Ag-Pb-Zn-Vererzung enthaelt neben den Hauptelementen eine Reihe von hochtoxischen Spurenelementen. Die Haupterzminerale Bleiglanz, Zinkblende und Melnikowitpyrit enthalten zusaetzlich Tl, Cd, As sowie Sb bis in den Prozentbereich. Im Detail wurde der Haupt- und Spurenelementgehalt von Erzen, Flotationsrueckstaenden und Schlacken untersucht. Ihre Verwitterungseigenschaften wurden in Abhaengigkeit der Standzeit anhand von sekundaeren Mineralneubildungen abgeschaetzt. Eine mehrere dm-weit reichende Elementverlagerung aus Halden in das Liegende (Loessdecke) konnte nachgewiesen werden. Starke Kontaminationen sind durch Auswaschung und Dispersion von As und Tl in landwirtschaftlich genutzen Flaechen nachzuweisen und in Pflanzen wiederfindbar. Zur quantitativen Abschaetzung des Stofftransfers wurde anhand von Elutionsversuchen die Metallfreisetzung von Schwermetallen und Arsen aus Erz, Flotationsabgaengen und Schlacken untersucht. Ausserdem konnte

Der Effekt von Akupunktur in der Prävention von Prüfungsangst

OpenAIRE

Krüger, Peter

2017-01-01

Prüfungsangst ist ein weit verbreitetes gesellschaftliches Phänomen, das bisher in nur wenigen wissenschaftlichen Ansätzen untersucht wurde. Die Zahl der Studenten, die Gehirn - Doping zur Leistungssteigerung und zur Minimierung von Prüfungsangst nutzen, steigt stetig an. In bisherigen Studien wurde Akupunktur an Herz 7 als vielversprechende Behandlungsalternative dargestellt. Basierend auf diesen Ergebnissen, wurde in dieser Arbeit untersucht, ob eine Einzelpunktakupunktur an Herz 7 die ...

Theodor von Grotthuss’ Contribution to Electrochemistry

International Nuclear Information System (INIS)

Pauliukaite, Rasa; Juodkazytė, Jurga; Ramanauskas, Rimantas

2017-01-01

Freiherr Christian Johann Dietrich Theodor von Grotthuss (1785-1822) lived and worked in Lithuania. Inspired by Volta's pile he proposed the first theory of water electrolysis, which was published in 1805 in Rome. Michael Faraday acknowledged T. Grotthuss for this theory in his further investigations of electrolysis processes. Having studied in Germany and France Grotthuss brought science to province by establishing his laboratory in Gedučiai village in his mother's real estate. Lithuanian scientists are proud that life of Theodor von Grotthuss was related to this country. Many events to remember this prominent scientist are organised in Vilnius and other places. His works and example provided a good basis for further development of electrochemical science in Lithuania. Grotthuss insights into the mechanism of proton transport still are of great relevance to such areas of modern science as membrane biochemistry, energy conversion and storage.

Schaltungskonzepte zum Betrieb von Leuchtdioden für die Allgemeinbeleuchtung

OpenAIRE

Pawellek, Alexander

2018-01-01

Licht bestimmt das Leben der Menschen und ohne eine künstliche Beleuchtung wäre die Gesellschaft in der heutigen Form undenkbar. Aktuelle Lichtquellen beruhen auf der Umwandlung von elektrischer Energie in Strahlungsenergie im sichtbaren Spektrum. Hierbei nimmt die Beleuchtung insgesamt einen Anteil von ca. 15 % am weltweiten elektrischen Energiebedarf ein, wobei für die Zukunft eine steigende Tendenz erwartet wird. Die Senkung der benötigten Energiemenge erfordert zwingend die Entwicklung in...

Nash y von Neumann: mundos posibles y juegos de lenguaje

Directory of Open Access Journals (Sweden)

Salazar , Boris

2004-06-01

Full Text Available Este ensayo emplea las nociones de juego de lenguaje y de equivalencia entre juegos para examinar la decisión de John Nash de no jugar el juego coalicional que propuso John von Neumann. El argumento central es que Nash concibió una clase de mundos posibles incompatible con la de von Neumann, y que en el origen de esa divergencia estarían sus distintas nociones de racionalidad.

Die Bedeutung internationaler Erfahrungen für den Karriereerfolg von Führungskräften

OpenAIRE

Biemann, Torsten

2009-01-01

Die langfristigen Auswirkungen internationaler Einsätze von Führungskräften auf deren Karrieren sind bislang kaum empirisch untersucht worden und die wenigen vorliegenden Ergebnisse sind widersprüchlich. Ziel dieser Studie ist deshalb die empirische Untersuchung der Auswirkungen internationaler Erfahrungen auf den Karriereerfolg von Führungskräften anhand eines Vergleichs von Führungskräften mit und ohne internationale Erfahrungen. Es zeigt sich, dass internationale Erfahrungen zu einem höher...

Networking Knowledge. Considering Alexander von Humboldt’s Legacy in a New Shared Space in Education

Directory of Open Access Journals (Sweden)

Karin Lundberg

2015-05-01

Full Text Available Zusammenfassung Weltbürgerschaft und kulturelle Vielfalt sind überall gegenwärtige Konzepte im heutigen Bildungswesen. In den Vereinigten Staaten werden Lernziele und Kompetenzen geformt, um die Studenten gegenüber den vielen kulturellen Hintergründen, die in den Bildungsinstitutionen vorzutreffen sind, zu sensibilisieren.Trotzdem wird wahre Globalität, wie sie heute in den vielfältigen Diskursen und Perspektiven der Welt repräsentiert ist, immer noch in Lehrplänen und Studienarbeiten vernachlässigt. Dieser Artikel untersucht die Möglichkeiten, die sich heute im Bildungswesen durch den neuen, gemeinsam geteilten, globalen Bildungsraum anbieten, in dem die multikulturelle Studentenbevölkerung verschiedene Formen vernetzten Wissens und facettenreiche Perspektiven der Welt eine globale Plattform des Austausches bildet. Das von Alexander von Humboldt am Anfang des neunzehnten Jahrhunderts beschriebene universale Wissenschaftskonzept, beleuchtet solch einen vernetzten Ansatz an ein Wissen um die Welt, der auf heutige Bildungskonzepte und Kursdesigns einen positiven Einfluss nehmen könnte. Humboldts Schriften unterstreichen die Bedeutung der Inklusivität und des Wechselspiels zwischen Kulturen und Naturphänomenen. Indem wir Studenten mit unterschiedlichem kulturellen Hintergrundwissen dazu einladen, ihre jeweiligen Diskurse des Wissens aktiv zu repräsentieren, werden diese gegenseitig mit einander verknüpten Beziehungen des Wissens transparenter. Auf diese Weise, entsteht die Möglichkeit, heutige Lernziele mit neuen, produktiven Formen des Weltwissens zu berreichern, worin sich ein wahres Weltbürgertum, wie es sich in diesem neuen Bildungsraum des globalen Austausches hervortut, wiederspiegeln würde. Summary Global citizenship and diversity are well-represented concepts in today’s higher education. Learning outcomes and competencies are designed to sensitize students to the many cultural backgrounds of U.S. learning institutions

Influence of tensides and lipophilic substrates on the biological availability of polycyclic aromatic hydrocarbons (PAHs); Ueber dem Einfluss von Tensiden und lipophilen Substraten auf die Bioverfuegbarkeit von polyzyklischen aromatischen Kohlenwasserstoffen (PAK)

Energy Technology Data Exchange (ETDEWEB)

Soeder, C.J. von; Kleespies, M; Eschner, C; Webb, L; Groeneweg, J [Forschungszentrum Juelich GmbH (Germany). IBT-3/ICG-6

1998-12-31

The objects of the study were as follows: isolation and characterization of PAH-degrading micro-organisms from lysimeters; tests relating to the experimental simulation of the conditions permitting pollutant degradation in soil; investigation of the influence of tensides and other dissolved organic compounds on the biological availability and degradation of PAHs. (orig./SR) [Deutsch] - Isolierung und Charakterisierung PAK-abbauender Mikroorganismen aus Lysimetern; Versuche zur experimentellen Simulation der Bedingungen, unter denen der Abbau von Schadstoffen im Boden erfolgt. - Untersuchung des Einflusses von Tensiden und anderen geloesten organischen Verbindungen auf Bioverfuegbarkeit und Abbau von PAK. (orig./SR)

Influence of tensides and lipophilic substrates on the biological availability of polycyclic aromatic hydrocarbons (PAHs); Ueber dem Einfluss von Tensiden und lipophilen Substraten auf die Bioverfuegbarkeit von polyzyklischen aromatischen Kohlenwasserstoffen (PAK)

Energy Technology Data Exchange (ETDEWEB)

Soeder, C.J. von; Kleespies, M.; Eschner, C.; Webb, L.; Groeneweg, J. [Forschungszentrum Juelich GmbH (Germany). IBT-3/ICG-6

1997-12-31

The objects of the study were as follows: isolation and characterization of PAH-degrading micro-organisms from lysimeters; tests relating to the experimental simulation of the conditions permitting pollutant degradation in soil; investigation of the influence of tensides and other dissolved organic compounds on the biological availability and degradation of PAHs. (orig./SR) [Deutsch] - Isolierung und Charakterisierung PAK-abbauender Mikroorganismen aus Lysimetern; Versuche zur experimentellen Simulation der Bedingungen, unter denen der Abbau von Schadstoffen im Boden erfolgt. - Untersuchung des Einflusses von Tensiden und anderen geloesten organischen Verbindungen auf Bioverfuegbarkeit und Abbau von PAK. (orig./SR)

Crystal structure of the cytoplasmic phosphatase and tensin homolog (PTEN)-like region of Ciona intestinalis voltage-sensing phosphatase provides insight into substrate specificity and redox regulation of the phosphoinositide phosphatase activity.

Science.gov (United States)

Matsuda, Makoto; Takeshita, Kohei; Kurokawa, Tatsuki; Sakata, Souhei; Suzuki, Mamoru; Yamashita, Eiki; Okamura, Yasushi; Nakagawa, Atsushi

2011-07-01

Ciona intestinalis voltage-sensing phosphatase (Ci-VSP) has a transmembrane voltage sensor domain and a cytoplasmic region sharing similarity to the phosphatase and tensin homolog (PTEN). It dephosphorylates phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate upon membrane depolarization. The cytoplasmic region is composed of a phosphatase domain and a putative membrane interaction domain, C2. Here we determined the crystal structures of the Ci-VSP cytoplasmic region in three distinct constructs, wild-type (248-576), wild-type (236-576), and G365A mutant (248-576). The crystal structure of WT-236 and G365A-248 had the disulfide bond between the catalytic residue Cys-363 and the adjacent residue Cys-310. On the other hand, the disulfide bond was not present in the crystal structure of WT-248. These suggest the possibility that Ci-VSP is regulated by reactive oxygen species as found in PTEN. These structures also revealed that the conformation of the TI loop in the active site of the Ci-VSP cytoplasmic region was distinct from the corresponding region of PTEN; Ci-VSP has glutamic acid (Glu-411) in the TI loop, orienting toward the center of active site pocket. Mutation of Glu-411 led to acquirement of increased activity toward phosphatidylinositol 3,5-bisphosphate, suggesting that this site is required for determining substrate specificity. Our results provide the basic information of the enzymatic mechanism of Ci-VSP.

Otto von Habsburg : III maailmasõda on läbi / Otto von Habsburg ; interv. Marianne Mikko

Index Scriptorium Estoniae

Habsburg, Otto von, 1912-2011

2002-01-01

Otto von Habsburg vastab küsimustele, mis puudutavad Euroopa konvendi presidendi teadet, et Türgi koht ei ole EL-is, Iraagi võimalikku ründamist, Hiina ja Venemaa suhteid, Tšetšeeniat, tshetsheene ja terrorismi, Venemaa, EL-i ja USA suhteid, III maailmasõda, Eesti Vabariigi tulevikku

Vorschrift oder Thunfisch? – Zur Langzeitverfügbarkeit von Forschungsdaten

Directory of Open Access Journals (Sweden)

Tim Hasler

2013-10-01

Full Text Available Ich mache ihm ein Angebot, das er nicht ablehnen kann.” Diese Aussage aus einem gänzlich anderen Kontext lässt sich recht treffend übertragen als Wunsch von Dienstleistern und Zweck von Dienstleistungen für Datenproduzenten im Forschungsdatenmanagement. Zwar wirkt Druck zur Datenübergabe nicht förderlich, die Eröffnung einer Option aber sehr wohl. Im vorliegenden Artikel geht es um das Verständnis der Nachhaltigkeit von Forschung und ihren Daten anhand der Erkenntnisse und Erfahrungen aus der ersten Phase des DFG-Projekts EWIG. [Fn 01] Eine Auswahl von Fallstricken beim Forschungsdatenmanagement wird anhand der Erkenntnisse aus Expertengesprächen und eigenen Erfahrungen beim Aufbau von LZA-Workflows vorgestellt. Erste Konzepte in EWIG zur Datenübertragung aus unterschiedlich strukturierten Datenquellen in die „Langfristige Domäne” werden beschrieben. "I'm gonna make him an offer he can't refuse". This quote from a completely different context can be aptly rendered as a statement of service providers as well as the purpose of services for data producers in the field of research data management. Although pressure is not the leverage of choice if you want researchers to deposit their research data in some kind of repository, offering an option does the trick quite well. In this article we present some of the concepts for sustainability of research and its data from the first phase the of the project EWIG, funded by the Deutsche Forschungsgemeinschaft. A selection of pitfalls in research data management is presented based on the findings from expert interviews and our own experiences in the construction of LTP workflows. First concepts in EWIG to transfer data from differently structured data sources into the "Permanent Domain" are described.

Christian Enichlmayr, Leiter der Oberösterreichischen Landesbibliothek von 1999 bis 2015, beantwortet 10 Fragen von Bruno Bauer

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Christian Enichlmayr

2016-05-01

Full Text Available Christian Enichlmayr beantwortet Fragen über seinen Start ins Berufsleben in der Verlagsbranche, seine Zeit an der Universitätsbibliothek Linz und seinen Wechsel an die Oberösterreichische Landesbibliothek. 1999 bis 2015 war er als deren Leiter auch in führender Position für die Transformation der Bundesstaatlichen Studienbibliothek zur Landesbibliothek sowie die Sanierung und Erweiterung des Bibliotheksgebäudes verantwortlich. Weitere Themen, die in den vergangenen 17 Jahren an der Landesbibliothek stark forciert wurden, erstrecken sich von der NS-Provenienzforschung über die Entwicklung der digitalen Landesbibliothek bis zur Stärkung der Rolle der Landesbibliothek im oberösterreichischen Kulturleben. Zuletzt spricht Enichlmayr über die Bedeutung von Kooperationen im Bibliothekswesen, die Ausrichtung des Bibliothekartages der Vereinigung Österreichischer Bibliothekarinnen und Bibliothekare 2004 in Linz sowie die Perspektive für Bibliotheken.

Investigations of time-dependent water pollution effects of overburden dumps - partial project 1. Final report; Untersuchungen gewaesserrelevanter Einfluesse von Bergbauhalden in Abhaengigkeit von der Standzeit - Teilprojekt 1. Abschlussbericht

Energy Technology Data Exchange (ETDEWEB)

Beuge, P.; Dunger, C.; Mibus, J.; Starke, R.

1998-02-01

Management of overburden dumps necessitates careful stocktaking and precise definitions of pollutant emissions so that, if necessary, conclusions can be drawn concerning sanitation concepts in consideration of emission limits and environmental balances. In view of the large number of overburden dumps in Saxony, Saxony-Anhalt and Thuringia caused the authors to restrict their investigations to ore mines and to select elements characteristic of the worked deposits and their potential environmental effects. The following problems were investigated: Are overburden dumps significant emitters of elements at all? Which elements are emitted in what concentrations, in what form and up to what distance from the dump? Are there really different patterns for gangue and impregnation types? How big is the real reaction space of the dump? Should the whole dump be assumed to be a reservoir of elements for emission or just parts of it? What are the factors that most strongly influence element mobilisation and/or retention? What measures should be recommended for emission reduction or prevention from the aspects of necessity, economic efficiency and long-term stability? (orig./SR) [Deutsch] Es ergibt sich fuer den Umgang mit Halden die Notwendigkeit einer gruendlichen Bilanzierung und schaerferen Definition von Schadstoffemission aus ihnen, um daraus Konsequenzen fuer eventuell erforderliche Sanierungskonzeptionen unter Beruecksichtigung von Grenzwerteinhaltung und Umweltbilanz abzuleiten. Der Umfang der einzelnen Fragestellungen und die Bedeutung der Halden in Sachsen, Sachsen-Anhalt und Thueringen sowie Anzahl und ihr Inhalt fuehrte zur Beschraenkung auf den Erzbergbau und auf die Kontrolle ausgewaehlter Elemente, die fuer den jeweils abgebauten Lagerstaetteninhalt charakteristisch und fuer die Wirkung auf die Umwelt von Bedeutung sind. Folgende konkrete Fragestellungen sollen verfolgt werden: - Sind Halden ueberhaupt nennenswerte Emittenten von Elementen? - Welche Elemente werden

Hydrogen sulfide prevents hydrogen peroxide-induced activation of epithelial sodium channel through a PTEN/PI(3,4,5P3 dependent pathway.

Directory of Open Access Journals (Sweden)

Jianing Zhang

Full Text Available Sodium reabsorption through the epithelial sodium channel (ENaC at the distal segment of the kidney plays an important role in salt-sensitive hypertension. We reported previously that hydrogen peroxide (H2O2 stimulates ENaC in A6 distal nephron cells via elevation of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5P3 in the apical membrane. Here we report that H2S can antagonize H2O2-induced activation of ENaC in A6 cells. Our cell-attached patch-clamp data show that ENaC open probability (PO was significantly increased by exogenous H2O2, which is consistent with our previous finding. The aberrant activation of ENaC induced by exogenous H2O2 was completely abolished by H2S (0.1 mM NaHS. Pre-treatment of A6 cells with H2S slightly decreased ENaC P(O; however, in these cells H2O2 failed to elevate ENaC PO . Confocal microscopy data show that application of exogenous H2O2 to A6 cells significantly increased intracellular reactive oxygen species (ROS level and induced accumulation of PI(3,4,5P3 in the apical compartment of the cell membrane. These effects of exogenous H2O2 on intracellular ROS levels and on apical PI(3,4,5P3 levels were almost completely abolished by treatment of A6 cells with H2S. In addition, H2S significantly inhibited H2O2-induced oxidative inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN which is a negative regulator of PI(3,4,5P3. Moreover, BPV(pic, a specific inhibitor of PTEN, elevated PI(3,4,5P3 and ENaC activity in a manner similar to that of H2O2 in A6 cells. Our data show, for the first time, that H2S prevents H2O2-induced activation of ENaC through a PTEN-PI(3,4,5P3 dependent pathway.

Der Einfluss von Mixed Emotions auf die Werbewirkung : eine experimentelle Studie

OpenAIRE

Bauer, Hans H.; Donnevert, Tobias; Exler, Stefanie; Hobusch, Sonja

2007-01-01

Emotionale Appelle haben heutzutage einen festen Platz in der Werbung. Neben rein positiven sowie rein negativen Emotionen werden auch Mixed Emotions verstärkt eingesetzt. Die Erforschung der konsumentenverhaltensrelevanten Wirkungen von Mixed Emotions, die das gleichzeitige oder sequentielle Erleben gegensätzlicher Emotionen bezeichnen, steckt jedoch noch in den Kinderschuhen. In der vorliegenden Studie wird daher der Einfluss von Mixed Emotions auf zentrale psychographische Werbewirku...

Gesichtslose Cliquen? : Die Bedeutung von Interaktionsform, Geschlecht und Motivation in Onlinespielen

OpenAIRE

Meißner, Malte

2009-01-01

In der vorliegenden Studie werden drei Arten von Onlinespielen anhand ihrer Interaktionsformen unterschieden: MMORPGs, E-Sports und Browserspiele. Hierzu wurden Datensätze von 4330 Spielern erhoben. Acht Faktoren konnten ermittelt werden, die für Onlinespieler im Spiel und im Umgang miteinander bedeutsam sind: Wettkampf, Freundschaft, Isolation, Glamour, Gewalterleben, Gemeinschaft, Anregung und Privatheit. Einige dieser Faktoren scheinen Einfluss darauf zu nehmen, wie lange Onlin...

Genetic variations in a PTEN/AKT/mTOR axis and prostate cancer risk in a Chinese population.

Directory of Open Access Journals (Sweden)

Jiawei Chen

Full Text Available Genetic variations in a PTEN/AKT/mTOR signaling axis may influence cellular functions including cell growth, proliferation and apoptosis, and then increase the individual's risk of cancer. Accordingly, we explore the association between single nucleotide polymorphisms (SNPs of these genes and prostate cancer (PCa in our Chinese population.Subjects were recruited from 666 PCa patients and 708 cancer-free controls, and eight SNPs in the PTEN/AKT/mTOR axis were determined by the TaqMan assay. Odds ratios (OR and 95% confidence intervals (95% CI were evaluated by logistic regression.We observed significant associations between PCa risk and mTOR rs2295080 [P = 0.027, OR = 0.85, 95%CI = 0.74-0.98], and AKT2 rs7254617 (P = 0.003, OR = 1.35, 95%CI = 1.11-1.64. When estimated these two SNPs together, the combined genotypes with 2-4 risk alleles (rs2295080 T and rs7254617 A alleles were associated with an increased risk of PCa compared with 0-1 risk alleles, which was more pronounced among subgroups of age >71 years, smokers, drinkers and no family history of cancer. Results of stratified analyses by cliniopathological parameters revealed that the frequencies of the combined genotypes with 2-4 risk alleles in advanced stage were significantly higher than in localized stage (P = 0.022, but there was no significant association in Gleason score and PSA level.Our results indicate, for the first time that the two variants in AKT2 and mTOR, particularly the joint genotypes with 2-4 risk alleles may influence PCa susceptibility and progression in Chinese, and the association appeared to be more strong in the subgroup of smokers and drinkers.

Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer.

Science.gov (United States)

Gillard, Marc; Lack, Justin; Pontier, Andrea; Gandla, Divya; Hatcher, David; Sowalsky, Adam G; Rodriguez-Nieves, Jose; Vander Griend, Donald; Paner, Gladell; VanderWeele, David

2017-12-08

Ductal adenocarcinoma of the prostate is an aggressive subtype, with high rates of biochemical recurrence and overall poor prognosis. It is frequently found coincident with conventional acinar adenocarcinoma. The genomic features driving evolution to its ductal histology and the biology associated with its poor prognosis remain unknown. To characterize genomic features distinguishing ductal adenocarcinoma from coincident acinar adenocarcinoma foci from the same patient. Ten patients with coincident acinar and ductal prostate cancer underwent prostatectomy. Laser microdissection was used to separately isolate acinar and ductal foci. DNA and RNA were extracted, and used for integrative genomic and transcriptomic analyses. Single nucleotide mutations, small indels, copy number estimates, and expression profiles were identified. Phylogenetic relationships between coincident foci were determined, and characteristics distinguishing ductal from acinar foci were identified. Exome sequencing, copy number estimates, and fusion genes demonstrated coincident ductal and acinar adenocarcinoma diverged from a common progenitor, yet they harbored distinct alterations unique to each focus. AR expression and activity were similar in both histologies. Nine of 10 cases had mutually exclusive CTNNB1 hotspot mutations or phosphatase and tensin homolog (PTEN) alterations in the ductal component, and these were absent in the acinar foci. These alterations were associated with changes in expression in WNT- and PI3K-pathway genes. Coincident ductal and acinar histologies typically are clonally related and thus arise from the same cell of origin. Ductal foci are enriched for cases with either a CTNNB1 hotspot mutation or a PTEN alteration, and are associated with WNT- or PI3K-pathway activation. These alterations are mutually exclusive and may represent distinct subtypes. The aggressive subtype ductal adenocarcinoma is closely related to conventional acinar prostate cancer. Ductal foci

Wir zeigen andere Bilder von Frauen ...

Directory of Open Access Journals (Sweden)

Bettina Rulofs

2010-03-01

Full Text Available Der vorliegende Beitrag beleuchtet die Bedeutung der Geschlechterordnung im Prozess der sportmedialen Kommunikation. Im Kern geht es um die Frage, inwiefern im Prozess der medialen Vermittlung von Sport traditionelle Geschlechterstereotype aufrechterhalten werden oder Möglichkeiten der Irritation solcher Stereotype bestehen. Dazu werden verschiedene Ebenen des massenmedialen Kommunikationsprozesses in den Blick genommen: die Medienprodukte, die Öffentlichkeitsarbeit und Selbst-Präsentation der Sportler/innen, die Medienrezeption und die Herstellungsprozesse von Medien in den Sportredaktionen. This article illustrates the relevance of gender in processes of sports media communication. The question in focus is in what way traditional gender stereotypes are perpetuated in the process of media communication in sport and how such stereotypes can be irritated. Therefore different levels of mass media communication are considered: the media products, the public relations of athletes and the presentation of themselves as athletes, the media-reception and the production processes in sport departments of media institutions.

Osteoporose bei Spondylitis ankylosans - Einfluß von Lebensgewohnheiten

Directory of Open Access Journals (Sweden)

Aglas F

2004-01-01

Full Text Available Krankheitsbedingte Artefakte können bei der SpA (Spondylitis ankylosans; Mb. Bechterew die Sensitivität einer Knochendichtemessung im Lumbalbereich beeinträchtigen. Das bei dieser rheumatischen Erkrankung bekannte Osteoporoserisiko ist neben genetischen Faktoren und Entzündungsmechanismen auch von verschiedenen exogenen Einflüssen abhängig. An 47 SpA-Patienten wurde mittels DEXA eine vergleichende Knochendichtemessung (BMD an der Hüfte (Schenkelhals und Ward'sches Dreieck sowie im Bereich der Wirbelsäule (L1-L4 vorgenommen. Zusätzlich erfolgte eine Erhebung der Lebens-Ernährungsgewohnheiten der SpA-Patienten in bezug auf die BMD, um exogene Einflüsse erfassen zu können. Die Knochendichtemessungen ergaben an der LWS wesentlich häufiger eine BMD im Normbereich als am proximalen Femur. Besonders deutliche Unterschiede traten im höheren Lebensalter auf, bei dem aufgrund von Kalzifizierungsvorgängen und Syndesmophyten an der LWS fälschlicherweise eine Dichtezunahme vorgetäuscht wird. Es kann daher bei SpA empfohlen werden, die wesentlich sensitivere Dichtemessung am Schenkelhals durchzuführen. Die über einen Zeitraum von 3 Jahren beobachteten, signifikant erhöhten, medianen CRP-Spiegel zeigen, daß eine permanente Aktivierung von Entzündungsprozessen bei SpA auch einen negativen Faktor betreffend des Knochenmasseverlustes darstellt. Die Analyse der Lebensgewohnheiten ergab, daß SpA-Patienten mit normaler BMD ausnahmslos regelmäßig kalziumreiche Nahrungsmittel zu sich nehmen; bei verminderter BMD wurde in der Mehrheit ein fehlender Konsum an Milchprodukten beobachtet. Leider war auch mit abnehmender BMD eine Verminderung der bei SpA empfohlenen Bewegungsübungen festzustellen. Aufgrund der Resultate ergibt sich eine generelle Empfehlung zu regelmäßigen Bewegungsübungen plus Osteoporosediät bei allen Bechterew-Patienten.

Wernher von Braun: Reflections on His Contributions to Space Exploration

Science.gov (United States)

Goldman, Arthur E.

2012-01-01

In 1950, Dr. Wernher von Braun and approximately 100 of his team members came to Huntsville, Alabama, to begin work with the Army on what would later become America's historic space program. He would later serve as the first director of the Marshall Space Flight Center and led the development of the Saturn V launch vehicle that launched seven crewed American mission to the moon, as well as America s first space station, Skylab. Von Braun is best known for his team s technical achievements. He realized his dream of exploring outer space by helping place humans on the moon. His engineering and managerial talent during the Apollo era had contributed to a technological revolution. He was by all accounts a good engineer, but he was only one among many. What set Von Braun apart were his charisma, his vision, and his leadership skills. He inspired loyalty and dedication in the people around him. He understood the importance of communicating his vision to his team, to political and business leaders and the public. Today, the Marshall Center continues his vision by pursuing engineering and scientific projects that will continue to open space to exploration. This presentation will discuss Von Braun's impact on Huntsville, the Marshall Center, the nation and the world and look at his contributions in context of where world space exploration is today.

Environmental monitoring of mercury in waters. Reagent-free and rapid determination of mercury at trace levels.; Umweltmonitoring von Quecksilber in Gewaessern. Reagenzienfreie und schnelle Bestimmung von Hg im Spurenbereich

Energy Technology Data Exchange (ETDEWEB)

Huber, Jessica; Leopold, Kerstin [Ulm Univ. (Germany). Inst. fuer Analytische und Bioanalytische Chemie

2013-05-15

With the help of nano gold collectors for the enrichment of the total mercury content of water samples can be analyzed fully automatically using atomic fluorescence spectrometry without extensive sample preparation. [German] Mit Hilfe von Nanogoldkollektoren zur Anreicherung kann der Gesamtquecksilber-Gehalt von Gewaesserproben vollautomatisiert mittels Atomfluoreszenzspektrometrie ohne aufwendige Probenvorbereitung analysiert werden.

The von Meyenburg complex; Der von Meyenburg Komplex

Energy Technology Data Exchange (ETDEWEB)

Schwab, S.A.; Bautz, W.; Uder, M.; Kuefner, M.A. [Erlangen-Nuernberg Univ., Erlangen (Germany). Inst. fuer Radiologie

2008-07-01

The von Meyenburg complex (VMC) describes bile duct hamartomas and presents a rare, benign incidental finding in liver imaging. We report on a 61-year-old man, who was referred for a follow up study 14 years after remission of Hodgkin's disease. Computed tomography (CT) revealed multiple hypodense lesions throughout the liver, primary suggesting recurrent Hodgkin's disease. Previous CT-examinations, which were obtained at a later date, showed those lesions in identical distribution and morphology over the years, leading to diagnosis of multiple bile duct hamartomas (VMC). Making imaging-based diagnosis of VMC including ultrasound, CT and magnetic resonance imaging is a challenging task for the radiologist. Based on literature research findings, the impact of different modalities in the diagnostic work-up of VMC is discussed. (orig.)

Measurements of emission rates of hydrocarbons from sunflower as a function of temperature, light intensity and stress (ozone levels); Bestimmung von Emissionsraten pflanzlicher Kohlenwasserstoffe bei Sonnenblumen in Abhaengigkeit von Temperatur, Lichtintensitaet und Stress, insbesondere von der Belastung mit Ozon

Energy Technology Data Exchange (ETDEWEB)

Schuh, G.; Wildt, J.; Kley, D.

1996-08-01

The emission rates of isoprene, mono- and sesquiterpenes from sunflower (Helianthus annuus L. cv. giganteus) were determined in an environmental chamber, a continuously stirred tank reactor. {alpha}-pinene, {beta}-caryophyllene and two oxygenated compounds were emitted. The emission rates of all terpenes increased exponentially with temperature. Substance specific differences of the rate of increase of the emission rates were observed. For all substances the dependence of their emission rates on temperature increased with increasing light intensity. Increasing lightflux resulted in an increase of the emission rates for all substances. The raise of emission rates with lightflux was dependent on temperature and increased with increasing temperature. During periods without plant stress the emission rates exhibited a good correlation with the rate of transpiration as well as with the rate of net photosynthesis. Sunflowers emitted higher amounts of terpenes when they were stressed by mechanical, wounding and ozone treatment as well as nutrient- or water deficiency. The emission rates increased by a factor of 5-300. Exposure with ozone had an effect on hydrocarbon emission rates with a delay-time. 3-4 h after exposure with 25-120 ppb ozone the emission rates increased by factor of 5-100. This increase was only observed on the first day of exposure. Nutrient deficiency resulted in an increase of emission rates by a factor of 10-300. In situations of mechanical, wounding and ozone stress, substance specific changes in the emission spectrum were observed. A model was developed to explain the observed phenomena. The main pathway of ozone loss in the chamber is caused by the uptake through the stomata of the plants. However, up to 50% of the ozone loss must be explained by other processes indirectly caused by the plants. (orig./MG) [Deutsch] In Laborversuchen wurden Emissionsraten biogener Kohlenwasserstoffe von Sonnenblumen gemessen. Die groessten Emissionsraten wiesen die

Zum 215. Gebutstag von Admiral Ferdinand Baron von Wrangell : (29. Dezember 1797 - 25. 25. Mai 1870) / Peter Krienitz

Index Scriptorium Estoniae

Krienitz, Peter

2012-01-01

Admiral Ferdinand Baron von Wrangellist tema 215. sünniaastapäeva puhul. Silmapaistavast Kirde-Siberi uurijast. Tema poliitilisest tegevusest ja elust Roela mõisas. Ferdinand Baroni poolt seatud viisil tähistati jõulusid Roelas kuni 1944. aasta lõpuni.

On the problem of completeness of QM: von Neumann against Einstein, Podolsky, and Rosen

OpenAIRE

Khrennikov, Andrei

2008-01-01

We performed a comparative analysis of the arguments of Einstein, Podolsky and Rosen -- EPR, 1935 (against the completeness of QM) and the theoretical formalism of QM (due to von Neumann, 1932). We found that the EPR considerations do not match at all with the von Neumann's theory. Thus EPR did not criticize the real theoretical model of QM. The root of EPR's paradoxical conclusion on incompleteness of QM is the misuse of von Neumann's projection postulate. EPR applied this postulate to obser...

Der kleine Unterschied. Zu den Selbstverhältnissen von Verantwortung und Pflicht

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Vogelmann Frieder

2015-12-01

Full Text Available Die Debatte um die Differenz von „Verantwortung“ und „Pflicht“ ist kein bloßer Streit um Wörter, geht es doch um Begriffe, für die der Anspruch erhoben wird, sie seien konstitutiv für moralische Normativität oder gar für Normativität per se. Doch welchen Unterschied macht es, die besondere Bindungskraft von Normativität über Verantwortung oder über Pflicht zu explizieren? Die Genealogie der philosophischen Reflexionen auf Verantwortung lokalisiert die Differenz zwischen Pflicht und Verantwortung in den jeweiligen Selbstverhältnissen, die mit diesen Begriffen verbunden werden. Die Analyse der Struktur dieser Selbstverhältnisse erklärt sowohl, warum Verantwortung häufig als moderner Ersatzbegriff für Pflicht gedacht wird, als auch, welchen Unterschied die Explikation der Bindungskraft von Normativität über Verantwortung oder Pflicht macht: Je nachdem, mit welchem Begriff normative Kraft erläutert wird, wandert das entsprechende Selbstverhältnis in die Verfasstheit von Normativität ein.

Small specimen test results and application of advanced models for fracture mechanics assessment of RPV integrity; Ergebnisse von Kleinproben und Anwendung von Modellansaetzen zur bruchmechanischen Bewertung der RDB-Integritaet

Energy Technology Data Exchange (ETDEWEB)

Keim, Elisabeth; Huemmer, Matthias [AREVA NP GmbH (Germany); Hoffmann, Harald [VGB (Germany); Nagel, Gerhard [e-on Kernkraft (Germany); Kuester, Karin [VENE (Germany); Koenig, Guenter; Ilg, Ulf [EnBW (Germany); Widera, Martin [RWE (Germany); Rebsamen, Daniel [KKW Goesgen (Germany)

2008-07-01

For the RPV (reactor pressure vessel) integrity assessment the transferability of specimen test results to components is of main importance. The international project TIMES (transferability of fracture toughness of irradiated materials to components and structures) is focussed on the transferability of fracture mechanical characteristics of irradiated materials to components or structures, in order to allow the quantification of differences between sample and component characteristics based on experiments and calculations. The studies were performed for the brittle and brittle-ductile regions of the material characteristics using specimens from original RPV materials in different conditions. Based on case studies the consequence of a component assessment with postulated defects are shown when specimen-related materials properties are used. Since it is not possible to prove the transferability for an RPV in detail, component-similar effects were investigated that allow in combination with numerical modelling to quantify the safety margin. Samples and experimental procedures were developed that simulated the real component situation. The effects of crack depth and multiaxial loads, relevant for real components, were investigated with these samples. A micromechanical model was developed based on the weakest link theory and the statistical failure probability; this model is used for the prediction of fracture toughness of samples and components with defects. For a component with postulated defects the safety margin was assessed using different methodologies, based on standard fracture mechanical samples, taking into account component specific aspects. [German] Fuer die Bewertung der RDB-Integritaet ist die Uebertragbarkeit von Probenkennwerten auf Bauteile von grosser Bedeutung. Dazu wurde das Projekt ''TIMES'' - ein internationales Projekt zur Uebertragbarkeit von Bruchzaehigkeitskennwerten von bestrahlten Materialien auf Komponenten und Strukturen - durchgefuehrt, um

Description of scattering material behaviour and damage in inelastic materials; Beschreibung von streuendem Materialverhalten und von Schaedigung bei inelastischen Werkstoffen

Energy Technology Data Exchange (ETDEWEB)

Pensky, H.M.H.

2000-07-01

For realistic numerical simulations of the stress-strain behaviour of structures, models are necessary which describe elastic-inelastic and scattering material behaviour. The developed models simulate elastic, viscoplastic and anisotropic damage material phenomena. An approach is proposed for covering stochastic material beahviour by correspondingly distributed parameters of the deterministic material model. Numerical simulations of biaxial material tests and structural tests demonstrate the range of applicability. (orig.) [German] Die realitaetsnahe numerische Simulation des Spannungs-Verformungsverhaltens von Bauteilen erfordert Modelle zur Beschreibung inelastischen und streuenden Materialverhaltens. Die hier entwickelten Modelle beschreiben elastische, viskoplastische und anisotrope Schaedigungsphaenomene des Materialverhaltens. Desweiteren wird ein Konzept vorgestellt, mit dem streuendes Materialverhalten mit streuenden Materialparametersaetzen deterministischer Stoffmodelle beschreibbar ist. Numerische Simulationen von Werkstoff- und Bauteilversuchen veranschaulichen den Anwendungsbereich der Modelle. (orig.)

Die Bundesstatistik als Anbieter und Nutzer von raumbezogenen Daten

Directory of Open Access Journals (Sweden)

R. Humbel

Einige konkrete und potentielle Anwendungen der vorhandenen Daten sollen das Potential und die Breite der Fragestellungen, die damit angegangen werden können, illustrieren. Eine besondere Stellung dürfte in Zukunft aber auch die Satellitenfernerkundung erhalten, deren Daten und Auswertungen eine willkommene Ergänzung für die eher traditionellen GIS-Datensätze bilden werden. Ein erster Pilotversuch wurde vor wenigen Monaten im BFS gestartet, der zum Ziel hat, die Machbarkeit einer gesamtschweizerischen Unterscheidung von Laub-, Nadel- und Mischwald als Ergänzung der auf der Grundlage von konventionellen Luftbildern erhobenen Arealstatistik nachzuweisen.

History and Pre-History of the Alexander von Humboldt Foundation

Directory of Open Access Journals (Sweden)

D. Platikanov

2014-02-01

Full Text Available In this paper a short review of the history of Alexander von Humboldt Foundation, Bonn - Bad Godesberg, Germany, on the occasion of its 60th anniversary is presented. This outstanding German foundation is actually the third one with the same name. Earlier two other Alexander von Humboldt Foundations consequently existed and they consist its pre-history, which is also shortly reviewed. The establishment of the present Foundation in 1953, its development and growth, its activities, information about the six presidents and five executive directors, as well as the main features, principles and guidelines are considered. During the last 60 years the Alexander von Humboldt Foundation became an important institution for the promotion of international research cooperation, which significantly influences the world science. It supported more than 27700 Humboldt fellows to carry out scientific research in Germany, and they form a large Humboldt family: a world-wide network. Large number Bulgarian Humboldt fellows are among the best scientists in Bulgaria.

Number-conserving cellular automata with a von Neumann neighborhood of range one

International Nuclear Information System (INIS)

Wolnik, Barbara; Dzedzej, Adam; Baetens, Jan M; De Baets, Bernard

2017-01-01

We present necessary and sufficient conditions for a cellular automaton with a von Neumann neighborhood of range one to be number-conserving. The conditions are formulated for any dimension and for any set of states containing zero. The use of the geometric structure of the von Neumann neighborhood allows for computationally tractable conditions even in higher dimensions. (paper)

Mädchenschule und Geschlecht: Eine fallrekonstruktive Untersuchung der kollektiven Orientierungen und Weiblichkeitskonstruktionen von Schülerinnen monoedukativer Schulen

OpenAIRE

Waburg, Wiebke

2010-01-01

Die Dissertation ist im Rahmen des Projektes "Schulkultur, Geschlechtersegregation und Mädchensozialisation – DIAM" (Projektleitung L. Herwartz-Emden; gefördert von der DFG) entstandenen. In der Arbeit erfolgt die Rekonstruktion der Geschlechtskonstruktionen von Schülerinnen aus Mädchenschulen. Untersucht werden die kollektiven (geschlechtsbezogenen) Orientierungen von Mädchen und jungen Frauen im Alter von 13-19 Jahren. Die Schülerinnen befinden sich in der kulturell definierten Altersphase ...

Energy generation from biomass with the aid of fuel cells; Energetische Nutzung von Biomasse mit Brennstoffzellenverfahren

Energy Technology Data Exchange (ETDEWEB)

NONE

1999-07-01

To provide an opportunity for information exchange at the interface between biomass use for energy generation and developers of fuel cells, the workshop 'Energy generation from biomass with the aid of fuel cells' was held by the Fachagentur Nachwachsende Rohstoffe on 9 and 10 December 1998. The lectures and discussions permit to assess better the opportunities and restraints resulting from the use of biogenous fuel gas in fuel cells. (orig.) [German] Um an der Schnittstelle zwischen der energetischen Nutzung von Biomasse und den Entwicklern von Brennstoffzellen einen Informationsaustausch zu ermoeglichen, wurde am 9. und 10. Dezember 1998 der Workshop 'Energetische Nutzung von Biomasse mit Brennstoffzellenverfahren' von der FNR veranstaltet. Die Vortraege und die Diskussion erlauben eine bessere Einschaetzung der Moeglichkeiten und Restriktionen, die sich bei dem Einsatz von biogenen Brenngasen in Brennstoffzellen ergeben. (orig.)

A newborn with very rare von Voss-Cherstvoy syndrome and literature review

Directory of Open Access Journals (Sweden)

Sharma D

2016-07-01

Full Text Available Deepak Sharma,1 Basudev Gupta,2 Sweta Shastri,3 Pradeep Sharma4 1Department of Pediatrics, Pt. Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, 2Department of Pediatrics, Civil Hospital, Palwal, Haryana, 3Department of Pathology, N.K.P. Salve Medical College, Nagpur, Maharashtra, 4Department of Medicine, Mahatma Gandhi Medical College and Research Institute, Jaipur, Rajasthan, India Introduction: von Voss-Cherstvoy syndrome is a part of a group of syndromes with radial and hematologic abnormalities, and until now approximately ten cases have been reported in the literature. This syndrome is characterized by a triad of radial ray defects, occipital encephalocele, and urogenital abnormalities.Case presentation: We report a neonate from Indian ethnicity who was diagnosed with von Voss-Cherstvoy syndrome. The neonate had radial ray defect, occipital encephalocele, tetralogy of Fallot, and bilateral agenesis of kidney, ureter, and bladder. The neonate was suspected to have von Voss-Cherstvoy syndrome on the basis of clinical features, which was further confirmed by fibroblast analysis showing somatic mosaicism for del(13q.Conclusion: von Voss-Cherstvoy syndrome is a very rare syndrome that can be suspected on the basis of typical clinical features and confirmed by fibroblast analysis showing somatic mosaicism for del(13q. This adds a second case of this chromosome anomaly described in this syndrome. Keywords: von Voss-Cherstvoy syndrome, radial ray defects, occipital encephalocele, urogenital abnormalities, somatic mosaicism for del(13q

Von eingebetteten Systemen zu Cyber-Physical Systems

Science.gov (United States)

Wedde, Rorst F.; Lehnhoff, Sebastian; Rehtanz, Christian; Krause, Olav

Das Hauptanliegen des Papiers ist, ein Paradigma für Probleme mit neuartigen Integrationsanforderungen für Forschung und Entwicklung in verteilten eingebetteten Echtzeitsystemen zu motivieren und vorzustellen, nämlich den Begriff Cyber-Physical Systems. Bei einer in letzter Zeit stark zunehmenden Anzahl von Realzeitanwendungen können ohne die Berücksichtigung solcher Forderungen keine praktisch brauchbaren Lösungen erwartet werden. Einige Anwendungsfelder werden angesprochen. Im Einzelnen werden dann für Elektroautos, die mit erneuerbaren Energien betrieben werden sollen, einerseits die Management-, verteilte Verhandlungs- und Verteilungsprobleme der benötigten Energie in einem bottom-up Ansatz gelöst. Andererseits wird als Teil unserer Projektarbeit die Bereitstellung von Reserveenergie für den allgemeinen Bedarf durch Autobatterien vorgestellt. Es zeigt sich, dass dies effizienter und wesentlich kurzfristiger in unserem verteilten Vorgehen geschehen kann als in traditionellen Verfahren.

Einfluss von Informationskompetenz-Veranstaltungen auf die Qualität von Masterarbeiten

Directory of Open Access Journals (Sweden)

Gary Seitz

2016-02-01

Full Text Available Am Geographischen Institut der Universität Zürich haben die Studierenden, welche als erster Jahrgang die IK-Veranstaltung als Pflichtmodul absolvierten, ihre Masterarbeit abgeschlossen. Mit einer quantitativen Auswertung wird untersucht, ob sich die Qualität der Quellen in den Masterarbeiten verbessert hat. Dazu werden die Literaturverzeichnisse einer bibliometrischen Analyse unterzogen. Anschliessend werden die erhaltenen Werte mit denjenigen verglichen, welche von Arbeiten ohne IK-Schulung erhoben wurden. Diese Methodik könnte ein Werkzeug darstellen, um Informationskompetenz-Veranstaltungen bezüglich ihrer Relevanz für wissenschaftliches Arbeiten evaluieren zu können.

Cofermentation of energy crops and organic residues; Ergebnisse der Kovergaerung von Energiepflanzen und organischen Reststoffen

Energy Technology Data Exchange (ETDEWEB)

Linke, B. [Institut fuer Agrartechnik Bornim e.V. (ATB), Potsdam-Bornim (Germany); Vollmer, G.R. [Biotechnologie Nordhausen (BTN) (Germany)

2002-07-01

There are currently more than 1500 agricultural biogas plans in Germany, most of which work by the liquid fermentation principle which is commercially available. At a mean hydraulic time of residue of 20 - 30 days and a charge of about 1.5 to 4 kg of organic matter m{sup -1}d{sup -1}, about 350 - 550 l of biogas can be produced per kg of organic matter (liquid or solid manure). Biogas yields are higher for cofermentation of liquid manure with energy crops and/or high-energy organic residues. Some figures are given: About 1000 l per kg{sup -1} for beetroot, pressed pellets of rape, sugarbeet, or rye, 600 - 700 l per kg{sup -1} for grass, malt residuum, sugar pulp, grape cake or potato pulp. In the case of silo-fermented corn, yields were higher than reported in earlier publications, i.e. about 800 instead of 200 l per kg{sup -1}. [German] Die Gewinnung von Biogas aus Guelle, Stallmist, pflanzlichen Biomassen oder organischen Reststoffen aus der Agro- oder Lebensmittelindustrie leistet heute durch das EEG in ueber 1500 Landwirtschaftsbetrieben Deutschlands einen Beitrag zur Sicherung des Einkommens. Die Landwirte nutzen hierfuer vorwiegend die Technik der Fluessigvergaerung, die von zahlreichen Firmen auf dem Markt angeboten werden. Bei mittleren hydraulischen Verweilzeiten von 20 bis 30 Tagen oder Faulraumbelastungen von etwa 1,5 bis 4 kg oS m{sup -3} d{sup -1} koennen aus Guelle oder Stallmist je kg zugefuehrte organische Substanz 350 bis 550 l Biogas gewonnen werden. Deutlich hoehere spezifische Biogasausbeuten erhaelt man durch die gemeinsame Vergaerung von Guelle mit Energiepflanzen und/oder energiereichen organischen Reststoffen (Kofermentation). Fuer Ruebensilage, Rapskuchen, Zuckerrueben-Pressschnitzel oder Roggen kann man oS-Biogasausbeuten von etwa 1000 l kg{sup -1} rechnen, waehrend sich der entsprechende Wert fuer Graeser, Schlempe, Melasse, Trester oder Kartoffelpuelpe im Bereich von 600 bis 700 l kg{sup -1} bewegt. Der in der Fachliteratur oft zu

Aufnahme, Analyse und Visualisierung von Bewegungen nativer Herzklappen in-vitro

Science.gov (United States)

Weiß, Oliver; Friedl, Sven; Kondruweit, Markus; Wittenberg, Thomas

Die hohe Zahl an Transplantationen von Herzklappen und viele nötige Re-Operationen machen eine detaillierte Analyse der Strömungen und Klappenbewegungen klinisch interessant. Ein neuer Ansatz ist hierbei der Einsatz von Hochgeschwindigkeitskameras um Bewegungsabl äufe der Herzklappen beobachten und auswerten zu können. Die hohen Datenraten erfordern allerdings eine möglichst automatisierte Analyse und möglichst komprimierte Darstellung des Schwingungsverhaltens. In dieser Arbeit wird ein Ansatz vorgestellt, bei dem Bewegungen nativer Herzklappen in-vitro aufgenommen, analysiert und kompakt visualisiert werden.

Von-Willebrand Disease Presenting as Intractable Epistaxis after Nasal Polypectomy

Directory of Open Access Journals (Sweden)

Jeong Jin Park

2014-01-01

Full Text Available Von-Willebrand disease (VWD is one of the platelet dysfunction disorders that results from a deficiency of Von-Willebrand factor, which is essential for hemostasis. VWD patients typically have normal laboratory results on screening for bleeding disorders. To suspect and diagnose VWD, a careful review of past medical history and laboratory tests is critical. A 59-year-old male patient presented with intractable nasal bleeding after nasal polypectomy. The bleeding was controlled by platelet transfusion, and he was later diagnosed with VWD.

Von Hippel–Lindau disease

Directory of Open Access Journals (Sweden)

Juhara Haron

2017-04-01

Full Text Available Von Hippel–Lindau (VHL disease is a rare autosomal dominantly inherited multisystem disorder characterised by the development of a variety of benign and malignant tumours. We report a case of VHL disease that was inherited by a daughter from her father, who both presented at a young age with progressive headache and were found to have a posterior fossa haemangioblastoma (HB on magnetic resonance imaging (MRI. Multiple benign pancreatic and renal cysts were also noted in both patients.

Marktorientierte Vertriebs-Reorganisation von Energieversorgungsunternehmen

OpenAIRE

Beutin, Nikolas; Scholl, Michael; Fürst, Andreas

2003-01-01

Seit der Liberalisierung des Energiemarktes im Jahre 1998 sehen sich Energieversorgungsunternehmen (EVUs) einer veränderten Markt- und Wettbewerbssituation gegenüber. Neben Risiken, wie dem Eintritt von Wettbewerbern in das vormals geschützte Gebiet, eröffnete sich ihnen hierdurch aber auch die Chance, außerhalb des eigenen Netzbereiches neue Kunden zu gewinnen. Um sowohl dem Margenverfall als auch der direkten Vergleichbarkeit mit ...

Moose von Inselbergen in Benin

OpenAIRE

Frahm, Jan-Peter; Porembski, Stefan

1998-01-01

Acht Leber- und zehn Laubmoosarten werden von Inselbergen aus Benin angegeben. Fünf der Lebermoose (Acrolejeunea emergens, Riccia atropurpurea, R. congoana, R. discolor, R. moenkemeyeri) und alle Laubmoose (Archidium ohioense, Brachymenium acuminatum, B. exile, Bryum arachnoideum, B. argenteum, Bryum deperssum, Garckea moenkemeyeri, Hyophila involuta, Philonotis mniobryoides und Weissia cf. edentula) werden neu für Benin angegeben. Eight liverworts and ten mosses are reported from inselber...

Ueber eine Anomalie von Acromitus flagellatus (Stiasny)

NARCIS (Netherlands)

Stiasny, G.

1934-01-01

Bei erneuter Durchsicht des reichhaltigen Materiales von Acromitus flagellatus (Stiasny) in der Scyphomedusen-Sammlung des Rijksmuseum van Natuurlijke Historie in Leiden (vergl. meine Mitteilungen daruber, 1920, Uebersichtstabelle III und 1921, p. 131/136) fand ich ein Exemplar, das eine

Von der lernenden Region zur "Smart Region“

OpenAIRE

Poschwatta, Wolfgang

2004-01-01

Von der lernenden Region zur "Smart Region“ / M. Hilpert, W. Poschwatta. - In: Nabizadeh-Araghi, Nima : Auf dem Weg zur "Smart Region" : regionale Entwicklung am Beispiel der Pistazienproduktion im Iran. - Augsburg : Müllerdruck, 2004. - S. 5-9. - (Terra facta ; 2)

UBER DIE SCHREIBUNG UND RECHTSCHREIBUNG MIT BESONDERER RÜCKSICHT AUF DIE RECHTSCHREIBUNGSLÖSUNGEN IN "FLUMINENSIA" VON FRAN KURELAC

Directory of Open Access Journals (Sweden)

Lada Badurina

1990-01-01

Full Text Available Im Artikel sind zunächst Grundsetzen der Schreibung und der Rechtschreibung dargestellt, demnach die Schreibung und die Rechtschreibung in "Fluminensia" von Fran Kurelac. Die von Kurelac vorgeschlagenen Lösungen sind mit den Lösungen seiner unmittelbaren Vorgänger und Zeitgenossen vergleicht, sowie mit der heutigen Rechtschreibungspraxis. Für die von Kurelac vorgeschlagne Schreibung ist festgestellt, daß es sich um ein beständiges System handelt, das von der Tradition ausgeht und das sich nur in eingen Lösungen von heutigen unterscheidet. In der Rechtschreibung überwiegt der morphologische Grundsatz, was leicht in Verbindung mit den Grundgedanken der Philologischen Schule in Rijeka zu steilen ist.

Quality management and reduction of processing time through automised preforming in the rotorblade manufacturing for wind turbines; Teilautomatisiertes preforming zur Qualitaetssicherung und Verkuerzung von Fertigungszeiten bei der Herstellung von Rotorblaettern von Windenergieanlagen

Energy Technology Data Exchange (ETDEWEB)

Doersch, C.; Ohlendorf, J.H.; Gebauer, I.; Mueller, D.H. [Bremer Institut fuer Konstruktionstechnik, Universitaet Bremen (Germany); Weigel, L. [Abeking Rasmussen Rotec GmbH and Co. KG, Lemwerder (Germany)

2007-11-15

Rotor blades of wind turbines are mainly manufactured from fibre reinforced plastics. These materials show an excellent performance concering the ratio of stiffness and weight. Basically the composite material of rotor blades is made out of glass fibres and thermosetting material. But growing technological and economical requirements to rotor blades by off-shore-application, in particular through increasing rotor blade diameter, have to meet successful. Although reduction of processing time and increased quality of rotor blades play a major role. To achieve the increasing requirements of the rotor blade manufacturing the Bremen Institute for Engineering Design and the rotor blade manufacturer Abeking and Rasmussen Rotec GmbH are working together on the handling and manufacturing of textile preforms. Preforms are made out of stacked and bonded dry textile layers and deposited in the mould as one textile part. Preforming allows the parallel processing of some manufacturing steps. This shows great advantages in the production of fibre reinforced plastics because of the long curing time of the resin component. This parallel processing is required to reach the aim of decreased overall cycle time. This essay is focussing on the handling of textiles and the textile preforming. Summarised aspects of quality management and economics in textile preforming will be discussed with the aim of automising the preforming process. (Abstract Copyright [2007], Wiley Periodicals, Inc.) [German] Rotorblaetter von Windenergieanlagen werden aufgrund des guten Verhaeltnisses von Steifigkeit und Gewicht zu grossen Teilen aus Faserverbundwerkstoffen gefertigt. Dabei kommen hauptsaechlich Glasfasern (GF) als verstaerkendes Material sowie duroplastische Harze als Matrix zur Anwendung. Um die wachsenden Herausforderungen des Offshore-Einsatzes von Windenergieanlagen, insbesondere die steigende Rotorblattgroesse, technisch und wirtschaftlich erfolgreich bewaeltigen zu koennen, wird die

MuSiK Projekt:Multimaterialdruck von C/Si/SiC-Keramiken

OpenAIRE

Marigo, Gloria; Wahl, Larissa; Nauditt, Gotthard

2017-01-01

Poster über den ersten 6 Monate von MuSiK Projekt. Additive Verfahren wurden ursprünglich zur effizienten Herstellung von Mustern und Prototypen entwickelt und bieten besondere Einsatzpotentiale, die mittlerweile auch für die Kleinserienproduktion hochinteressant sind. Im Bereich der keramischen Komponenten ist der Einsatz additiver Verfahren bislang nicht weit verbreitet. Ein Grund dafür ist unter anderem die eingeschränkte Verfügbarkeit der notwendigen Fertigungsanlagen und entsprech...

Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy

Science.gov (United States)

Ibeawuchi, Chinyere; Schmidt, Hartmut; Voss, Reinhard; Titze, Ulf; Abbas, Mahmoud; Neumann, Joerg; Eltze, Elke; Hoogland, Agnes Marije; Jenster, Guido; Brandt, Burkhard; Semjonow, Axel

2015-01-01

The multifocal nature of prostate cancer (PCa) creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0–9.7 (mean 5.4) years, copy number variation (CNV) data was evaluated for association with patients’ PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2–10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05). The implication of PTEN and FAS loss (10q23.31) support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2–10q23.31) may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy. PMID:25679447

Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy

Directory of Open Access Journals (Sweden)

Chinyere Ibeawuchi

2015-02-01

Full Text Available The multifocal nature of prostate cancer (PCa creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0–9.7 (mean 5.4 years, copy number variation (CNV data was evaluated for association with patients’ PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2–10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05. The implication of PTEN and FAS loss (10q23.31 support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2–10q23.31 may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy.

Konzepte und Methoden zur Qualitätssicherung bei der Produktion von hypertextuellen Online-Lernumgebungen

Directory of Open Access Journals (Sweden)

Christian Swertz

2002-04-01

Full Text Available Die didaktische Ontologie der Webdidaktik ermöglicht die Qualitätssicherung von Prozessen und Ergebnissen bei der Produktion von Online- Lernumgebungen. Die Qualität wird durch die am pädagogischen Prozess beteiligten Menschen bestimmt. Der Qualitätssicherungsprozess kann durch Software unterstützt werden. Für diese Prozesse der Qualitätssicherung bringt der Autor Beispiele aus dem Lerndorf (www.lerndorf.de und der Lernumgebung des von der Deutschen Bundesstiftung Umwelt geförderten Forschungs- und Entwicklungsprojekt «Zentrum für Umweltwissen und Bildung» (ZUB.

Multifocal spinal hemangioblastoma in von Hippel-Lindau syndrome: A case report and literature review

Energy Technology Data Exchange (ETDEWEB)

Kim, Ok Hwa [Dept. of Radiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan (Korea, Republic of)

2015-03-15

Hemangioblastoma is a benign vascular neoplasm of the central nervous system that occurs frequently in the cerebellum and other areas of the central nervous system including spinal cord and brainstem. Spinal hemangioblastoma can present as a sporadic isolated lesion or as a component of von Hippel-Lindau syndrome. The author presents a case of 32-year-old man with von Hippel-Lindau syndrome and spinal hemangioblastomas represented by multiple small spinal lesions, with an emphasis on the magnetic resonance imaging findings and clinical characteristics of von Hippel-Lindau syndrome-associated spinal hemangioblastomas.