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Sample records for vhl von hippel-lindau

  1. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    These clinical guidelines outline the criteria and recommendations for diagnostic and genetic work-up of families suspected of von Hippel-Lindau disease (vHL), as well as recommendations for prophylactic surveillance for vHL patients. The guideline has been composed by the Danish Coordination Group...... for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations...... cell carcinoma), the adrenal glands (pheochromocytoma), the pancreas, as well as in other organs. As many different organs can be affected, several medical specialities often take part in both diagnosis and treatment of manifestations. vHL should be suspected in individuals with a family history...

  2. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    These clinical guidelines outline the criteria and recommendations for diagnostic and genetic work-up of families suspected of von Hippel-Lindau disease (vHL), as well as recommendations for prophylactic surveillance for vHL patients. The guideline has been composed by the Danish Coordination Group...... for vHL which is comprised of Danish doctors and specialists interested in vHL. The recommendations are based on longstanding clinical experience, Danish original research, and extensive review of the international literature. vHL is a hereditary multi-tumour disease caused by germline mutations...... of the disease, and/or in individuals with a vHL-associated manifestation; i.e. a hemangioblastoma in the retina or the central nervous system, familial or bilateral pheochromocytomas, familial, multiple, or early onset renal cell carcinomas, and in individuals with an endolymphatic sac tumour in the inner ear...

  3. 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...... the challenges of prophylactic ELST screening and to explore the role of audiometry in pre-symptomatic ELST screening....

  4. Surveillance in von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Poulsen, Marie Louise Mølgaard; Budtz-Jørgensen, E; Bisgaard, M L

    2010-01-01

    54 living vHL-mutation carriers, risks of intercurrent manifestations in-between surveillance examinations were determined and clinical consequences of surveillance findings evaluated. Current recommendations of annual ophthalmic and abdominal examinations corresponded to acceptably low intercurrent...... for the patient. Also, pre-symptomatic surveillance increased cumulative incidence of clinical vHL diagnosis from 46% to 72% and from 89% to 94% by age 30 and 50 years, respectively. The present results promote optimization of surveillance, expectantly improving clinical vHL outcomes....

  5. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    cell carcinoma), the adrenal glands (pheochromocytoma), the pancreas, as well as in other organs. As many different organs can be affected, several medical specialities often take part in both diagnosis and treatment of manifestations. vHL should be suspected in individuals with a family history...

  6. Von Hippel-Lindau disease (vHL)

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Bisgaard, Søs Marie Luise; Harbud, Vibeke

    2013-01-01

    in the VHL gene. vHL is inherited in an autosomal dominant manner. Predisposed individuals are advised to undergo prophylactic examinations, as they are at lifelong risk of developing multiple cysts and tumours, especially in the cerebellum, the spinal cord, the retina (hemangioblastomas), the kidneys (renal...... are recommended to start in infancy with annual paediatric examinations and ophthalmoscopy until the age of five years. From five to 14 years, annual plasma-metanephrine and plasma-normetanephrine tests, as well as annual hearing examinations are added. Also, an MRI (Magnetic Resonance Imaging) examination....../MRI of the abdomen, e) annual plasma-metanephrine, plasma-normetanephrine, and plasma-chromogranin A tests, and f) annual hearing examination at a department of audiology. It is advised that one doctor takes on the responsibility of coordination of and referral to the many examinations, and the communication...

  7. De ziekte van Von Hippel-Lindau

    NARCIS (Netherlands)

    Los, M.; Links, T.P.; Lenders, J.W.M.; Voest, E.E.

    2000-01-01

    Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited cancer syndrome. The disease was diagnosed in three patients: a 22-year-old woman who presented with decreased vision due to retinal angiomatosis and in whom a renal carcinoma was diagnosed five years later at a routine VHL analysis,

  8. Hypoxia-inducible factor-2α stabilizes the von Hippel-Lindau (VHL) disease suppressor, Myb-related protein 2.

    Science.gov (United States)

    Okumura, Fumihiko; Joo-Okumura, Akiko; Nakatsukasa, Kunio; Kamura, Takumi

    2017-01-01

    Ubiquitin ligase von Hippel-Lindau tumor suppressor (pVHL) negatively regulates protein levels of hypoxia-inducible factor-α (HIF-α). Loss of pVHL causes HIF-α accumulation, which contributes to the pathogenesis of von Hippel-Lindau (VHL) disease. In contrast, v-Myb avian myeloblastosis viral oncogene homolog-like 2 (MYBL2; B-Myb), a transcription factor, prevents VHL pathogenesis by regulating gene expression of HIF-independent pathways. Both HIF-α and B-Myb are targets of pVHL-mediated polyubiquitination and proteasomal degradation. Here, we show that knockdown of HIF-2α induces downregulation of B-Myb in 786-O cells, which are deficient in pVHL, and this downregulation is prevented by proteasome inhibition. In the presence of pVHL and under hypoxia-like conditions, B-Myb and HIF-2α are both upregulated, and the upregulation of B-Myb requires expression of HIF-2α. We also show that HIF-2α and B-Myb interact in the nucleus, and this interaction is mediated by the central region of HIF-2α and the C-terminal region of B-Myb. These data indicate that oncogenic HIF-2α stabilizes B-Myb to suppress VHL pathogenesis.

  9. [Prenatal exclusion of von Hippel-Lindau syndrome in a Mexican family carrying a novel VHL gene mutation].

    Science.gov (United States)

    Chacón-Camacho, Oscar Francisco; Benitez-Granados, Jesús; Zenteno, Juan Carlos

    2014-03-01

    von Hippel-Lindau (VHL) disease is an autosomal dominant and familial multisystemic syndrome that is caused by the inactivation of the VHL gene and it is characterized by diverse types of high vasculated tumours of benign and malign nature. In this work we describe the clinical characteristics and the prenatal diagnosis of a woman with VHL. Describe the first exclusion prenatal case by DNA analysis of the VHL syndrome in Latinoamerican population. Analysis of a Mexican familial pedigree showed 5 affected subjects with VHL on 3 consecutive generations. The proband was a 7 weeks pregnancy woman who was referred to our service for familiar and personal history of this disease. Maternal DNA was obtained from peripheral blood leukocytes, while fetal DNA was isolated from amniotic liquid cells on the 15th week. The maternal and fetal DNA analysis were done by the Polymerase Chain reaction (PCR) and the direct nucleotide sequence of the VHL gene. A novel mutation (c. 161_168 dup GGAGGCCG) in the VHL gene was identified in maternal DNA. Fetal DNA analysis indicated that the fetus inherited the wild-type allele from the mother. A novel VHL gene mutation was identified in a familial case of the disease, expanding the mutational spectrum in this disorder. The molecular prenatal testing in the affected woman at 15 weeks of gestation, demonstrated that the fetus did nor inherited the mutated allele. To the best of our knowledge, this is the first example of prenatal-molecular exclusion on VHL syndrome in Latinoamerica population.

  10. A patient with bilateral pheochromocytoma as part of a Von Hippel-Lindau (VHL syndrome type 2C

    Directory of Open Access Journals (Sweden)

    Rinkes Inne

    2007-10-01

    Full Text Available Abstract Background Von Hippel-Lindau (VHL disease is an autosomal dominant inherited disease. It is relatively recent that type 2C was identified as a separate group solely presenting with pheochromocytomas. As an illustration, an interesting case is presented of a pregnant woman with refractory hypertension. It proved to be the first manifestation of bilateral pheochromocytomas. The family history may indicate the diagnosis, but only identification of a germ line mutation in the DNA of a patient will confirm carriership. Case presentation A 27 year pregnant patient with intra uterine growth retardation presented with hypertension and pre-eclampsia. Magnetic resonance imaging revealed bilateral adrenal pheochromocytoma. She underwent laparoscopic adrenelectomy and a missense mutation (Gly93Ser in exon 1 of the VHL gene on chromosome 3 (p25 – p26 was shown in the patient, her father and her daughter confirming the diagnosis of VHL. Conclusion In almost all VHL families molecular genetic analysis of DNA will demonstrate an inherited mutation. Because of the involvement in several organs, periodic clinical evaluation should take place in a well coordinated, multidisciplinary setting. VHL disease can be classified into several subtypes. VHL type 2C patients present with pheochromocytomas without evidence of haemangioblastomas in the central nervous system and/or retina and a low risk of renal cell carcinoma. Therefore, in such families, periodic clinical screening can be focussed on pheochromocytomas.

  11. Von Hippel-Lindau (VHL inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.

    Directory of Open Access Journals (Sweden)

    Lee E Moore

    2011-10-01

    Full Text Available Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs. VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5. Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20-1.31 and current: OR = 0.56 (0.32-0.99; P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.

  12. Prevalence, birth incidence, and penetrance of von Hippel-Lindau disease (vHL) in Denmark

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Galanakis, Michael Carter Bisgaard; Budtz-Jørgensen, Esben

    2017-01-01

    . We further used national health registers to identify individuals who fulfilled the clinical diagnostic vHL criteria based on their registered diagnostic codes, but had not been diagnosed with vHL. We also assessed the medical histories of first-degree relatives to identify familial cases. This study...

  13. Kidney Tumor in a von Hippel-Lindau (VHL) Patient With Intensely Increased Activity on 68Ga-DOTA-TATE PET/CT.

    Science.gov (United States)

    Papadakis, Georgios Z; Millo, Corina; Sadowski, Samira M; Bagci, Ulas; Patronas, Nicholas J

    2016-12-01

    Renal and pancreatic cysts and tumors are the most common visceral manifestations of von Hippel-Lindau (VHL) disease, a heritable multisystem cancer syndrome characterized by development of a variety of malignant and benign tumors. We report a case of a VHL patient with multiple renal cystic and complex cystic/solid lesions. The patient underwent Ga-DOTA-TATE-PET/CT showing intensely increased activity by a solid lesion which demonstrated enhancement on both CT and MRI scans, raising high suspicion for malignancy. The presented case indicates application of SSTR-imaging using Ga-DOTA-conjugated peptides in VHL-patients and emphasizes the need for cautious interpretation of renal parenchyma Ga-DOTATATE activity.

  14. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL

    DEFF Research Database (Denmark)

    Staller, Peter; Sulitkova, Jitka; Lisztwan, Joanna

    2003-01-01

    Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source...... regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutation of the VHL...... gene in most cases revealed an association of strong CXCR4 expression with poor tumour-specific survival. These results suggest a mechanism for CXCR4 activation during tumour cell evolution and imply that VHL inactivation acquired by incipient tumour cells early in tumorigenesis confers not only...

  15. Pregnancy-related hemangioblastoma progression and complications in von Hippel-Lindau disease.

    NARCIS (Netherlands)

    Frantzen, C.; Kruizinga, R.C.; Asselt, S.J. van; Zonnenberg, B.A.; Lenders, J.W.M.; Herder, W.W. de; Walenkamp, A.M.; Giles, R.H.; Hes, F.J.; Sluiter, W.J.; Pampus, M.G. van; Links, T.P.

    2012-01-01

    OBJECTIVE: We studied the reciprocal effect of pregnancy and von Hippel-Lindau (VHL) disease by analyzing the influence of pregnancy on VHL disease-related lesions and VHL disease on pregnancy outcome. METHODS: Medical charts and imaging reports from the VHL disease expertise centers in the

  16. Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

    Science.gov (United States)

    Uematsu, Keiji; Byrne, Stuart D.; Hirano, Mie; Joo-Okumura, Akiko; Nishikimi, Akihiko; Shuin, Taro; Fukui, Yoshinori; Nakatsukasa, Kunio

    2016-01-01

    pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxia-inducible factor α (HIF-α) for proteasomal degradation. Although HIF-α activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-α alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-α-independent pathway in VHL pathogenesis. Here, we show that the transcription factor B-Myb is a pVHL substrate that is degraded via the ubiquitin-proteasome pathway and that vascular endothelial growth factor (VEGF)- and/or platelet-derived growth factor (PDGF)-dependent tyrosine 15 phosphorylation of B-Myb prevents its degradation. Mice injected with B-Myb knockdown 786-O cells developed dramatically larger tumors than those bearing control cell tumors. Microarray screening of B-Myb-regulated genes showed that the expression of HIF-α-dependent genes was not affected by B-Myb knockdown, indicating that B-Myb prevents HIF-α-dependent tumorigenesis through an HIF-α-independent pathway. These data indicate that the regulation of B-Myb by pVHL plays a critical role in VHL disease. PMID:27090638

  17. Von Hippel-Lindau Syndrome

    Science.gov (United States)

    ... with an assisted reproduction specialist at a fertility clinic. How common is VHL? It is estimated that about 1 in 30,000 people has VHL. About 20% of people with VHL do not have any family history of the condition. They have a de novo ...

  18. The von Hippel Lindau tumor suppressor limits longevity.

    Science.gov (United States)

    Müller, Roman-Ulrich; Fabretti, Francesca; Zank, Sibylle; Burst, Volker; Benzing, Thomas; Schermer, Bernhard

    2009-12-01

    Many genes are responsible for the modulation of lifespan in model organisms. In addition to regulating adaptive biologic responses that control stress signaling and longevity, some of these genes participate in tumor formation. The mechanisms that determine longevity and link regulation of lifespan with tumorigenesis are poorly understood. Here, we show that the tumor suppressor von Hippel-Lindau (VHL), which has widely known roles in renal carcinogenesis and the formation of kidney cysts, controls longevity in Caenorhabditis elegans. Loss of vhl-1 significantly increased lifespan and resulted in accelerated basal signaling of the p38 mitogen-activated protein kinase PMK-3. Furthermore, the VHL-1 effect on the regulation of lifespan was independent of the insulin/IGF-1-like signaling pathway, suggesting a mechanism for stress resistance that controls both lifespan and tumorigenesis. These findings define VHL-1 as a player in longevity signaling and connect aging, regulation of lifespan, and stress responses with formation of renal cell carcinomas.

  19. Cigarette smoking, von Hippel-Lindau gene mutations and sporadic renal cell carcinoma

    NARCIS (Netherlands)

    Dijk, B.A.C. van; Schouten, L.J.; Oosterwijk, E.; Hulsbergen van de; Kaa, C.A.; Kiemeney, L.A.L.M.; Goldbohm, R.A.; Schalken, J.A.; Brandt, P.A. van den

    2006-01-01

    We investigated whether smoking is associated with mutations in the Von Hippel-Lindau (VHL) gene in 337 cases of sporadic renal cell carcinoma (RCC) among 120 852 people followed for 11.3 years; the findings suggest that smoking causes RCC independently of VHL gene mutations. © 2006 Cancer Research.

  20. Psychosocial impact of Von Hippel-Lindau disease : levels and sources of distress

    NARCIS (Netherlands)

    Lammens, C. R. M.; Bleiker, E. M. A.; Verhoef, S.; Hes, F. J.; Ausems, M. G. E. M.; Majoor-Krakauer, D.; Sijmons, R. H.; van der Luijt, R. B.; van den Ouweland, A. M. W.; Van Os, Tam; Hoogerbrugge, N.; Garcia, E. B. Gomez; Dommering, C. J.; Gundy, C. M.; Aaronson, N. K.

    Von Hippel-Lindau disease (VHL) is a hereditary tumor susceptibility syndrome, characterized by an increased risk of developing multiple benign and malignant tumors at various sites and ages with limited preventive options. This study evaluates the prevalence of distress among VHL family members and

  1. New von Hippel-Lindau manifestations develop at the same or decreased rates in pregnancy

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Budtz-Jørgensen, Esben; Bisgaard, Søs Marie Luise

    2015-01-01

    OBJECTIVE: In a national retrospective cohort study, we aimed to determine the effect of pregnancy on new von Hippel-Lindau (vHL) tumor development during pregnancy and at 1, 3, and 5 years after conception. METHODS: We included 52 VHL mutation carriers (26 men and 26 women) with 581 manifestatio...

  2. Pancreatic cyst development: insights from von Hippel-Lindau disease

    Directory of Open Access Journals (Sweden)

    van Asselt Sophie J

    2013-02-01

    Full Text Available Abstract Pancreatic cysts are a heterogeneous group of lesions, which can be benign or malignant. Due to improved imaging techniques, physicians are more often confronted with pancreatic cysts. Little is known about the origin of pancreatic cysts in general. Von Hippel-Lindau (VHL disease is an atypical ciliopathy and inherited tumor syndrome, caused by a mutation in the VHL tumor suppressor gene encoding the VHL protein (pVHL. VHL patients are prone to develop cysts and neuroendocrine tumors in the pancreas in addition to several other benign and malignant neoplasms. Remarkably, pancreatic cysts occur in approximately 70% of VHL patients, making it the only hereditary tumor syndrome with such a discernible expression of pancreatic cysts. Cellular loss of pVHL due to biallelic mutation can model pancreatic cystogenesis in other organisms, suggesting a causal relationship. Here, we give a comprehensive overview of various pVHL functions, focusing on those that can potentially explain pancreatic cyst development in VHL disease. Based on preclinical studies, cilia loss in ductal cells is probably an important early event in pancreatic cyst development.

  3. Carotenoid and vitamin intake, von Hippel-Lindau gene mutations and sporadic renal cell carcinoma.

    NARCIS (Netherlands)

    Dijk, B.A.C. van; Schouten, L.J.; Oosterwijk, E.; Hulsbergen- van de Kaa, C.A.; Kiemeney, L.A.L.M.; Goldbohm, R.A.; Schalken, J.A.; Brandt, P.A. van den

    2008-01-01

    OBJECTIVE: We investigated whether dietary carotenoid and vitamin intake and supplemental vitamin use were inversely associated with RCC risk and with Von Hippel-Lindau (VHL)-gene mutations in clear-cell renal cell carcinoma (RCC). METHODS: The Netherlands Cohort Study on diet and cancer (NLCS)

  4. Carotenoid and vitamin intake, von Hippel-Lindau gene mutations and sporadic renal cell carcinoma

    NARCIS (Netherlands)

    Dijk, B.A.C. van; Schouten, L.J.; Oosterwijk, E.; Hulsbergen van de; Kaa, C.A.; Kiemeney, L.A.L.M.; Goldbohm, R.A.; Schalken, J.A.; Brandt, P.A. van den

    2008-01-01

    Objective: We investigated whether dietary carotenoid and vitamin intake and supplemental vitamin use were inversely associated with RCC risk and with Von Hippel-Lindau (VHL)-gene mutations in clear-cell renal cell carcinoma (RCC). Methods: The Netherlands Cohort Study on diet and cancer (NLCS)

  5. Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease

    OpenAIRE

    Chávez Mireya; Rodríguez Yaneth; Sosa Ana-Luisa; Yescas Petra; Familiar Itziar; De Biase Irene; Ochoa Adriana; Alonso Elisa; Rasmussen Astrid; López-López Marisol; Bidichandani Sanjay I

    2010-01-01

    Abstract Background von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children. Methods We tested 17 families (n = 109 individuals) for VHL mutations including 43 children under the a...

  6. Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study.

    NARCIS (Netherlands)

    Houwelingen, K.P. van; Dijk, B.A. van; Hulsbergen- van de Kaa, C.A.; Schouten, L.J.; Gorissen, H.; Schalken, J.A.; Brandt, P.A. van den; Oosterwijk, E.

    2005-01-01

    BACKGROUND: Biallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC). We studied the VHL mutation status in a large population-based case group. METHODS: Cases were identified within the

  7. Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry

    NARCIS (Netherlands)

    Bausch, Birke; Wellner, Ulrich; Peyre, Mathieu; Boedeker, Carsten C.; Hes, Frederik J.; Anglani, Mariagiulia; de Campos, Jose M.; Kanno, Hiroshi; Maher, Eamonn R.; Krauss, Tobias; Sanso, Gabriela; Barontini, Marta; Letizia, Claudio; Hader, Claudia; Schiavi, Francesca; Zanoletti, Elisabetta; Suarez, Carlos; Offergeld, Christian; Malinoc, Angelica; Zschiedrich, Stefan; Glasker, Sven; Bobin, Serge; Sterkers, Olivier; Huy, Patrice Tran Ba; Giraud, Sophie; Links, Thera; Eng, Charis; Opocher, Giuseppe; Richard, Stephane; Neumann, Hartmut P. H.

    Background. Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. Methods. Systematic

  8. Alcohol consumption and mutations or promoter hypermethylation of the von Hippel-Lindau gene in renal cell carcinoma.

    NARCIS (Netherlands)

    Schouten, L.J.; Dijk, B.A.C. van; Oosterwijk, E.; Engeland, M. van; Hulsbergen- van de Kaa, C.A.; Kiemeney, L.A.L.M.; Goldbohm, R.A.; Kester, A.; Vogel, S de; Schalken, J.A.; Brandt, P.A. van den

    2008-01-01

    Alcohol consumption has been associated with a decreased risk for renal cell cancer in several studies. We investigated whether alcohol is associated with (epi)genetic changes of the von Hippel-Lindau (VHL) gene in renal cell cancer. The Netherlands Cohort Study (NLCS) on Diet and Cancer started in

  9. Alcohol consumption and mutations or promoter hypermethylation of the von Hippel-Lindau gene in renal cell carcinoma

    NARCIS (Netherlands)

    Schouten, L.J.; Dijk, B.A.C.van; Oosterwijk, E.; Engeland, M. van; Hulsbergen - Kaa, C.A. van de; Kiemeney, L.A.L.M.; Goldbohm, R.A.; Kester, A.; Vogel, S. de; Schalken, J.A.; Brandt, P.A. van den

    2008-01-01

    Alcohol consumption has been associated with a decreased risk for renal cell cancer in several studies. We investigated whether alcohol is associated with (epi)genetic changes of the von Hippel-Lindau (VHL) gene in renal cell cancer. The Netherlands Cohort Study (NLCS) on Diet and Cancer started in

  10. Survival and causes of death in patients with von Hippel-Lindau disease

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Jensen, Annette Møller; Budtz-Jørgensen, Esben

    2017-01-01

    . Surveillance is especially beneficial for truncating mutation carriers, who have the greatest RCC and central nervous system (CNS) hemangioblastoma risk.  Conclusions: vHL survival has improved over time and has become closer to that of siblings without vHL and the general population. Even though the risk of v......Background: Historically, the survival of patients with von Hippel-Lindau disease (vHL) has been poorer than that of the general population. We aimed to determine whether the survival of VHL mutation carriers and their risk of vHL-related death has changed over time and how it has been affected...... by sex, genotype and surveillance attendance.  Methods: In a retrospective cohort study, we included all known Danish vHL families with a VHL mutation. We assessed the survival and causes of death for 143 VHL mutation carriers using Cox regression models and compared vHL survival with that of 137...

  11. A case of von Hippel-Lindau disease with exudative maculopathy

    Directory of Open Access Journals (Sweden)

    Basel T Ba′arah

    2009-01-01

    Full Text Available Von Hippel-Lindau (VHL disease is a rare multisystem familial tumor syndrome of autosomal dominant inheritance. Hallmark lesions include retinal, cerebellum and spinal cord hemangioblastomas, renal cell carcinomas, adrenal pheochromocytomas, angiomatous or cystic lesions of the kidneys, pancreas, and epididymis. We report a case of VHL disease in a 26-year-old patient who presented with exudative macular edema. Ocular and systemic studies revealed the presence of retinal and central nervous system hemangioblastomas, adrenal pheochromocytoma, multiple pancreatic, and kidney cysts. The retinal angiomas were successfully treated with argon laser photocoagulation and cryotherapy.

  12. Pathology of the Nervous System in Von Hippel-Lindau Disease

    Directory of Open Access Journals (Sweden)

    Alexander O. Vortmeyer

    2015-06-01

    Full Text Available Von Hippel-Lindau (VHL disease is a tumor syndrome that frequently involves the central nervous system (CNS. It is caused by germline mutation of the VHL gene. Subsequent VHL inactivation in selected cells is followed by numerous well-characterized molecular consequences, in particular, activation and stabilization of hypoxia-inducible factors HIF1 and HIF2. The link between VHL gene inactivation and tumorigenesis remains poorly understood. Hemangioblastomas are the most common manifestation in the CNS; however, CNS invasion by VHL disease-associated endolymphatic sac tumors or metastatic renal cancer also occur, and their differentiation from primary hemangioblastoma may be challenging. Finally, in this review, we present recent morphologic insights on the developmental concept of VHL tumorigenesis which is best explained by pathologic persistence of temporary embryonic progenitor cells. 

  13. 68Ga-DOTA-NOC PET/CT detects somatostatin receptors expression in von hippel-lindau cerebellar disease.

    Science.gov (United States)

    Ambrosini, Valentina; Campana, Davide; Allegri, Vincenzo; Opocher, Giuseppe; Fanti, Stefano

    2011-01-01

    A case of Von-Hippel Lindau (VHL) disease has been studied using 68Ga-DOTA-NOC PET/CT. PET/CT demonstrated the presence of somatostatin receptors within 2 focal areas in the cerebellum corresponding to the lesions detected by MRI. Considering the heterogeneous lesions localizations in VHL disease, PET/CT may be a useful imaging modality for diagnosing lesions of central nervous system and neuroendocrine lesions and for direct demonstration of somatostatin receptors for targeted treatment.

  14. Ga-68 Somatostatin Receptor PET/CT in von Hippel-Lindau Disease

    Energy Technology Data Exchange (ETDEWEB)

    Oh, Jong-Ryool; Min, Jung-Joon [Chonnam National Univ. Hwasun Hospital, Hwasun (Korea, Republic of); Kulkarui, Harshad; Carreras, Cecilia; Schalch, Georg; Baum, Richard P. [Nuclear Medicine and Center for PET/CT, Zentralk Bad Berka, Bad Verka (Germany)

    2012-06-15

    Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome with a variety of benign and malignant tumors such as retinal and central nervous system hemangioblastomas, endolymphatic sac tumors, renalcysts and tumors, pancreatic cysts and tumors, pheochromo-cytomas, and epididymal cystadenomas. Cross-sectional mo-dalities (computed tomography and magnetic resonance imaging) as well as ultrasound play a major role in the initial evaluation and follow-up of the various manifestations of VHL disease. Ga-68-labeled somatostatin receptor analogs already have a significant role in the diagnosis, staging, and therapy management of neuroendocrine neoplasms and neural crest tumors. Herein, we report a case presenting a variety of malignancies in VHL and showing the usefulness of Ga-68 somatostatin receptor PET/CT as a one-stop-shop imaging modality in the management of VHL disease.

  15. Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia

    NARCIS (Netherlands)

    van Rooijen, E.; Voest, E.E.; Logister, I.; Korving, J.; Schwerte, T.; Schulte-Merker, S.; Giles, R.H.; van Eeden, F.J.

    2009-01-01

    We have generated 2 zebrafish lines carrying inactivating germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene ortholog vhl. Mutant embryos display a general systemic hypoxic response, including the up-regulation of hypoxia-induced genes by 1 day after fertilization and a severe

  16. Body Mass Index and von Hippel-Lindau Gene Mutations in Clear-cell Renal Cancer: Results of the Netherlands Cohort Study on Diet and Cancer

    NARCIS (Netherlands)

    Smits, K.M.; Schouten, L.J.; Hudak, E.; Verhage, B.; Dijk, B.A.C. van; Hulsbergen - Kaa, C.A. van de; Goldbohm, R.A.; Oosterwijk, E.; Brandt, P.A. van den

    2010-01-01

    Purpose: Body mass index (BMI) is an important risk factor for clear-cell renal cancer (cc-RCC). A common molecular alteration in cc-RCC is loss-of-function of the von Hippel-Lindau (VHL) gene. We evaluated the association between BMI and VHL mutations in cc-RCC by using data from the Netherlands

  17. 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.

  18. Suppression of von Hippel-Lindau Protein in Fibroblasts Protects against Bleomycin-Induced Pulmonary Fibrosis.

    Science.gov (United States)

    Zhou, Qiyuan; Chen, Tianji; Zhang, Wei; Bozkanat, Melike; Li, Yongchao; Xiao, Lei; van Breemen, Richard B; Christman, John W; Sznajder, Jacob I; Zhou, Guofei

    2016-05-01

    We have reported that von Hippel-Lindau protein (pVHL) expression is elevated in human and mouse fibrotic lungs and that overexpression of pVHL stimulates fibroblast proliferation. We sought to determine whether loss of pVHL in fibroblasts prevents injury and fibrosis in mice that are treated with bleomycin. We generated heterozygous fibroblast-specific pVHL (Fsp-VHL) knockdown mice (Fsp-VHL(+/-)) and homozygous Fsp-VHL knockout mice (Fsp-VHL(-/-)) by crossbreeding vhlh 2-lox mice (VHL(fl/fl)) with Fsp-Cre recombinase mice. Our data show that Fsp-VHL(-/-) mice, but not Fsp-VHL(+/-) mice, have elevated red blood cell counts, hematocrit, hemoglobin content, and expression of hypoxia-inducible factor (HIF) targets, indicating HIF activation. To examine the role of pVHL in bleomycin-induced lung injury and fibrosis in vivo, we administered PBS or bleomycin to age-, sex-, and strain-matched 8-week-old VHL(fl/fl), Fsp-VHL(+/-), and Fsp-VHL(-/-) mice. In Fsp-VHL(+/-) and Fsp-VHL(-/-) mice, bleomycin-induced collagen accumulation, fibroblast proliferation, differentiation, and matrix protein dysregulation were markedly attenuated. Suppression of pVHL also decreased bleomycin-induced Wnt signaling and prostaglandin E2 signaling but did not affect bleomycin-induced initial acute lung injury and lung inflammation. These results indicate that pVHL has a pivotal role in bleomycin-induced pulmonary fibrosis, possibly via an HIF-independent pathway. Paradoxically, pVHL does not affect bleomycin-induced lung injury and inflammation, indicating a separation of the mechanisms involved in injury/inflammation from those involved in pulmonary fibrosis.

  19. Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene

    Energy Technology Data Exchange (ETDEWEB)

    Gross, D.J.; Avishai, N.; Meiner, V.; Abeliovich, D.; Filon, D. [Hadassah Univ. Hospital and the Hebrew Univ.-Hadassah Medical School, Jerusalem (Israel)] [and others

    1996-01-01

    We report a three generation, 25 member kindred with familial pheochromocytoma. Seven subjects of generations I and II had pheochromocytoma, in five of the seven, the tumors were bilateral, and in two of the seven, the tumors were both adrenal and extraadrenal. One patient also had a carotid body chemodectoma, and one patient had a malignant adrenal tumor and abdominal paraganglioma. In the patient with the chemodectoma, a cerebellar hemagioblastoma became manifest 25 yr after his initial diagnosis with pheochromocytoma, leading only then to a clinical diagnosis of von Hippel-Lindau disease (VHL). A mutational analysis of the VHL gene revealed a novel nucleotide 709 G{r_arrow}T transversion present in all affected subjects and in four presymptomatic children. In familial pheochromocytoma the diagnosis of VHL should be considered, even when the formal criteria for diagnosis of the syndrome are lacking. 16 refs., 2 figs.

  20. Risk of new tumors in von Hippel-Lindau patients depends on age and genotype

    DEFF Research Database (Denmark)

    Binderup, Marie Louise Mølgaard; Budtz-Jørgensen, Esben; Bisgaard, Søs Marie Luise

    2016-01-01

    PURPOSE: The von Hippel-Lindau (vHL) phenotype is variable, which complicates genetic counseling and surveillance. We describe how the rate of new tumor development varies through the lifetimes of vHL patients and how it is influenced by age and genotype. METHODS: In a national cohort study, we...... is not constant throughout the life span of vHL patients; instead, it varies significantly with age and genotype and depends on anatomical location. Retinal surveillance is crucial during the teenage years, whereas cerebellar surveillance is especially important in adulthood.Genet Med advance online publication...... 02 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.44....

  1. SOMATIC MUTATIONS OF THE VON HIPPEL-LINDAU DISEASE TUMOR-SUPPRESSOR GENE IN NONFAMILIAL CLEAR-CELL RENAL-CARCINOMA

    NARCIS (Netherlands)

    FOSTER, K; PROWSE, A; van den Berg, Anke; FLEMING, S; HULSBEEK, MMF; CROSSEY, PA; RICHARDS, FM; CAIRNS, P; FERGUSONSMITH, MA; BUYS, CHCM; MAHER, ER

    1994-01-01

    Loss of heterozygosity (LOH) studies have suggested that somatic mutations of a tumour suppressor gene or genes on chromosome 3p are a critical event in the pathogenesis of non-familial renal cell carcinoma (RCC). Germline mutations of the von Hippel - Lindau (VHL) disease gene predispose to early

  2. Tid-1 interacts with the von Hippel-Lindau protein and modulates angiogenesis by destabilization of HIF-1alpha.

    Science.gov (United States)

    Bae, Moon-Kyoung; Jeong, Joo-Won; Kim, Se-Hee; Kim, Soo-Young; Kang, Hye Jin; Kim, Dong-Min; Bae, Soo-Kyung; Yun, Il; Trentin, Grace A; Rozakis-Adcock, Maria; Kim, Kyu-Won

    2005-04-01

    The von Hippel-Lindau protein (pVHL) is a major tumor suppressor protein and also associated with the inhibition of angiogenesis via HIF-1alpha ubiquitination and proteasomal degradation. To further elucidate the biological activity of pVHL in angiogenesis, pVHL-interacting proteins were screened using the yeast two-hybrid system. We found that a mouse homologue of the long form of Drosophila tumor suppressor l(2)tid, Tid-1(L), directly interacts with pVHL in vitro and in vivo. Furthermore, Tid-1(L) protein; enhanced the interaction between HIF-1alpha and pVHL, leading to the destabilization of HIF-1alpha protein; therefore, Tid-1(L) protein decreased vascular endothelial growth factor expression and inhibited angiogenesis in vivo and in vitro. These findings propose that Tid-1(L) may play a critical role in pVHL-mediated tumor suppression by modulating the pVHL-dependent HIF-1alpha stability.

  3. Managing Renal Cell Carcinoma Associated Paraneoplastic Syndrome with Nephron-sparing Surgery in a Patient with von Hippel-Lindau

    Directory of Open Access Journals (Sweden)

    John M. DiBianco

    2017-07-01

    Full Text Available A patient with germline von Hippel-Lindau (VHL gene alteration and history of multiple tumors present with classical paraneoplastic syndrome (PNS associated with renal cell carcinoma (RCC. She underwent open nephron sparing surgery with resolution of symptoms. She remained without recurrence of RCC for the initial 2 years of her follow-up. To the best of our knowledge, this case represents the first in which PNS was specifically resolved using a partial nephrectomy in a patient with VHL. This case report provides initial evidence for the potential role of nephron sparing surgery in the management of paraneoplastic symptoms associated with hereditary RCC.

  4. Von Hippel-Lindau Syndrome: Diagnosis and Management of Hemangioblastoma and Pheochromocytoma

    Directory of Open Access Journals (Sweden)

    P. Vaganovs

    2013-01-01

    Full Text Available Introduction. Von Hippel-Lindau (VHL syndrome is a pathological condition that causes various clinical symptoms and is difficult to diagnose. The most common pathological lesions are hemangioblastomas of the central nervous system, retinal angiomas, renal clear cell carcinomas, and pheochromocytomas. Case Report. A 23-year-old female had a syncope episode in 2008. Magnetic resonance imaging (MRI revealed a right temporal hemangioblastoma, which was treated surgically. Genetic screening identified a VHL gene mutation, and computed tomography (CT revealed a left adrenal mass. Since it was unclear whether the mass was a pheochromocytoma, or another benign or malignant tumors, laparoscopic adrenalectomy was performed. A month after surgery, the patient complained of general fatigue, poor concentration, loss of appetite, and insomnia. After careful clinical investigation, the patient was referred to a psychiatrist due to suspected depression, which was confirmed. Conclusions. VHL genetic screening should be performed in cases of hemangioblastoma. In VHL syndrome cases, pheochromocytoma cannot always be diagnosed by biochemical catecholamine analyses; therefore, CT or MRI scanning of the abdomen must be performed. Due to the long treatment period, some patients may develop episodes of depression, which can simulate VHL syndrome.

  5. Von Hippel-Lindau disease: an evaluation of natural history and functional disability

    Science.gov (United States)

    Feletti, Alberto; Anglani, Mariagiulia; Scarpa, Bruno; Schiavi, Francesca; Boaretto, Francesca; Zovato, Stefania; Taschin, Elisa; Gardi, Mario; Zanoletti, Elisabetta; Piermarocchi, Stefano; Murgia, Alessandra; Pavesi, Giacomo; Opocher, Giuseppe

    2016-01-01

    Background Although many studies have been published about specific lesions characterizing von Hippel-Lindau(VHL) disease, none have dealt with the natural history of the whole disease and the consequent disabilities. We aim to define the comprehensive natural history of VHL disease and to describe the functional disabilities and their impact upon patients' quality of life, thereby tailoring the follow-up schedule accordingly. Methods We performed a prospective analysis on 128 VHL-affected patients beginning in 1996. For each affected organ, we defined intervals between the first and subsequent VHL-related manifestations and compared them with current VHL surveillance protocols. We looked for any association of the number of involved organs with age, sex, type of VHL gene mutation, and functional domain mutation. Ultimately, we assessed the organ-specific disabilities caused by VHL disease. Results Hemangioblastomas show different patterns of progression depending on their location, whereas both renal cysts and carcinomas have similar progression rates. Surgery for pheochromocytoma and CNS hemangioblastoma is performed earlier than for pancreatic or renal cancer. The number of involved organs is associated with age but not with sex, type of VHL gene mutation, or functional domain mutation. A thorough analysis of functional disabilities showed that age is related to the first-appearing functional impairment, but it is not predictive of the final number of disabilities. Conclusions Our study defines the disease progression and provides a comprehensive view of the syndrome over time. We analyzed for the first time the functional disability of VHL patients, assessing the progression for each function. PMID:26763786

  6. Cytogenetic abnormalities in tumors of patients with von Hippel-Lindau disease.

    Science.gov (United States)

    Jordan, D K; Patil, S R; Divelbiss, J E; Vemuganti, S; Headley, C; Waziri, M H; Gurll, N J

    1989-10-15

    Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that causes the development of benign and malignant tumors in several organ systems. Tumors causing significant morbidity include retinal angioma, cerebellar hemangioblastoma (CH), renal cell carcinoma (RCC), and pheochromocytoma (Pheo). Cytogenetic studies of tumors in VHL patients are rare. Cytogenetic findings in tumors from 12 patients with VHL disease, including four RCCs, three CHs, and five Pheos are presented. Three of the four RCC cases were abnormal. Monosomy 3 or a deletion of 3p was present in all three abnormal cases. Complete or partial trisomy of chromosome 5 was present in two cases. A deletion of 14q, trisomy 7, and a missing Y were each observed in one case. These findings indicate that a deletion of 3p may be a primary cytogenetic change in RCCs associated with VHL disease in addition to playing a role in sporadic RCC. Duplications of 5q and deletions of 14q may be important secondary changes in the progression of the malignant phenotype. No visible cytogenetic abnormalities were observed in the three CHs, or in four of the Pheos. One of the five Pheos was found to exhibit mosaic trisomy 7; its significance is unclear at the present time.

  7. Von Hippel-Lindau disease associated with myasthenia gravis not related to thymoma

    Directory of Open Access Journals (Sweden)

    Paolo Pozzato

    2013-04-01

    Full Text Available BACKGROUND Von Hippel-Lindau disease (VHL is a rare autosomal dominant inherited disorder characterized by an increased risk of tumours in a number of locations (eyes, brain, adrenal gland, pancreas, liver, kidneys, or other areas of the body. It is caused by germline mutation in the VHL gene. The VHL gene is a tumour suppressor gene that has been identified on the short arm of chromosome 3. CASE REPORT We report a case of a 60 year-old female with the clinical diagnosis of VHL type 1 (cerebellar haemangioblastoma, pancreatic cysts with subsequent steatorrhoea, and bilateral renal carcinoma who developed weakness and fatigability of skeletal muscles, left lid ptosis, snarling expression and nasal timbre speech. Acetylcholine receptor antibodies were negative in serum, while the electrodiagnostic test demonstrated an alteration of neuromuscolar junction which was consistent with the diagnosis of myasthenia gravis. Contrast-enhanced TC scan of the anterior mediastinum was performed, which excluded thymus enlargement. VHL gene evaluation in this patient identified a new mutation (c279delC9 and polymorphism c291C>G. At present the patient still suffers from ataxia and dysmetria due to cerebellar involvement in VHL, while fatigue and lid ptosis improved after the treatment with oral pyridostigmine 60 mg tid. DISCUSSION AND CONCLUSIONS To our knowledge this is the first report of a case of VHL associated with myasthenia gravis without thymoma. A case of VHL associated with a form of myasthenia gravis related to thymoma has been recently reported. In our case the absence of acetylcholine receptor antibodies may suggest a genetic origin also for the myasthenia gravis.

  8. Endolymphatic sac tumour in von Hippel-Lindau disease: management strategies.

    Science.gov (United States)

    Zanoletti, E; Girasoli, L; Borsetto, D; Opocher, G; Mazzoni, A; Martini, A

    2017-10-01

    Endolymphatic sac tumour (ELST) is infrequent, as emerges from small series reported in the literature. It is a slow-growing malignancy with local aggressiveness and a low risk of distant metastases. It is often misdiagnosed because of the late onset of symptoms and difficulty in obtaining a biopsy. Its frequency is higher in von Hippel-Lindau (VHL) disease (a genetic systemic syndrome involving multiple tumours), with a prevalence of around 25%. The diagnosis is based on radiology, with specific patterns on contrast-enhanced MRI and typical petrous bone erosion on bone CT scan. Our experience of ELST in the years between 2012-2015 concerns 7 cases, one of which was bilateral, in patients with VHL disease. Four of the 7 patients underwent 5 surgical procedures at our institution. Each case is described in detail, including clinical symptoms, and the intervals between symptom onset, diagnosis and therapy. Postoperative morbidity was low after early surgery on small tumours, whereas extensive surgery for large tumours was associated with loss of cranial nerve function (especially VII, IX, X). The critical sites coinciding with loss of neurological function were the fallopian canal, jugular foramen, petrous apex and intradural extension into the posterior cranial fossa. Early surgery on small ELST is advocated for patients with VHL disease, in whom screening enables a prompt diagnosis and consequently good prognosis. © Copyright by Società Italiana di Otorinolaringologia e Chirurgia Cervico-Facciale, Rome, Italy.

  9. von Hippel-Lindau disease: surveillance strategy for endolymphatic sac tumors

    DEFF Research Database (Denmark)

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

    2011-01-01

    : Up to 16% of patients with the hereditary von Hippel-Lindau disease develop endolymphatic sac tumors of the inner ear. Early diagnosis and treatment of endolymphatic sac tumors can prevent audiovestibular morbidity, but optimal endolymphatic sac tumor surveillance strategy has yet...... to be determined. We aimed to evaluate endolymphatic sac tumor surveillance to determine the best surveillance strategy....

  10. Management of renal cell carcinoma in von Hippel-Lindau disease.

    Science.gov (United States)

    Hes, F J; Slootweg, P J; van Vroonhoven, T J; Hené, R J; Feldberg, M A; Zewald, R A; Ploos van Amstel, J K; Höppener, J W; Pearson, P L; Lips, C J

    1999-01-01

    An evaluation of nephron-sparing surgery (NSS) or radical nephrectomy (RN) for treating renal cell carcinoma (RCC) in patients with von Hippel-Lindau disease (VHL) was carried out. Between 1976 and 1997, 10 patients with RCC from four VHL families, of whom seven were from one family, were studied by clinical and histopathological examination. Before 1991, three patients were treated using RN, and thereafter five patients were treated using NSS. Two patients were not operated on. RCCs in our patients showed a slow growth rate (on average 0.3 cm year-1), and asymptomatic patients presented with tumours of low-grade malignancy. In all patients, tumours were surrounded by a fibrous pseudocapsule. In 5 out of 17 tumours, pseudocapsular invasion was observed, and three of these five tumours broke through the pseudocapsule. To date, these patients have not shown a less favourable outcome than those without pseudocapsular involvement by tumour growth. Multicentricity of RCC was relatively low (4.6 lesions per kidney). In two of the three RN patients, only a single satellite lesion, in the direct vicinity of a RCC, was found in one kidney. Six tumours (1.8-5.5 cm) were enucleated by NSS. During a mean follow-up of 30 months, renal function in these patients was well preserved. In our patients, RCCs grew slowly, were of low grade, had a dense fibrous pseudocapsule and were thus good candidates for NSS.

  11. Implications of Von Hippel-Lindau Syndrome and Renal Cell Carcinoma

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    Kenan Ashouri

    2015-09-01

    Full Text Available Von Hippel-Lindau syndrome (VHLS is a rare hereditary neoplastic disorder caused by mutations in the vhl gene leading to the development of tumors in several organs including the central nervous system, pancreas, kidneys, and reproductive organs. Manifestations of VHLS can present at different ages based on the affected organ and subclass of disease. In the subclasses of VHLS that cause renal disease, renal involvement typically begins closer to the end of the second decade of life and can present in different ways ranging from simple cystic lesions to solid tumors. Mutations in vhl are most often associated with clear cell renal carcinoma, the most common type of renal cancer, and also play a major role in sporadic cases of clear cell renal carcinoma. The recurrent, multifocal nature of this disease presents difficult challenges in the long-term management of patients with VHLS. Optimization of renal function warrants the use of several different approaches common to the management of renal carcinoma such as nephron sparing surgery, enucleation, ablation, and targeted therapies. In VHLS, renal lesions of 3 cm or bigger are considered to have metastatic potential and even small lesions often harbor malignancy. Many of the aspects of management revolve around optimizing both oncologic outcome and long-term renal function. As new surgical strategies and targeted therapies develop, the management of this complex disease evolves.  This review will discuss the key aspects of the current management of VHLS.

  12. Management of endolymphatic sac tumors: sporadic cases and von Hippel-Lindau disease.

    Science.gov (United States)

    Nevoux, Jérôme; Nowak, Catherine; Vellin, Jean-François; Lepajolec, Christine; Sterkers, Olivier; Richard, Stéphane; Bobin, Serge

    2014-06-01

    To analyze the difference between the endolymphatic sac tumors (ELSTs) in sporadic cases and in von Hippel-Lindau (VHL) disease. Retrospective case review in a tertiary referral center. Fourteen cases of ELST, occurring since 1998, were reviewed. We analyzed the initial symptoms, characteristics of the tumor, treatment, sequelae, and follow-up for each group. The ELSTs were sporadic in 6 cases and associated with VHL disease in 8 cases. The mean age at the time of the first surgery was 26 years (range, 12-41). All except two of the patients presented with a unilateral tumor. The initial symptoms were hearing loss (n = 9), tinnitus (n = 7), and/or vertigo (n = 5). Hearing loss was more prevalent in the sporadic cases. Preoperative arteriography was performed for 4 patients, with embolization performed for 1 patient. The size of the tumor was significantly larger in the sporadic cases (31.7 mm) than in the cases of VHL disease (19.3 mm). The surgical approach was more extensive in the sporadic cases. The surgeons found 2 types of tumors. Cystic tumors with massive bleeding invading the surrounding structures (the dura mater or jugular bulb) were more common in the sporadic cases. Fibrous tumors that infiltrate the bone and have moderate bleeding were more common in the cases associated with VHL disease.Two patients with small lesions were not operated on but were followed for 6 years without tumor growth. They died of metastasis from gastric and kidney cancer. Four recurrences occurred during the 14 years of follow-up. Four facial palsies and 8 cases of profound deafness were encountered postoperatively. Sporadic tumors are more aggressive than those associated with VHL disease. Complete surgical resection should be the goal of treatment. Preoperative angiography with embolization is recommended. In some cases, embolization may be impossible, and preoperative or postoperative radiotherapy should be discussed.

  13. Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry.

    Science.gov (United States)

    Bausch, Birke; Wellner, Ulrich; Peyre, Mathieu; Boedeker, Carsten C; Hes, Frederik J; Anglani, Mariagiulia; de Campos, Jose M; Kanno, Hiroshi; Maher, Eamonn R; Krauss, Tobias; Sansó, Gabriela; Barontini, Marta; Letizia, Claudio; Hader, Claudia; Schiavi, Francesca; Zanoletti, Elisabetta; Suárez, Carlos; Offergeld, Christian; Malinoc, Angelica; Zschiedrich, Stefan; Glasker, Sven; Bobin, Serge; Sterkers, Olivier; Ba Huy, Patrice Tran; Giraud, Sophie; Links, Thera; Eng, Charis; Opocher, Giuseppe; Richard, Stephane; Neumann, Hartmut P H

    2016-04-01

    Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers' registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients. Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST. Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. © 2015 Wiley Periodicals, Inc. Head Neck 38: 673-679, 2016. © 2015 Wiley Periodicals, Inc.

  14. Von Hippel-Lindau Disease (VHL)

    Science.gov (United States)

    ... ALS) Information Page NINDS Anencephaly Information Page NINDS Angelman Syndrome Information Page NINDS Antiphospholipid Syndrome Information Page ... ALS) Information Page NINDS Anencephaly Information Page NINDS Angelman Syndrome Information Page NINDS Antiphospholipid Syndrome Information Page ...

  15. Preimplantation genetic diagnosis of Von Hippel-Lindau disease cancer syndrome by combined mutation and segregation analysis

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    Denilce R. Sumita

    2007-03-01

    Full Text Available Von Hippel-Lindau (VHL disease is an autosomal dominant cancer syndrome, associated with the development of tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The VHL disease tumor suppressor gene (VHL maps to 3p25-p26 and mutations ranging from a single base change to large deletions have been detected in patients with VHL disease. We developed a single cell PCR protocol for preimplantation genetic diagnosis (PGD of VHL disease to select unaffected embryos on the basis of the detection of the specific mutation and segregation analysis of polymorphic linked markers. Multiplex-nested PCR using single buccal cells of an affected individual were performed in order to test the accuracy and reliability of this single-cell protocol. For each locus tested, amplification efficiency was 83% to 87% and allelic drop-out rates ranged from 12% to 8%. Three VHL disease PGD cycles were performed on cells from a couple with paternal transmission of a 436delC mutation in exon 2 of the VHL gene, leading to the identification of three unaffected embryos. Independent of the mutation present, this general PGD protocol for the diagnosis of VHL disease can be used in families informative for either the D3S1038 or D3S1317 microsatellite markers.

  16. Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease

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    Chávez Mireya

    2010-01-01

    Full Text Available Abstract Background von Hippel-Lindau (VHL disease is a hereditary cancer syndrome caused by germline mutations in the VHL gene. Patients have significant morbidity and mortality secondary to vascular tumors. Disease management is centered on tumor surveillance that allows early detection and treatment. Presymptomatic genetic testing is therefore recommended, including in at-risk children. Methods We tested 17 families (n = 109 individuals for VHL mutations including 43 children under the age of 18. Personalized genetic counseling was provided pre and post-test and the individuals undergoing presymptomatic testing filled out questionnaires gathering socio-demographic, psychological and psychiatric data. Mutation analysis was performed by direct sequencing of the VHL gene. Mutation-carriers were screened for VHL disease-related tumors and were offered follow-up annual examinations. Results Mutations were identified in 36 patients, 17 of whom were asymptomatic. In the initial screening, we identified at least one tumor in five of 17 previously asymptomatic individuals. At the end of five years, only 38.9% of the mutation-carriers continued participating in our tumor surveillance program. During this time, 14 mutation carriers developed a total of 32 new tumors, three of whom died of complications. Gender, education, income, marital status and religiosity were not found to be associated with adherence to the surveillance protocol. Follow-up adherence was also independent of pre-test depression, severity of disease, or number of affected family members. The only statistically significant predictor of adherence was being symptomatic at the time of testing (OR = 5; 95% CI 1.2 - 20.3; p = 0.02. Pre-test anxiety was more commonly observed in patients that discontinued follow-up (64.7% vs. 35.3%; p = 0.01. Conclusions The high initial uptake rate of genetic testing for VHL disease, including in minors, allowed the discontinuation of unnecessary screening

  17. Differing von Hippel Lindau genotype in paired primary and metastatic tumors in patients with clear cell renal cell carcinoma

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    Susan A.J. Vaziri

    2012-05-01

    Full Text Available In sporadic clear cell renal cell carcinoma (CCRCC, the von Hippel Lindau (VHL gene is inactivated by mutation or methylation in the majority of primary (P tumors. Due to differing effects of wild-type (WT and mutant (MT VHL gene on downstream signaling pathways regulating angiogenesis, VHL gene status could impact clinical outcome. In CCRCC, comparative genomic hybridization (CGH analysis studies have reported genetic differences between paired P and metastatic (M tumors. We thus sequenced the VHL gene in paired tumor specimens from 10 patients to determine a possible clonal relationship between the P tumor and M lesion(s in patients with CCRCC. Using paraffin embedded specimens, genomic DNA from microdissected samples (>80% tumor of paired P tumor and M lesions from all 10 patients, as well as in normal tissue from 6 of these cases, was analyzed. The DNA was used for PCR-based amplification of each of the 3 exons of the VHL gene. Sequences derived from amplified samples were compared to the wild-type VHL gene sequence (GeneBank Accession No. AF010238. Methylation status of the VHL gene was determined using VHL methylation-specific PCR primers after DNA bisulfite modification. In 4/10 (40% patients the VHL gene status differed between the P tumor and the M lesion. As expected, when the VHL gene was mutated in both the P tumor and M lesion, the mutation was identical. Further, while the VHL genotype differed between the primary tumor in different kidneys or multiple metastatic lesions in the same patient, the VHL germline genotype in the normal adjacent tissue was always wild-type irrespective of the VHL gene status in the P tumor. These results demonstrate for the first time that the VHL gene status can be different between paired primary and metastatic tissue in patients with CCRCC.

  18. Pathological and Clinical Features and Management of Central Nervous System Hemangioblastomas in von Hippel-Lindau Disease

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    Hiroshi Kanno

    2014-08-01

    Full Text Available Central nervous system (CNS hemangioblastoma is the most common manifestation of von Hippel-Lindau (VHL disease. It is found in 70-80% of VHL patients. Hemangioblastoma is a rare form of benign vascular tumor of the CNS, accounting for 2.0% of CNS tumors. It can occur sporadically or as a familial syndrome. CNS hemangioblastomas are typically located in the posterior fossa and the spinal cord. VHL patients usually develop a CNS hemangioblastoma at an early age. Therefore, they require a special routine for diagnosis, treatment and follow-up. The surgical management of symptomatic tumors depends on many factors such as symptom, location, multiplicity, and progression of the tumor. The management of asymptomatic tumors in VHL patients is controversial since CNS hemangioblastomas grow with intermittent quiescent and rapid-growth phases. Preoperative embolization of large solid hemangioblastomas prevents perioperative hemorrhage but is not necessary in every case. Radiotherapy should be reserved for inoperable tumors. Because of complexities of VHL, a better understanding of the pathological and clinical features of hemangioblastoma in VHL is essential for its proper management.

  19. von Hippel-Lindau development in children and adolescents

    DEFF Research Database (Denmark)

    Launbjerg, Karoline; Bache, Iben; Galanakis, Michael

    2017-01-01

    on expert opinions. We aimed to describe the course of vHL development in children and adolescents, focusing on age at first manifestation, manifestation frequencies, and types. The prevalence of vHL diagnosis as well as manifestations in childhood were evaluated based on 99 patients, who had started...

  20. Clinical and molecular features of familial and sporadic cases of von Hippel-Lindau disease from Mexico.

    Science.gov (United States)

    Chacon-Camacho, Oscar F; Rodriguez-Dennen, Fernando; Camacho-Molina, Alejandra; Rasmussen, Astrid; Alonso-Vilatela, Elisa; Zenteno, Juan C

    2010-04-01

    von Hippel-Lindau disease (VHL) is an uncommon autosomal dominant condition predisposing to the development of tumours in a variety of body organs and caused by germline mutations in VHL, a tumour suppressor gene located on 3p. Up to 60% of VHL patients show ocular involvement with retinal hemangioblastoma being the most common observed lesion. In this study, we describe the clinical and genetic characteristics of two familial and one apparently non-familial case of VHL ascertained at our institution. Clinical evaluation included ophthalmologic examination and imaging exams for tumours identification; molecular analysis consisted of PCR amplification of the complete VHL gene coding sequence (three exons) and automated nucleotide sequencing. A total of eight affected subjects were demonstrated to carry a causative mutation in VHL. Affected subjects from family #1 had a c.245G > C change, predicting a p.R82P substitution, affected individuals from family #2 were shown to have a c.266T > C change, leading to a p.L89P missense substitution, whereas the apparently non-familial case had a c.298-299insA mutation. One subject from family #2 was a non-penetrant carrier. No ocular anomalies were found in two adult affected subjects carrying the p.L89P mutation. Considerable interfamilial and intrafamilial clinical variability as well as one instance of non penetrance were recorded in these VHL disease cases. Three different mutations were demonstrated, including the c.298-299insA one base insertion, which has been previously described in two unrelated families from our country. Although additional studies are needed, our data suggest that this insertion could be a 'founder' mutation.

  1. Endolymphatic sac tumor with von Hippel-Lindau disease: report of a case with atypical pathology of endolymphatic sac tumor.

    Science.gov (United States)

    Yang, Xiang; Liu, Xue-Song; Fang, Yuan; Zhang, Xiu-Hui; Zhang, Yue-Kang

    2014-01-01

    The authors described a case of a patient with co-existing endolymphatic sac tumor (ELST) and hemangioblastoma in the posterior cranial fossa, which belonged to a subtype of Von Hippel-Lindau (VHL) disease confirmed by the test of VHL-gene. The signs in this 42-year-old female included intermittent headache and dizziness. Imaging revealed a giant mass in the right cerebellopontine angle (CPA) region and another lesion in the left cerebellar hemisphere. The results of biopsy after two operations confirmed the diagnosis respectively. Both of the tumors were resected totally. Nevertheless, we had to confess the misdiagnosis as vascular tumor instead of ELST at the initial diagnosis because of the rarity of ELST associated with atypical histological characteristics. The purposes we reported this case were to describe the atypical pathological feature of ELST and the mutation of germline VHL not mentioned in previously literature, furthermore, to foster understanding of ELSTs with the avoidance of the similar misdiagnosis as far as possible in future.

  2. Patient-specific factors influence somatic variation patterns in von Hippel-Lindau disease renal tumours.

    Science.gov (United States)

    Fei, Suzanne S; Mitchell, Asia D; Heskett, Michael B; Vocke, Cathy D; Ricketts, Christopher J; Peto, Myron; Wang, Nicholas J; Sönmez, Kemal; Linehan, W Marston; Spellman, Paul T

    2016-05-13

    Cancer development is presumed to be an evolutionary process that is influenced by genetic background and environment. In laboratory animals, genetics and environment are variables that can largely be held constant. In humans, it is possible to compare independent tumours that have developed in the same patient, effectively constraining genetic and environmental variation and leaving only stochastic processes. Patients affected with von Hippel-Lindau disease are at risk of developing multiple independent clear cell renal carcinomas. Here we perform whole-genome sequencing on 40 tumours from six von Hippel-Lindau patients. We confirm that the tumours are clonally independent, having distinct somatic single-nucleotide variants. Although tumours from the same patient show many differences, within-patient patterns are discernible. Single-nucleotide substitution type rates are significantly different between patients and show biases in trinucleotide mutation context. We also observe biases in chromosome copy number aberrations. These results show that genetic background and/or environment can influence the types of mutations that occur.

  3. Adrenal Cortex-Sparing Surgery for Bilateral Multiple Pheochromocytomas in a Patient with Von Hippel-Lindau Disease

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    Tarık Esen

    2012-01-01

    Full Text Available Pheochromocytomas can be a part of familial neoplastic syndromes, in which case they tend to be multiple and involve both adrenal glands. Therefore, sparing adrenocortical function represents a major concern while dealing with these hereditary lesions. Herein, we describe the clinical characteristics and the management strategy of a patient with von Hippel-Lindau (VHL disease who had multiple, bilateral pheochromocytomas as well as bilateral renal masses, pancreatic masses, and a paracaval mass. Only a portion of the left adrenal gland has remained in situ after two consecutive open surgeries and a percutaneous radiofrequency ablation which have been performed to treat the various components of this syndrome. No adrenal or extra-adrenal pheochromocytoma recurrences have been detected during a follow-up period of more than 2 years. Pancreatic and adrenal functions were normal throughout the postoperative period and never necessitated any replacement therapy. Adrenal cortex-sparing surgery is a valid option for VHL disease patients who present with synchronous bilateral adrenal pheochromocytomas.

  4. Von Hippel-Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster.

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    Perrotta, Silverio; Nobili, Bruno; Ferraro, Marcella; Migliaccio, Carmela; Borriello, Adriana; Cucciolla, Valeria; Martinelli, Vincenzo; Rossi, Francesca; Punzo, Francesca; Cirillo, Paola; Parisi, Giuseppe; Zappia, Vincenzo; Rotoli, Bruno; Della Ragione, Fulvio

    2006-01-15

    Chuvash polycythemia (MIM 263400) is an autosomal recessive disorder characterized by a high hemoglobin level, relatively high serum erythropoietin, and early death. It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1alpha activity and erythrocyte production in the face of normoxia. This polycythemia is endemic in Chuvashia, whereas its worldwide frequency is very low. We investigated the incidence of the Chuvash-type VHL mutation in Campania (South Italy) and identified 14 affected subjects (5 families). Twelve live on the island of Ischia (Bay of Naples). From analysis of the mutated allele, we found that the disease was more frequent on Ischia (0.070) than in Chuvashia (0.057). The haplotype of all patients matched that identified in the Chuvash cluster, thereby supporting the single-founder hypothesis. We also found that nonaffected heterozygotes had increased HIF-1alpha activity, which might confer a biochemical advantage for mutation maintenance. In conclusion, we have identified the first large cluster of Chuvash erythrocytosis outside Chuvashia, which suggests that this familial polycythemia might be endemic in other regions of the world.

  5. 18F-FDG and 68Ga-DOTATATE PET/CT in von Hippel-Lindau Disease-Associated Retinal Hemangioblastoma.

    Science.gov (United States)

    Papadakis, Georgios Z; Millo, Corina; Jassel, Inderbir S; Bagci, Ulas; Sadowski, Samira M; Karantanas, Apostolos H; Patronas, Nicholas J

    2017-03-01

    Retinal hemangioblastomas are highly vascular benign tumors that can be encountered either sporadically or within the von Hippel-Lindau (VHL) syndrome. We report a case of a VHL patient with retinal hemangioblastoma who underwent PET/CT scans using F-FDG and Ga-DOTATATE. The tumor showed low-level F-FDG and increased Ga-DOTATATE activity, suggesting cell-surface overexpression of somatostatin receptors. The presented case indicates the clinical applications of somatostatin receptor imaging with Ga-DOTA-conjugated peptides in detection and follow-up of VHL manifestations, screening of asymptomatic gene carriers, and in diagnosis of sporadic retinal hemangioblastomas, which may have similar features on MRI with other retinal tumors.

  6. Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from the Netherlands cohort study

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    Schalken Jack A

    2005-06-01

    Full Text Available Abstract Background Biallelic von Hippel-Lindau (VHL gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC. We studied the VHL mutation status in a large population-based case group. Methods Cases were identified within the Netherlands cohort study on diet and cancer, which includes 120,852 men and women. After 11.3 years of follow-up, 337 incident cases with histologically confirmed epithelial cancers were identified. DNA was isolated from paraffin material collected from 51 pathology laboratories and revised by one pathologist, leaving material from 235 cases. VHL mutational status was assessed by SSCP followed by direct sequencing, after testing SSCP as a screening tool in a subsample. Results The number of mutations was significantly higher for clear-cell RCC compared to other histological types. We observed 131 mutations in 114 out of 187 patients (61% with clear-cell RCC. The majority of mutations were truncating mutations (47%. The mean tumor size was 72.7 mm for mutated tumors compared to 65.3 mm for wildtype tumors (p = 0.06. No statistically significant differences were observed for nuclear grade, TNM distribution or stage. In other histological types, we observed 8 mutations in 7 out of 48 patients (15%, 1 mutation in 1 of 6 oncocytoma, 3 mutations in 2 of 7 chromophobe RCC, 2 mutations in 2 of 30 papillary RCC, no mutations in 1 collecting duct carcinoma and 2 mutations in 2 of 4 unclassified RCC. Conclusion VHL mutations were detected in 61% of sporadic clear-cell RCC. VHL mutated and wildtype clear-cell RCC did not differ with respect to most parameters.

  7. [Surgical treatment of a pheocromocytoma bilateral in a 5 year old patient with the von Hippel-Lindau disease].

    Science.gov (United States)

    Blanco, J A; Blanco, D; Alastrue, A; Castellví, A; Isnard, R M; Pintos, G; Mangas, A; Roig, N; Casasa, J M

    2004-01-01

    The disease of Von Hippel Lindau (VHL) is hereditary and causes a predisposition to the development of tumours. Organs such as the cerebellum, the pancreas, the kidney, the suprarenal glands and the retina are more usually affected by this disease. We present the case of a 5-year-old patient who suffers from asiymptomatic high blood pressure. In the family antecedents, it is relevant the case of the father, with pheocromocytoma bilateral, which led us to carry out a genetic study of his two sons. Our patient, the younger; presented a mutation of the VHL gene in the short arm of the chromosome 3. In one of the periodic controls, it could be detected high blood pressure of 160/100 mm. Hg, clinically asymptomatic. The other child did not present a genetic mutation and has no disease. The presence of high catecholamines, the detection of a 3 cm left suprarenal mass through the ecography, the TAC that did not show a right suprarenal pathology and the MBIG scintigraphy confirmed the diagnostic of pheocromocytoma. The RNM showed another 0.8-cm mass which confirmed a pheocromocytoma bilateral. We started the treatment against high blood pressure with fenoxibenzamine and diltiazem, and we controlled this problem. We also prepared the pre-and-post operation anesthetic strategy, which is so important for the surgical success. The operation started by a laparoscopic, we made left adrenalectomy and we had to reconvert to laparotomy to make partial right adrenalectomy. Six months after the operation, the patient is free from symptomatology and follows a treatment with glucocorticoides with smaller and smaller doses. The case is exceptional because it embodies the following characteristics: early diagnostic age, family affectation and discovery of asymptomatic high blood pressure. It needed an appropriate preanesthetic and anesthetic preparation, which gave way to an operation without complications. The postoperation was also stable and presented no complications.

  8. Through the looking glass: an exploratory study of the lived experiences and unmet needs of families affected by Von Hippel-Lindau disease.

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    Kasparian, Nadine A; Rutstein, Alison; Sansom-Daly, Ursula M; Mireskandari, Shab; Tyler, Janet; Duffy, Jessica; Tucker, Katherine M

    2015-01-01

    Despite well-established protocols for the medical management of Von Hippel-Lindau disease (VHL), families affected by this rare tumour syndrome continue to face numerous psychological, social, and practical challenges. To our knowledge, this is one of the first qualitative studies to explore the psychosocial difficulties experienced by families affected by VHL. A semi-structured interview was developed to explore patients' and carers' experiences of VHL along several life domains, including: self-identity and self-esteem, interpersonal relationships, education and career opportunities, family communication, physical health and emotional well-being, and supportive care needs. Quantitative measures were also used to examine the prevalence of anxiety, depression, and disease-specific distress in this sample. Participants were recruited via the Hereditary Cancer Clinic at the Prince of Wales Hospital in Sydney, Australia. A total of 23 individual telephone interviews were conducted (15 patients, 8 carers), yielding a response rate of 75%. A diverse range of experiences were reported, including: sustained uncertainty about future tumour development, frustration regarding the need for lifelong medical screening, strained family relationships, difficulties communicating with others about VHL, perceived social isolation and limited career opportunities, financial and care-giving burdens, complex decisions in relation to childbearing, and difficulties accessing expert medical and psychosocial care. Participants also provided examples of psychological growth and resilience, and voiced support for continued efforts to improve supportive care services. More sophisticated systems for connecting VHL patients and their families with holistic, empathic, and person-centred medical and psychosocial care are urgently needed.

  9. Identification of 3 novel VHL germ-line mutations in Danish VHL patients

    DEFF Research Database (Denmark)

    Dandanell, Mette; Friis-Hansen, Lennart Jan; Sunde, Lone

    2012-01-01

    von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene.......von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome in which the patients develop retinal and central nervous system hemangioblastomas, pheochromocytomas and clear-cell renal tumors. The autosomal dominant disease is caused by mutations in the VHL gene....

  10. Perioperative outcomes of syndromic paraganglioma and pheochromocytoma resection in patients with von Hippel-Lindau disease, multiple endocrine neoplasia type 2, or neurofibromatosis type 1.

    Science.gov (United States)

    Butz, James J; Yan, Qi; McKenzie, Travis J; Weingarten, Toby N; Cavalcante, Alexandre N; Bancos, Irina; Young, William F; Schroeder, Darrell R; Martin, David P; Sprung, Juraj

    2017-12-01

    Pheochromocytoma and/or paraganglioma associated with neurofibromatosis type 1, multiple endocrine neoplasia type 2A, and von Hippel-Lindau disease have different catecholamine biochemical phenotypes. We examined perioperative outcomes of pheochromocytoma/paraganglioma resection in 3 syndromic forms. Retrospective review of patients undergoing resection of syndromic pheochromocytoma/paraganglioma from 2000 through 2016. Eighty-one patients underwent pheochromocytoma/paraganglioma resection (multiple endocrine neoplasia type 2A, n = 36; neurofibromatosis type 1, n = 26; von Hippel-Lindau disease, n = 19). Tumor size differed across groups; patients with neurofibromatosis type 1 and von Hippel-Lindau disease had the largest tumors (P = .017). Larger tumor volumes correlated with higher urine 24-hour total metanephrine (r = 0.94, P neoplasia type 2A, von Hippel-Lindau disease, and neurofibromatosis type 1, respectively). High adrenergic secretion (24-hour urine metanepinephrine) was found in neurofibromatosis type 1 (median, 861 μg/24 h), similar to that found in multiple endocrine neoplasia type 2A (median, 809 μg/24 h). The highest noradrenergic secretion (24-hour urine normetanephrine) occurred with von Hippel-Lindau disease (median, 4,598 μg/24 h), followed by neurofibromatosis type 1 and multiple endocrine neoplasia type 2A (median, 1,607 and 923 μg/24 h, respectively). The highest graded complications occurred among patients with neurofibromatosis type 1 (P = .036). However, when comparing postoperative outcomes across 3 groups in those who had laparoscopic resection, there was no significant difference (P = .955). Patients with neurofibromatosis type 1 had the most volatile intraoperative hemodynamic course and more severe postoperative complications. These complications are related to large tumors associated with abundant catecholamine secretion and the fact that a high proportion underwent open resection. Among only patients who underwent

  11. A mutation at IVS1 + 5 of the von Hippel-Lindau gene resulting in intron retention in transcripts is not pathogenic in a patient with a tongue cancer?: case report

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    Asakawa Takeshi

    2012-03-01

    Full Text Available Abstract Background Von Hippel-Lindau disease (VHL is a dominantly inherited familial cancer syndrome predisposing the patient to a variety of malignant and benign neoplasms, most frequently hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors. VHL is caused by mutations of the VHL tumor suppressor gene on the short arm of chromosome 3, and clinical manifestations develop if both alleles are inactivated according to the two-hit hypothesis. VHL mutations are more frequent in the coding region and occur occasionally in the splicing region of the gene. Previously, we reported that the loss of heterozygosity (LOH of the VHL gene is common in squamous cell carcinoma tissues of the tongue. Case Presentation We describe a case of squamous cell carcinoma in the tongue caused by a point mutation in the splicing region of the VHL gene and discuss its association with VHL disease. Sequence analysis of DNA extracted from the tumor and peripheral blood of the patient with squamous cell carcinoma revealed a heterozygous germline mutation (c. 340 + 5 G > C in the splice donor sequence in intron 1 of the VHL gene. RT-PCR analysis of the exon1/intron1 junction in RNA from tumor tissue detected an unspliced transcript. Analysis of LOH using a marker with a heterozygous mutation of nucleotides (G or C revealed a deletion of the mutant C allele in the carcinoma tissues. Conclusions The fifth nucleotide G of the splice donor site of the VHL gene is important for the efficiency of splicing at that site. The development of tongue cancer in this patient was not associated with VHL disease because the mutation occurred in only a single allele of the VHL gene and that allele was deleted in tumor cells.

  12. Paraplegia in a patient with Von Hippel Lindau syndrome: surgical and reconstructive treatment of Marjolin's ulcer. A case report.

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    Scalise, A; Tartaglione, C; Pierangeli, M; Bolletta, E; Fraccalvieri, M; Grassetti, L; Ottonello, M; Nicoletti, G; Massone, A; Di Benedetto, G

    2014-11-01

    Marjolin's ulcer is a squamous cell carcinoma that develops in posttraumatic scars and chronic wounds. Suspicion of such lesions should be raised in chronic wounds demonstrating characteristic changes. We have reported the peculiar phenomenon of malignant transformation of chronic pressure sores that occurred in a paraplegic patient. The aim of this study was to cover the extensive defects by a last resort reconstructive option. Department of Plastic and Reconstructive Surgery, Università Politecnica delle Marche, Ancona, Italy. A 40-year-old paraplegic man, with multiple hemangioblastomas of the brain and spinal cord due to Von Hippel Lindau syndrome developed pressure ulcers with unstable healing over the sacral, trochanteric, bilateral, and ischiatic areas after 15 years from neurosurgery. The biopsy result showed an invasive squamous carcinoma. Carcinomas in pressure sores are highly aggressive, and they need to be treated more radically. In our case we opted for a demolitive surgical treatment including musculocutaneous rotational flap harvested from total left thigh to cover the extensive defects. The limb was previously disarticulated. In Marjolin's ulcer, multiple biopsies are the first-line modality for the early diagnosis as they are a safe method with high rate of accuracy. First-line treatment is surgery consisting of radical excision with lymph node dissection, if they are involved. Adjuvant radiation therapy may be used in selected patients. Management of massive pelvic defects can be a challenging problem. The pedicled lower limb flap offers a technique that can be considered as a last resort procedure for extensive defects where other options are insufficient or not available anymore. In our case the patient is disease-free after 2 years of follow-up.

  13. Pancreatic neuroendocrine tumor with complete replacement of the pancreas by serous cystic neoplasms in a patient with von Hippel-Lindau disease: a case report.

    Science.gov (United States)

    Maeda, Shimpei; Motoi, Fuyuhiko; Oana, Shuhei; Ariake, Kyohei; Mizuma, Masamichi; Morikawa, Takanori; Hayashi, Hiroki; Nakagawa, Kei; Kamei, Takashi; Naitoh, Takeshi; Unno, Michiaki

    2017-09-25

    von Hippel-Lindau disease is a dominantly inherited multi-system syndrome with neoplastic hallmarks. Pancreatic lesions associated with von Hippel-Lindau include serous cystic neoplasms, simple cysts, and neuroendocrine tumors. The combination of pancreatic neuroendocrine tumors and serous cystic neoplasms is relatively rare, and the surgical treatment of these lesions must consider both preservation of pancreatic function and oncological clearance. We report a patient with von Hippel-Lindau disease successfully treated with pancreas-sparing resection of a pancreatic neuroendocrine tumor where the pancreas had been completely replaced by serous cystic neoplasms, in which pancreatic function was preserved. A 39-year-old female with von Hippel-Lindau disease was referred to our institution for treatment of a pancreatic neuroendocrine tumor. Abdominal computed tomography demonstrated a well-enhanced mass, 4 cm in diameter in the tail of the pancreas, and two multilocular tumors with several calcifications, 5 cm in diameter, in the head of the pancreas. There was complete replacement of the pancreas by multiple cystic lesions with diameters ranging from 1 to 3 cm. Magnetic resonance cholangiopancreatography showed innumerable cystic lesions on the whole pancreas and no detectable main pancreatic duct. Endoscopic ultrasound-guided fine-needle aspiration of the mass in the pancreatic tail showed characteristic features of a neuroendocrine tumor. A diagnosis of pancreatic neuroendocrine tumor in the tail of the pancreas and mixed-type serous cystic neoplasms replacing the whole pancreas was made and she underwent distal pancreatectomy while avoiding total pancreatectomy. The stump of the pancreas was sutured as firm as possible using a fish-mouth closure. The patient made a good recovery and was discharged on postoperative day 9. She is currently alive and well with no symptoms of endocrine or exocrine pancreatic insufficiency 8 months after surgery. A pancreas

  14. The oncolytic activity of Newcastle disease virus in clear cell renal carcinoma cells in normoxic and hypoxic conditions: the interplay between von Hippel-Lindau and interferon-β signaling.

    Science.gov (United States)

    Ch'ng, Wei-Choong; Stanbridge, Eric J; Yusoff, Khatijah; Shafee, Norazizah

    2013-07-01

    Viral-mediated oncolysis is a promising cancer therapeutic approach offering an increased efficacy with less toxicity than the current therapies. The complexity of solid tumor microenvironments includes regions of hypoxia. In these regions, the transcription factor, hypoxia inducible factor (HIF), is active and regulates expression of many genes that contribute to aggressive malignancy, radio-, and chemo-resistance. To investigate the oncolytic efficacy of a highly virulent (velogenic) Newcastle disease virus (NDV) in the presence or absence of HIF-2α, renal cell carcinoma (RCC) cell lines with defective or reconstituted wild-type (wt) von Hippel-Lindau (VHL) activity were used. We show that these RCC cells responded to NDV by producing only interferon (IFN)-β, but not IFN-α, and are associated with increased STAT1 phosphorylation. Restoration of wt VHL expression enhanced NDV-induced IFN-β production, leading to prolonged STAT1 phosphorylation and increased cell death. Hypoxia augmented NDV oncolytic activity regardless of the cells' HIF-2α levels. These results highlight the potential of oncolytic NDV as a potent therapeutic agent in the killing of hypoxic cancer cells.

  15. Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition

    Directory of Open Access Journals (Sweden)

    Chintala Sreenivasulu

    2012-07-01

    Full Text Available Abstract Background Clear cell renal cell carcinoma (ccRCC accounts for more than 80% of the cases of renal cell carcinoma. In ccRCC deactivation of Von-Hippel-Lindau (VHL gene contributes to the constitutive expression of hypoxia inducible factors 1 and 2 alpha (HIF-α, transcriptional regulators of several genes involved in tumor angiogenesis, glycolysis and drug resistance. We have demonstrated inhibition of HIF-1α by Se-Methylselenocysteine (MSC via stabilization of prolyl hydroxylases 2 and 3 (PHDs and a significant therapeutic synergy when combined with chemotherapy. This study was initiated to investigate the expression of PHDs, HIF-α, and VEGF-A in selected solid cancers, the mechanism of HIF-α inhibition by MSC, and to document antitumor activity of MSC against human ccRCC xenografts. Methods Tissue microarrays of primary human cancer specimens (ccRCC, head & neck and colon were utilized to determine the incidence of PHD2/3, HIF-α, and VEGF-A by immunohistochemical methods. To investigate the mechanism(s of HIF-α inhibition by MSC, VHL mutated ccRCC cells RC2 (HIF-1α positive, 786–0 (HIF-2α positive and VHL wild type head & neck cancer cells FaDu (HIF-1α were utilized. PHD2 and VHL gene specific siRNA knockdown and inhibitors of PHD2 and proteasome were used to determine their role in the degradation of HIF-1α by MSC. Results We have demonstrated that ccRCC cells express low incidence of PHD2 (32%, undetectable PHD3, high incidence of HIF-α (92%, and low incidence of VEGF-A compared to head & neck and colon cancers. This laboratory was the first to identify MSC as a highly effective inhibitor of constitutively expressed HIF-α in ccRCC tumors. MSC did not inhibit HIF-1α protein synthesis, but facilitated its degradation. The use of gene knockdown and specific inhibitors confirmed that the inhibition of HIF-1α was PHD2 and proteasome dependent and VHL independent. The effects of MSC treatment on HIF-α were associated with

  16. Role of VEGFA, CXCR4 and VHL mutation in tumour behaviour

    NARCIS (Netherlands)

    Kruizinga, Roeliene

    2014-01-01

    De ziekte van Von Hippel Lindau (VHL) is een zeldzaam kankersyndroom. Patiënten met deze ziekte krijgen zowel goedaardige als kwaadaardige tumoren in verschillende organen. VHL-patiënten hebben een niet goed werkend VHL-eiwit waardoor er meer CXCR4, een chemokine receptor, en VEGFA, een

  17. Two childhood pheochromocytoma cases due to von Hippel -Lindau disease, one associated with pancreatic neuroendocrine tumor; a rare manifestation.

    Science.gov (United States)

    Dağdeviren Çakır, Aydilek; Turan, Hande; Aykut, Ayça; Durmaz, Asude; Ercan, Oya; Evliyaoğlu, Olcay

    2017-10-12

    (VHL) disease is an autosomal dominantly inherited disorder characterized by hemangioblastomas of retina and central nervous system (CNS); renal cysts, clear cell carcinoma; PCC; endolymphatic sac tumors; cystadenomas of the epididymis in males, broad ligament of uterus in females; pancreatic cysts, cystadenomas and neuroendocrine tumors. We here report two cases of VHL disease presented with PCC as the first manifestation. Hemangioblastoma of CNS in the first case and PNET in the second case developed during follow- up and led to the diagnosis of VHL disease. Genetic analyses of cases revealed p.Arg161Gln (c.482G>A) and p.Leu129Pro(c.386T>G) heterozygous missense mutation in VHL gene, respectively. In children, PCC may be the only and/or initial manifestation of the disease with delayed manifestations of the syndrome in other organs. PNET is a very rare manifestation of VHL disease. To best of our knowledge, this is the second case in literature, presenting with combination of PNET and bilateral PCC as components of childhood VHL disease. Pediatric patients diagnosed with PCC should be investigated for the genetic causes especially for VHL.

  18. Potential value of EUS in pancreatic surveillance of VHL patients

    NARCIS (Netherlands)

    van Asselt, Sophie Josephien; Brouwers, Adrienne H; van Dullemen, Hendrik M; van der Jagt, Eric J; Bongaerts, Alfons H; Koopmans, Klaas P; Kema, Ido; Zonnenberg, Bernard A; Timmers, Henri Jlm; de Herder, Wouter; Sluiter, Wim; de Vries, Elisabeth G E; Links, T P

    Background: Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and

  19. Difference in CXCR4 expression between sporadic and VHL-related hemangioblastoma

    NARCIS (Netherlands)

    Kruizinga, Roeliene C; van Marion, Denise M S; den Dunnen, Wilfred F A; de Groot, Jan C; Hoving, Eelco W; Oosting, Sjoukje F; Timmer-Bosscha, Hetty; Derks, Rosalie P H; Cornelissen, Chantal; van der Luijt, Rob B; Links, Thera P; de Vries, Elisabeth G E; Walenkamp, Annemiek M E

    2016-01-01

    Central nervous system hemangioblastomas occur sporadically and in patients with von Hippel-Lindau (VHL) disease due to a VHL germline mutation. This mutation leads to enhanced transcription of chemokine receptor 4 (CXCR4), its ligand (CXCL12) and vascular endothelial growth factor A (VEGFA). We

  20. Potential role of {sup 68}Ga-DOTATOC PET/CT in screening for pancreatic neuroendocrine tumour in patients with von Hippel-Lindau disease

    Energy Technology Data Exchange (ETDEWEB)

    Prasad, Vikas; Brenner, Winfried [Charite Universitaetsmedizin Berlin, Department of Nuclear Medicine, Campus Virchow-Klinikum, Berlin (Germany); Tiling, Nikolaus; Ploeckinger, Ursula [Charite Universitaetsmedizin Berlin, Interdisziplinaeren Stoffwechsel-Centrum, Campus Virchow Klinikum, Berlin (Germany); Denecke, Timm [Charite Universitaetsmedizin Berlin, Department of Radiology, Berlin (Germany)

    2016-10-15

    Neuroendocrine tumours of the pancreas (pNET) are observed in 8 - 17 % of patients with von Hippel-Lindau disease (vHLD), and 11 - 20 % of these patients develop metastatic disease. MRI and CT have a very high resolution; however, their sensitivity and specificity for the detection of pNET amongst cystic lesions in the pancreas of vHLD patients are generally considered insufficient. In contrast, {sup 68}Ga-DOTATOC PET/CT demonstrates a high sensitivity for the diagnosis and staging of neuroendocrine tumours. In this study we investigated the potential role of {sup 68}Ga-DOTATOC PET/CT in screening of patients with vHLD. {sup 68}Ga-DOTATOC PET/three-phase contrast-enhanced CT was performed according to guidelines in all consecutive vHLD patients between January 2012 and November 2015. All patients underwent additional MRI imaging of the abdomen, spine, and head. Chromogranin A (CgA) was determined at the time of the PET/CT examination. A lesion seen on {sup 68}Ga-DOTATOC PET in the pancreas was defined as positive if the uptake was visually higher than in the surrounding tissues. Lesions were quantified using maximum SUV. Overall, 20 patients (8 men, 12 women; mean age 44.7 ± 11.1 years) were prospectively examined. Genetically, 12 patients had type 1 vHLD and 8 had type 2 vHLD. {sup 68}Ga-DOTATOC PET/CT detected more pNET than morphological imaging (CT or MRI): 11 patients (55 %; 8 type 1, 3 type 2) vs. 9 patients (45 %; 6 type 1, 3 type 2). The concentration of CgA was mildly elevated in 2 of 11 patients with pNET. The mean SUVmax of the pancreatic lesions was 18.9 ± 21.9 (range 5.0 - 65.6). Four patients (36.4 %) had multiple pNETs. The mean size of the lesions on CT and/or MRI was 10.4 ± 8.3 mm (range 4 - 38 mm), and 41.1 % were larger than 10 mm. In addition, somatostatin receptor-positive cerebellar and spinal haemangioblastomas were detected in three patients (SUVmax 2.1 - 10.1). One patient presented with a solitary somatostatin receptor-positive lymph

  1. The allele frequency of two single nucleotide polymorphisms in the von Hippel-Lindau (VHL tumor suppressor gene in the Taiwanese population

    Directory of Open Access Journals (Sweden)

    Wen-Chung Wang

    2011-10-01

    Conclusion: We found that the G allele frequency at these two loci in the Taiwanese population is much lower than that in people from Western countries. This phenomenon may be attributed to ethnic effects.

  2. Novel homozygous VHL mutation in exon 2 is associated with congenital polycythemia but not with cancer.

    Science.gov (United States)

    Lanikova, Lucie; Lorenzo, Felipe; Yang, Chunzhang; Vankayalapati, Hari; Drachtman, Richard; Divoky, Vladimir; Prchal, Josef T

    2013-05-09

    Germline von Hippel-Lindau (VHL) gene mutations underlie dominantly inherited familial VHL tumor syndrome comprising a predisposition for renal cell carcinoma, pheochromocytoma/paraganglioma, cerebral hemangioblastoma, and endolymphatic sac tumors. However, recessively inherited congenital polycythemia, exemplified by Chuvash polycythemia, has been associated with 2 separate 3' VHL gene mutations in exon 3. It was proposed that different positions of loss-of-function VHL mutations are associated with VHL syndrome cancer predisposition and only C-terminal domain-encoding VHL mutations would cause polycythemia. However, now we describe a new homozygous VHL exon 2 mutation of the VHL gene:(c.413C>T):P138L, which is associated in the affected homozygote with congenital polycythemia but not in her, or her-heterozygous relatives, with cancer or other VHL syndrome tumors. We show that VHL(P138L) has perturbed interaction with hypoxia-inducible transcription factor (HIF)1α. Further, VHL(P138L) protein has decreased stability in vitro. Similarly to what was reported in Chuvash polycythemia and some other instances of HIFs upregulation, VHL(P138L) erythroid progenitors are hypersensitive to erythropoietin. Interestingly, the level of RUNX1/AML1 and NF-E2 transcripts that are specifically upregulated in acquired polycythemia vera were also upregulated in VHL(P138L) granulocytes.

  3. The homozygous VHL(D126N) missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension.

    Science.gov (United States)

    Sarangi, Susmita; Lanikova, Lucie; Kapralova, Katarina; Acharya, Suchitra; Swierczek, Sabina; Lipton, Jeffrey M; Wolfe, Lawrence; Prchal, Josef T

    2014-11-01

    von Hippel-Lindau (VHL) protein is the principal negative regulator of hypoxia sensing mediated by transcription factors. Mutations in exon 3 of the VHL gene lead to Chuvash (VHL(R200W)) and Croatian (VHL(H191D)) polycythemias. Here, we describe an infant of Bangladesh ethnicity with a novel homozygous VHL(D126N) mutation with congenital polycythemia and dramatically elevated erythropoietin (EPO) levels, who developed severe fatal pulmonary hypertension. In contrast to Chuvash polycythemia, erythroid progenitors (BFU-Es) did not reveal a marked EPO hypersensitivity. Further, NF-E2 and RUNX1 transcripts that correlate with BFU-Es EPO hypersensitivity in polycythemic mutations were not elevated. © 2014 Wiley Periodicals, Inc.

  4. Playing Tag with HIF: The VHL Story

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    Sherri K. Leung

    2002-01-01

    Full Text Available Inactivation of the von Hippel-Lindau (VHL tumour suppressor gene product pVHL is the cause of inherited VHL disease and is associated with sporadic kidney cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1 forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets the α subunits of hypoxia-inducible factor (HIF for ubiquitin-mediated destruction. Consequently, tumour cells lacking functional pVHL overproduce the products of HIF-target genes such as vascular endothelial growth factor (VEGF, which promotes angiogenesis. This likely accounts for the hypervascular nature of VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle, differentiation, and the regulation of extracellular matrix assembly, microenvironment pH, and tissue invasiveness, this review will focus on the recent insights into the molecular mechanisms governing the E3 ubiquitin ligase function of VEC.

  5. VHL genetic alteration in CCRCC does not determine de-regulation of HIF, CAIX, hnRNP A2/B1 and osteopontin.

    LENUS (Irish Health Repository)

    Nyhan, Michelle J

    2012-01-31

    BACKGROUND: von Hippel-Lindau (VHL) tumour suppressor gene inactivation is associated with clear cell renal cell carcinoma (CCRCC) development. The VHL protein (pVHL) has been proposed to regulate the expression of several proteins including Hypoxia Inducible Factor-alpha (HIF-alpha), carbonic anhydrase (CA)IX, heterogeneous nuclear ribonucleoprotein (hnRNP) A2\\/B1 and osteopontin. pVHL has been characterized in vitro, however, clinical studies are limited. We evaluated the impact of VHL genetic alterations on the expression of several pVHL protein targets in paired normal and tumor tissue. METHODS: The VHL gene was sequenced in 23 CCRCC patients and VHL transcript levels were evaluated by real-time RT-PCR. Expression of pVHL\\'s protein targets were determined by Western blotting in 17 paired patient samples. RESULTS: VHL genetic alterations were identified in 43.5% (10\\/23) of CCRCCs. HIF-1alpha, HIF-2alpha and CAIX were up-regulated in 88.2% (15\\/17), 100% (17\\/17) and 88.2% (15\\/17) of tumors respectively and their expression is independent of VHL status. hnRNP A2\\/B1 and osteopontin expression was variable in CCRCCs and had no association with VHL genetic status. CONCLUSION: As expression of these proposed pVHL targets can be achieved independently of VHL mutation (and possibly by hypoxia alone), these data suggests that other pVHL targets may be more crucial in renal carcinogenesis.

  6. Genetics Home Reference: von Hippel-Lindau syndrome

    Science.gov (United States)

    ... ears, as well as ringing in the ears (tinnitus) and problems with balance. Without treatment, these tumors ... Information from MedlinePlus (5 links) Diagnostic Tests Drug Therapy Genetic Counseling Palliative Care Surgery and Rehabilitation Related ...

  7. Small activating RNA induced expression of VHL gene in renal cell carcinoma.

    Science.gov (United States)

    Kang, Moo Rim; Park, Ki Hwan; Lee, Chang Woo; Lee, Myeong Youl; Han, Sang-Bae; Li, Long-Cheng; Kang, Jong Soon

    2018-02-06

    Recent studies have reported that chemically synthesized double-stranded RNAs (dsRNAs), also known as small activating RNA (saRNAs), can specifically induce gene expression by targeting promoter sequences by a mechanism termed RNA activation (RNAa). In the present study, we designed 4 candidate saRNAs targeting the Von Hippel-Lindau (VHL) gene promoter. Among these saRNAs, dsVHL-821 significantly inhibited cell growth by up-regulating VHL at both the mRNA and protein levels in renal cell carcinoma 769-P cells. Functional analysis showed that dsVHL-821 induced apoptosis by increasing p53, decreasing Bcl-xL, activating caspase 3/7 and poly-ADP-ribose polymerase in a dose-dependent manner. Chromatin immunoprecipitation analysis revealed that dsVHL-821 increased the enrichment of Ago2 and RNA polymerase II at the dsVHL-821 target site. In addition, Ago2 depletion significantly suppressed dsVHL-821-induced up-regulation of VHL gene expression and related effects. Single transfection of dsVHL-821 caused long-lasting (14 days) VHL up-regulation. Furthermore, the activation of VHL by dsVHL-821 was accompanied by an increase in dimethylation of histone 3 at lysine 4 (H3K4me2) and acetylation of histone 4 (H4ac) and a decrease in dimethylation of histone 3 at lysine 9 (H3K9me2) and lysine 27 (H3K27me2) in the dsVHL-821 target region. Taken together, these results demonstrate that dsVHL-821, a novel saRNA for VHL, induces the expression of the VHL gene by epigenetic changes, leading to inhibition of cell growth and induction of apoptosis, and suggest that targeted activation of VHL by dsVHL-821 may be explored as a novel treatment of renal cell carcinoma. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. VHL type 2B mutations retain VBC complex form and function.

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    Kathryn E Hacker

    Full Text Available von Hippel-Lindau disease is characterized by a spectrum of hypervascular tumors, including renal cell carcinoma, hemangioblastoma, and pheochromocytoma, which occur with VHL genotype-specific differences in penetrance. VHL loss causes a failure to regulate the hypoxia inducible factors (HIF-1alpha and HIF-2alpha, resulting in accumulation of both factors to high levels. Although HIF dysregulation is critical to VHL disease-associated renal tumorigenesis, increasing evidence points toward gradations of HIF dysregulation contributing to the degree of predisposition to renal cell carcinoma and other manifestations of the disease.This investigation examined the ability of disease-specific VHL missense mutations to support the assembly of the VBC complex and to promote the ubiquitylation of HIF. Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF. We additionally demonstrated that Type 2B mutant pVHL forms a remnant VBC complex containing the active members ROC1 and Cullin-2 which retains the ability to ubiquitylate HIF-1alpha.Our results suggest that subtypes of VHL mutations support an intermediate level of HIF regulation via a remnant VBC complex. These findings provide a mechanism for the graded HIF dysregulation and genetic predisposition for cancer development in VHL disease.

  9. BASED TO CLINICAL CASE. VON HIPLEA-LINDAU SYNDROME

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    Brzeziński Piotr

    2011-01-01

    Full Text Available von Hippel-Lindau syndrome (VHL is a rare, genetic multi-system disorder characterized by the abnormal growth of tumors in certain parts of the body (angiomatosis. The tumors of the central nervous system (CNS are benign and are comprised of a nest of blood vessels and are called hemangioblastomas. Hemangioblastomas may develop in the brain, the retina of the eyes, and other areas of the nervous system. Other types of tumors develop in the adrenal glands, the kidneys, or the pancreas. Symptoms of VHL vary among patients and depend on the size and location of the tumors. Symptoms may include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure. Cysts (fluid-filled sacs and/or tumors (benign or cancerous may develop around the hemangioblastomas and cause the symptoms listed above. Individuals with VHL are also at a higher risk than normal for certain types of cancer, especially kidney cancer. Based on the case of 30-year old patient with characteristics of von Hippel-Lindau syndrome as phakomatosis.

  10. Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes

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    Isanova Bella

    2009-07-01

    Full Text Available Abstract Background In von Hippel-Lindau (VHL disease, germline mutations in the VHL tumor suppressor gene cause clear cell renal carcinomas, hemangioblastomas, and pheochromocytomas. The VHL gene product is part of an ubiquitin E3 ligase complex and hypoxia-inducible factor alpha (HIF-α is a key substrate, although additional VHL functions have been described. A genotype-phenotype relationship exists in VHL disease such that specific VHL mutations elicit certain subsets of these tumors. Here, we examine VHL genotype-phenotype correlations at the cellular level, focusing on the regulation of tight junctions and cell morphology. Methods Wild-type and various mutant VHL proteins representing VHL disease subtypes were stably expressed in 3 VHL-negative renal carcinoma cell lines. Using these cell lines, the roles of various VHL-associated cellular functions in regulation of cell morphology were investigated. Results As a whole, type 1 mutants varied greatly from type 2 mutants, demonstrating high levels of HIF-2α, cyclin D1 and α5 integrin, lower p27 levels, and a spindly, fibroblastic cellular appearance. Type 2 mutations demonstrated an epithelial morphology similar to wild-type VHL in the majority of the renal cell lines used. Knockdown of p27 in cells with wild-type VHL led to perturbations of both epithelial morphology and ZO-1 localization to tight junctions. ZO-1 localization correlated well with VHL disease subtypes, with greater mislocalization observed for genotypes associated with a higher risk of renal carcinoma. HIF-2α knockdown in 786-O partially restored ZO-1 localization, but did not restore an epithelial morphology. Conclusion VHL has both HIF-α dependent and HIF-α independent functions in regulating tight junctions and cell morphology that likely impact the clinical phenotypes seen in VHL disease.

  11. Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma

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    David A. Rowbotham

    2014-01-01

    Full Text Available Pheochromocytomas (PCC are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation.

  12. Identification of the Lipodepsipeptide MDN-0066, a Novel Inhibitor of VHL/HIF Pathway Produced by a New Pseudomonas Species.

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    Bastien Cautain

    Full Text Available Throughout recent history, metabolites of microbial origin have had an extraordinary impact on the welfare of humanity. In fact, natural products have largely been--and still are--considered an exceedingly valuable platform for the discovery of new drugs against diverse pathologies. Such value is partly due to their higher complexity and chemical diversity as compared to those of synthetic and combinatorial compounds. Mutations in the Von Hippel-Lindau (vhl gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types. The primary cause of morbidity and mortality for these patients arises from progression of Renal Cell Carcinoma (RCC or end-stage renal disease. Inactivation of the Von Hippel-Lindau (vhl tumor suppressor gene arises in the majority of Renal Cell Carcinoma (RCC as well as in other types of cancer and is associated with a high degree of vascularization and poor prognosis. Loss of pVHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. In this study, renal carcinoma cell lines with naturally occurring vhl mutations (RCC4 VA and their genetically matched wild-type vhl (RCC4 VHL counterparts were seeded onto 96-well plates and treated with a collection of 1,040 organic extracts obtained from 130 bacterial strains belonging to at least 25 genera of the phyla Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes. This strategy allowed us to identify several extracts obtained from bacterial strain F-278,770T, the type strain of the recently proposed new species Pseudomonas granadensis, showing biological activities not associated with previously known bioactive metabolites. The fractionation and structural elucidation of one of these extracts led to the discovery of a new lipodepsipeptide (MDN-0066 with specific toxicity in pVHL deficient cells that is not detectable in cells with pVHL expression rescue. This specific toxicity is associated with

  13. Identification of the Lipodepsipeptide MDN-0066, a Novel Inhibitor of VHL/HIF Pathway Produced by a New Pseudomonas Species.

    Science.gov (United States)

    Cautain, Bastien; de Pedro, Nuria; Schulz, Christian; Pascual, Javier; Sousa, Thiciana da S; Martin, Jesús; Pérez-Victoria, Ignacio; Asensio, Francisco; González, Ignacio; Bills, Gerald F; Reyes, Fernando; Genilloud, Olga; Vicente, Francisca

    2015-01-01

    Throughout recent history, metabolites of microbial origin have had an extraordinary impact on the welfare of humanity. In fact, natural products have largely been--and still are--considered an exceedingly valuable platform for the discovery of new drugs against diverse pathologies. Such value is partly due to their higher complexity and chemical diversity as compared to those of synthetic and combinatorial compounds. Mutations in the Von Hippel-Lindau (vhl) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types. The primary cause of morbidity and mortality for these patients arises from progression of Renal Cell Carcinoma (RCC) or end-stage renal disease. Inactivation of the Von Hippel-Lindau (vhl) tumor suppressor gene arises in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer and is associated with a high degree of vascularization and poor prognosis. Loss of pVHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. In this study, renal carcinoma cell lines with naturally occurring vhl mutations (RCC4 VA) and their genetically matched wild-type vhl (RCC4 VHL) counterparts were seeded onto 96-well plates and treated with a collection of 1,040 organic extracts obtained from 130 bacterial strains belonging to at least 25 genera of the phyla Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes. This strategy allowed us to identify several extracts obtained from bacterial strain F-278,770T, the type strain of the recently proposed new species Pseudomonas granadensis, showing biological activities not associated with previously known bioactive metabolites. The fractionation and structural elucidation of one of these extracts led to the discovery of a new lipodepsipeptide (MDN-0066) with specific toxicity in pVHL deficient cells that is not detectable in cells with pVHL expression rescue. This specific toxicity is associated with apoptosis

  14. Endemic polycythemia in Russia: mutation in the VHL gene.

    Science.gov (United States)

    Ang, Sonny O; Chen, Hua; Gordeuk, Victor R; Sergueeva, Adelina I; Polyakova, Lydia A; Miasnikova, Galina Y; Kralovics, Robert; Stockton, David W; Prchal, Josef T

    2002-01-01

    Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash families which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1 alpha gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score >2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1 alpha), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1 alpha resulting in accumulation of HIF-1 alpha, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis.

  15. LOSS OF JAK2 REGULATION VIA VHL-SOCS1 E3 UBIQUITIN HETEROCOMPLEX UNDERLIES CHUVASH POLYCYTHEMIA

    Science.gov (United States)

    Russell, Ryan C.; Sufan, Roxana I.; Zhou, Bing; Heir, Pardeep; Bunda, Severa; Sybingco, Stephanie S.; Greer, Samantha N.; Roche, Olga; Heathcote, Samuel A.; Chow, Vinca W.K.; Boba, Lukasz M.; Richmond, Terri D.; Hickey, Michele M.; Barber, Dwayne L.; Cheresh, David A.; Simon, M. Celeste; Irwin, Meredith S.; Kim, William Y.; Ohh, Michael

    2011-01-01

    SUMMARY Chuvash polycythemia (CP) is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the von Hippel-Lindau (VHL) gene whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark features of CP such as hypersensitivity to erythropoietin are unclear. Here, we show that VHL directly binds suppressor of cytokine signalling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated (p)JAK2 for ubiquitin-mediated destruction. In contrast, CP-associated VHL mutants have altered affinity for SOCS1 and fail to engage and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reverses the disease phenotype in vhlR200W/R200W knock-in mice, a model that faithfully recapitulates human CP. These results reveal VHL as a SOCS1-cooperative negative regulator of JAK2 and provide compelling biochemical and preclinical evidence for JAK2- targeted therapy in CP patients. PMID:21685897

  16. Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.

    Science.gov (United States)

    Russell, Ryan C; Sufan, Roxana I; Zhou, Bing; Heir, Pardeep; Bunda, Severa; Sybingco, Stephanie S; Greer, Samantha N; Roche, Olga; Heathcote, Samuel A; Chow, Vinca W K; Boba, Lukasz M; Richmond, Terri D; Hickey, Michele M; Barber, Dwayne L; Cheresh, David A; Simon, M Celeste; Irwin, Meredith S; Kim, William Y; Ohh, Michael

    2011-06-19

    Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.

  17. Microtubular stability affects pVHL-mediated regulation of HIF-1alpha via the p38/MAPK pathway in hypoxic cardiomyocytes.

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    Miao Teng

    Full Text Available BACKGROUND: Our previous research found that structural changes of the microtubule network influence glycolysis in cardiomyocytes by regulating the hypoxia-inducible factor (HIF-1α during the early stages of hypoxia. However, little is known about the underlying regulatory mechanism of the changes of HIF-1α caused by microtubule network alternation. The von Hippel-Lindau tumor suppressor protein (pVHL, as a ubiquitin ligase, is best understood as a negative regulator of HIF-1α. METHODOLOGY/PRINCIPAL FINDINGS: In primary rat cardiomyocytes and H9c2 cardiac cells, microtubule-stabilization was achieved by pretreating with paclitaxel or transfection of microtubule-associated protein 4 (MAP4 overexpression plasmids and microtubule-depolymerization was achieved by pretreating with colchicine or transfection of MAP4 siRNA before hypoxia treatment. Recombinant adenovirus vectors for overexpressing pVHL or silencing of pVHL expression were constructed and transfected in primary rat cardiomyocytes and H9c2 cells. With different microtubule-stabilizing and -depolymerizing treaments, we demonstrated that the protein levels of HIF-1α were down-regulated through overexpression of pVHL and were up-regulated through knockdown of pVHL in hypoxic cardiomyocytes. Importantly, microtubular structure breakdown activated p38/MAPK pathway, accompanied with the upregulation of pVHL. In coincidence, we found that SB203580, a p38/MAPK inhibitor decreased pVHL while MKK6 (Glu overexpression increased pVHL in the microtubule network altered-hypoxic cardiomyocytes and H9c2 cells. CONCLUSIONS/SIGNIFICANCE: This study suggests that pVHL plays an important role in the regulation of HIF-1α caused by the changes of microtubular structure and the p38/MAPK pathway participates in the process of pVHL change following microtubule network alteration in hypoxic cardiomyocytes.

  18. Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism.

    Science.gov (United States)

    Dirckx, Naomi; Tower, Robert J; Mercken, Evi M; Vangoitsenhoven, Roman; Moreau-Triby, Caroline; Breugelmans, Tom; Nefyodova, Elena; Cardoen, Ruben; Mathieu, Chantal; Van der Schueren, Bart; Confavreux, Cyrille B; Clemens, Thomas L; Maes, Christa

    2018-02-12

    The skeleton has emerged as an important regulator of systemic glucose homeostasis, with osteocalcin and insulin representing prime mediators of the interplay between bone and energy metabolism. However, genetic evidence indicates that osteoblasts can influence global energy metabolism through additional, as yet unknown, mechanisms. Here, we report that constitutive or postnatally induced deletion of the hypoxia signaling pathway component von Hippel-Lindau (VHL) in skeletal osteolineage cells of mice led to high bone mass as well as hypoglycemia and increased glucose tolerance, not accounted for by osteocalcin or insulin. In vitro and in vivo data indicated that Vhl-deficient osteoblasts displayed massively increased glucose uptake and glycolysis associated with upregulated HIF-target gene expression, resembling the Warburg effect that typifies cancer cells. Overall, the glucose consumption by the skeleton was increased in the mutant mice, as revealed by 18F-FDG radioactive tracer experiments. Moreover, the glycemia levels correlated inversely with the level of skeletal glucose uptake, and pharmacological treatment with the glycolysis inhibitor dichloroacetate (DCA), which restored glucose metabolism in Vhl-deficient osteogenic cells in vitro, prevented the development of the systemic metabolic phenotype in the mutant mice. Altogether, these findings reveal a novel link between cellular glucose metabolism in osteoblasts and whole-body glucose homeostasis, controlled by local hypoxia signaling in the skeleton.

  19. Elevated homocysteine, glutathione and cysteinylglycine concentrations in patients homozygous for the Chuvash polycythemia VHL mutation

    Science.gov (United States)

    Sergueeva, Adelina I.; Miasnikova, Galina Y.; Okhotin, Daniel J.; Levina, Alla A.; Debebe, Zufan; Ammosova, Tatiana; Niu, Xiaomei; Romanova, Elena A.; Nekhai, Sergei; DiBello, Patricia M.; Jacobsen, Donald W.; Prchal, Josef T.; Gordeuk, Victor R.

    2010-01-01

    In Chuvash polycythemia, homozygous von Hippel-Lindau (VHL) 598C>T leads to increased hypoxia inducible factor-1α and 2α, thromboses and lower systemic blood pressures. Circulating homocysteine, glutathione, γ-glutamyltransferase and cysteinylglycine concentrations were higher in 34 VHL598C>T homozygotes than in 37 normal controls and cysteine was lower. Multivariate analysis showed elevated homocysteine independently associated with higher mean systemic blood pressures and elevated glutathione was associated with lower pressures to a similar degree. Among VHL598C>T homozygotes, homocysteine was elevated with low and normal folate concentrations, consistent with a possible defect in the remethylation pathway. The elevated glutathione and γ-glutamyltranserase levels correlated positively with cysteinylglycine, consistent with possible upregulation of a glutathione synthetic enzyme and γ-glutamyltransferase. Cysteinylglycine correlated inversely with cysteine, consistent with possible reduced cysteinyldipeptidase activity. We conclude that up-regulated hypoxia-sensing may influence multiple steps in thiol metabolism. The effects of the resultant elevated levels of homocysteine and glutathione on systemic blood pressure may largely balance each other out. PMID:18223282

  20. The VHL-dependent regulation of microRNAs in renal cancer

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    Rawlings Lesley H

    2010-10-01

    Full Text Available Abstract Background The commonest histological type of renal cancer, clear cell renal cell carcinoma (cc RCC, is associated with genetic and epigenetic changes in the von Hippel-Lindau (VHL tumour suppressor. VHL inactivation leads to induction of hypoxia-inducible factors (HIFs and a hypoxic pattern of gene expression. Differential levels of specific microRNAs (miRNAs are observed in several tumours when compared to normal tissue. Given the central role of VHL in renal cancer formation, we examined the VHL-dependent regulation of miRNAs in renal cancer. Methods VHL-dependent miRNA expression in cc RCC was determined by microarray analysis of renal cell line RCC4 with mutated VHL (RCC4-VHL and reintroduced wild-type VHL (RCC4 + VHL. Five miRNAs highly upregulated in RCC4 + VHL and five miRNAs highly downregulated in RCC4 + VHL were studied further, in addition to miR-210, which is regulated by the HIF-VHL system. miRNA expression was also measured in 31 cc RCC tumours compared to adjacent normal tissue. Results A significant increase in miR-210, miR-155 and miR-21 expression was observed in the tumour tissue. miR-210 levels also showed a correlation with a HIF-regulated mRNA, carbonic anhydrase IX (CAIX, and with VHL mutation or promoter methylation. An inverse correlation was observed between miR-210 expression and patient survival, and a putative target of miR-210, iron-sulfur cluster assembly protein (ISCU1/2, shows reciprocal levels of mRNA expression in the tumours. Conclusions We have identified VHL-regulated miRNAs and found that for some the regulation is HIF-dependent and for others it is HIF-independent. This pattern of regulation was also seen in renal cancer tissue for several of these miRNAs (miR-210, miR-155, let-7i and members of the miR-17-92 cluster when compared with normal tissue. miR-210 showed marked increases in expression in renal cancer and levels correlated with patient survival. The inverse correlation between miR-210

  1. [Optical Coherence Tomography Angiography in Diagnosis and Post-Treatment Assessment of Hemangioblastomas in Hippel-Lindau Disease].

    Science.gov (United States)

    Lang, S J; Evers, C; Cakir, B; Ludwig, F; Lange, C; Agostini, H

    2017-09-01

    Background Optical coherence tomography angiography (OCTA) offers the possibility to visualize, non-invasively, blood vessels of the retina. In vascular tumors, especially hemangioblastomas in Hippel-Lindau disease, new information can be obtained with OCTA concerning structure of the tumor, tumor activity and treatment success. Patients Ten eyes of 10 patients with retinal hemangioblastoma in Hippel-Lindau disease were included. The age of the patients ranged from 19 years to 65 years (median 44 years). Results A total of 10 active and one inactive hemangioblastomas were examined with OCTA. In larger tumors, only the superficial blood flow could be visualized. Four hemangioblastomas were not treated due to their location near the optic nerve head. Six hemangioblastomas in the peripheral retina were treated with laser photocoagulation. In 4 eyes, a reduced blood flow could be shown directly after the treatment. The visualization of the perfusion was partially blocked after laser treatment. Conclusion OCTA enables innovative methods of pre- and postoperative assessment of retinal hemangioblastomas. It has the potential to give new information about the morphology, activity and effects of treatment. Prospective studies with longer follow-up are needed to evaluate the therapeutic relevance of this new imaging method. Georg Thieme Verlag KG Stuttgart · New York.

  2. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma12

    Science.gov (United States)

    Arias-González, Laura; Moreno-Gimeno, Inmaculada; del Campo, Antonio Rubio; Serrano-Oviedo, Leticia; Valero, María Llanos; Esparís-Ogando, Azucena; de la Cruz-Morcillo, Miguel Ángel; Melgar-Rojas, Pedro; García-Cano, Jesús; Cimas, Francisco José; Hidalgo, María José Ruiz; Prado, Alfonso; Callejas-Valera, Juan Luis; Nam-Cha, Syong Hyun; Giménez-Bachs, José Miguel; Salinas-Sánchez, Antonio S; Pandiella, Atanasio; del Peso, Luis; Sánchez-Prieto, Ricardo

    2013-01-01

    Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas. PMID:23730213

  3. ERK5/BMK1 Is a Novel Target of the Tumor Suppressor VHL: Implication in Clear Cell Renal Carcinoma

    Directory of Open Access Journals (Sweden)

    Laura Arias-González

    2013-06-01

    Full Text Available Extracellular signal-regulated kinase 5 (ERK5, also known as big mitogen-activated protein kinase (MAPK 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas.

  4. Gclust Server: 158408 [Gclust Server

    Lifescience Database Archive (English)

    Full Text Available 158408 DME_CG13221_17864658 Cluster Sequences - 178 Vhl: von Hippel-Lindau CG13221-...o cluster sequences Cluster Sequences Link to related sequences - Sequence length 178 Representative annotation Vhl: von Hippel-Linda

  5. Radioactive seed localization of renal cell carcinoma in a patient with Von Hippel-Lindau disease

    DEFF Research Database (Denmark)

    Hassing, Christina Marie Schiøttz; Tvedskov, Tove Filtenborg; Kroman, Niels

    2017-01-01

    This report describes the case of a patient, who had successful radioactive seed localization (RSL) performed to improve the identification and excision of a renal cell carcinoma. RSL is a new method of preoperative localization, which can ease the surgical procedure, minimize tissue trauma......, and ultimately benefit the patient....

  6. Human Papillomavirus 16 E6 Contributes HIF-1α Induced Warburg Effect by Attenuating the VHL-HIF-1α Interaction

    Directory of Open Access Journals (Sweden)

    Yi Guo

    2014-05-01

    Full Text Available Cervical cancer is still one of the leading causes of cancer deaths in women worldwide, especially in the developing countries. It is a major metabolic character of cancer cells to consume large quantities of glucose and derive more energy by glycolysis even in the presence of adequate oxygen, which is called Warburg effect that can be exaggerated by hypoxia. The high risk subtype HPV16 early oncoprotein E6 contributes host cell immortalization and transformation through interacting with a number of cellular factors. Hypoxia-inducible factor 1α (HIF-1α, a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth, is highly increased by HPV E6. HIF-1α is a best-known target of the von Hippel-Lindau tumor suppressor (VHL as an E3 ligase for degradation. In the present work, we found that HPV16 E6 promotes hypoxia induced Warburg effect through hindering the association of HIF-1α and VHL. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These results suggest that oncoprotein E6 plays a major role in the regulation of Warburg effect and can be a valuable therapeutic target for HPV-related cancer.

  7. VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC{delta}-driven migration.

    Science.gov (United States)

    Razorenova, Olga V; Finger, Elizabeth C; Colavitti, Renata; Chernikova, Sophia B; Boiko, Alexander D; Chan, Charles K F; Krieg, Adam; Bedogni, Barbara; LaGory, Edward; Weissman, Irving L; Broome-Powell, Marianne; Giaccia, Amato J

    2011-02-01

    A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.

  8. Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate.

    Science.gov (United States)

    Merlo, Anna; Bernardo-Castiñeira, Cristóbal; Sáenz-de-Santa-María, Inés; Pitiot, Ana S; Balbín, Milagros; Astudillo, Aurora; Valdés, Nuria; Scola, Bartolomé; Del Toro, Raquel; Méndez-Ferrer, Simón; Piruat, José I; Suarez, Carlos; Chiara, María-Dolores

    2017-01-24

    The hypoxia-inducible factor 1α (HIF-1α) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge. Herein is described an in vivo genetic analysis of the role of VHL, HIF1A and SDH on miR-210 by using knockout murine models, siRNA gene silencing, and analyses of human tumors. HIF-1α knockout abolished hypoxia-induced miR-210 expression in vivo but did not alter its constitutive expression in paraganglia. Normoxic miR-210 levels substantially increased by complete, but not partial, VHL silencing in paraganglia of knockout VHL-mice and by over-expression of p76del-mutated pVHL. Similarly, VHL-mutated PGLs, not those with decreased VHL-gene/mRNA dosage, over-expressed miR-210 and accumulate HIF-1α in most tumor cells. Ablation of SDH activity in SDHD-null cell lines or reduction of the SDHD or SDHB protein levels elicited by siRNA-induced gene silencing did not induce miR-210 whereas the presence of SDH mutations in PGLs and tumor-derived cell lines was associated with mild increase of miR-210 and the presence of a heterogeneous, HIF-1α-positive and HIF-1α-negative, tumor cell population. Thus, activation of HIF-1α is likely an early event in VHL-defective PGLs directly linked to VHL mutations, but it is a late event favored but not directly triggered by SDHx mutations. This combined analysis provides insights into the mechanisms of HIF-1α/miR-210 regulation in normal and tumor tissues potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings.

  9. Homology modeling and molecular dynamics simulation of the HIF2α degradation-related HIF2α-VHL complex.

    Science.gov (United States)

    Dong, Xiaotian; Su, Xiaoru; Yu, Jiong; Liu, Jingqi; Shi, Xiaowei; Pan, Qiaoling; Yang, Jinfeng; Chen, Jiajia; Li, Lanjuan; Cao, Hongcui

    2017-01-01

    Hypoxia-inducible factor 2 alpha (HIF2α), prolyl hydroxylase domain protein 2 (PHD2), and the von Hippel Lindau tumor suppressor protein (pVHL) are three principal proteins in the oxygen-sensing pathway. Under normoxic conditions, a conserved proline in HIF2α is hydroxylated by PHD2 in an oxygen-dependent manner, and then pVHL binds and promotes the degradation of HIF2α. However, the crystal structure of the HIF2α-pVHL complex has not yet been established, and this has limited research on the interaction between HIF and pVHL. Here, we constructed a structural model of a 23-residue HIF2α peptide (528-550)-pVHL-ElonginB-ElonginC complex by using homology modeling and molecular dynamics simulations. We also applied these methods to HIF2α mutants (HYP531PRO, F540L, A530 V, A530T, and G537R) to reveal structural defects that explain how these mutations weaken the interaction with pVHL. Homology modeling and molecular dynamics simulations were used to construct a three-dimensional (3D) structural model of the HIF2α-VHL complex. Subsequently, MolProbity, an active validation tool, was used to analyze the reliability of the model. Molecular mechanics energies combined with the generalized Born and surface area continuum solvation (MM-GBSA) and solvated interaction energy (SIE) methods were used to calculate the binding free energy between HIF2a and pVHL, and the stability of the simulation system was evaluated by using root mean square deviation (RMSD) analysis. We also determined the secondary structure of the system by using the definition of secondary structure of proteins (DSSP) algorithm. Finally, we investigated the structural significance of specific point mutations known to have clinical implications. We established a reliable structural model of the HIF2α-pVHL complex, which is similar to the crystal structure of HIF1α in 1LQB. Furthermore, we compared the structural model of the HIF2α-pVHL complex and the HIF2α (HYP531P, F540L, A530V, A530T, and G537

  10. Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHL(R200W) mutation (Chuvash polycythemia).

    Science.gov (United States)

    Sable, Craig A; Aliyu, Zakari Y; Dham, Niti; Nouraie, Mehdi; Sachdev, Vandana; Sidenko, Stanislav; Miasnikova, Galina Y; Polyakova, Lydia A; Sergueeva, Adelina I; Okhotin, Daniel J; Bushuev, Vladimir; Remaley, Alan T; Niu, Xiaomei; Castro, Oswaldo L; Gladwin, Mark T; Kato, Gregory J; Prchal, Josef T; Gordeuk, Victor R

    2012-02-01

    Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. The objectives of this study were to provide a comprehensive echocardiographic assessment of cardiovascular physiology and to identify clinical, hematologic and cardiovascular risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia. This cross-sectional observational study of 120 adult and pediatric VHL(R200W) homozygotes and 31 controls at outpatient facilities in Chuvashia, Russian Federation included echocardiography assessment of pulmonary artery pressure (tricuspid regurgitation velocity), cardiac volume, and systolic and diastolic function, as well as hematologic and clinical parameters. We determined the prevalence and risk factors for elevation of tricuspid regurgitation velocity in this population and its relationship to phlebotomy. The age-adjusted mean ± SE tricuspid regurgitation velocity was higher in VHL(R200W) homozygotes than controls with normal VHL alleles (2.5±0.03 vs. 2.3±0.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.8±0.05 vs. 4.5±0.09 cm, P=0.005) and left atrial diameter (3.4±0.04 vs. 3.2±0.08 cm, P=0.011) were also greater in the VHL(R200W) homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHL(R200W) homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29; P=0.009). Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic pressure, even after adjustment for

  11. Cyclin D1 genotype and expression in sporadic hemangioblastomas.

    NARCIS (Netherlands)

    Gijtenbeek, J.M.M.; Sprenger, S.H.E.; Franke, B.; Wesseling, P.; Jeuken, J.W.M.

    2005-01-01

    Central nervous system (CNS) hemangioblastomas are highly-vascularized tumors occurring in sporadic form or as a manifestation of von Hippel-Lindau disease (VHL). The VHL protein (pVHL) regulates various target genes, one of which is the CCND1 gene, encoding cyclin D1, a protein that plays a

  12. VHL Manifestations

    Science.gov (United States)

    ... Us Website References Search Patients / What is VHL? / Manifestations People who have VHL disease may experience tumors ... very important to check regularly for possible VHL manifestations throughout a person’s lifetime. Most of these VHL ...

  13. Identification of Somatic Mutations in the von Hippel–Lindau (VHL Gene in a Patient With Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Wen-Chung Wang

    2009-11-01

    Full Text Available One of the known causal molecular events in renal cell carcinoma is somatic mutation in the von Hippel–Lindau (VHL gene. Our study describes a 51-year-old Taiwanese man who had bilateral renal cell carcinoma. The patient underwent radical nephrectomy without postoperative chemotherapy or radiotherapy, and is still alive after renal transplantation without tumor recurrence after > 5 years. To clarify his predisposition for bilateral tumors, we performed molecular genetic analysis of the VHL gene in this study. Polymerase chain reaction–single-strand conformation polymorphism and direct sequencing were performed on DNA of blood samples and paraffin-embedded tumor specimens from this patient. DNA from peripheral blood lymphocytes tested negative for germline mutations. However, there were two heterozygous alleles in the promoter and 3′ untranslated regions of this gene. Nonetheless, the DNA from his tumors showed loss of heterozygosity (LOH in these two loci. In addition to the LOH, we identified some different somatic mutations in his tumor tissues: C287T and G460A in the right-sided tumor, and G244A and G390A in the left-sided tumor. The possible roles of these genetic polymorphisms and point mutations in his renal tumorigenesis are discussed. This report provides new insights into renal cell carcinoma that result from VHL gene alterations in Taiwan.

  14. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma

    NARCIS (Netherlands)

    Eisenhofer, G.; Lenders, J.W.M.; Timmers, H.; Mannelli, M.; Grebe, S.K.; Hofbauer, L.C.; Bornstein, S.R.; Tiebel, O.; Adams, K.; Bratslavsky, G.; Linehan, W.M.; Pacak, K.

    2011-01-01

    BACKGROUND: Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and

  15. A case of renal cell carcinoma and angiomyolipoma in an ...

    African Journals Online (AJOL)

    tuberous sclerosis and von Hippel Lindau. (VHL) syndrome. ... not caused problems until now. She had .... sclerosis? These are important considerations in this case that may offer some treatment options. For example, she could receive treatment with everolimus (Afinitor), which is used for TSC and has been proven to have ...

  16. Systematic genetic screening in a prospective group of Danish patients with pheochromocytoma

    DEFF Research Database (Denmark)

    Hansen, Morten Steen Svarer; Jacobsen, Niels; Frederiksen, Anja Lisbeth

    2017-01-01

    for mutations in the VHL, RET, SDHB, SDHC, and SDHD genes. A total of 41 patients were included, and genetic data were available in 35. In four of the 35 patients, a pathogenic variant was identified prior to the diagnosis of pheochromocytoma (von Hippel-Lindau disease, n=2; neurofibromatosis type 1, n=2...

  17. Duplication of the VHL and IRAK2 genes in a patient with mental retardation/multiple congenital anomalies, epilepsy and ectomorphic habitus.

    Science.gov (United States)

    Chabchoub, E; Michils, G; Vermeesch, J R; De Cock, P; Lagae, L; Fryns, J P

    2010-01-01

    Partial 3p duplications are very rare. Often they are reported in translocations involving other chromosomes, whereas deletions encompassing the VHL gene in 3p25.3 predispose to Van-Hippel Lindau syndrome. We report here a paternally-inherited microduplication of 3p25.3 detected by array comparative genomic hybridisation (aCGH) in a 17 year-old male patient presenting with mental retardation and multiple congenital anomalies (MR/MCA), epilepsy and ectomorphic habitus. He has no tumour and there is no history of familial cancer. We refined the duplication by Multiplex Ligation-dependent Probe Amplification (MLPA) to a 251 kb region encompassing the VHL and IRAK2 genes. The duplication is likely to be causal. Interestingly, duplication of IRAK2 can cause epilepsy. Disruption of the GHRL gene can explain the ectomorphic habitus. To our knowledge, this is the smallest 3p duplication encompassing the VHL region. Its prognosis is unknown and a long-term follow-up is essential for an early diagnosis of malignancy.

  18. Von hippel-lindaus disease: Report of three cases and review of the literature Doença de von Hippel-Lindau: relato de três casos e revisão da literatura

    Directory of Open Access Journals (Sweden)

    Luiz F. Bleggi-Torres

    1995-12-01

    Full Text Available The authors present the autopsy findings of two related patients and the biopsy findings of a thrid member of the family. The oldest member was 34 years old at death and on postmortem examination he had haemangioblastomas in the retina, cerebellum, medulla and spinal cord. Other findings were renal cell carcinoma, phaechromocytoma, cysts of kidney and pancreas, hydromyelia and atypical meningiomas. His brother died when 30 years old. The autopsy revealed haemangioblastomas of cerebellum, renal cell carcinoma and a clear cell cystadenoma of epididymus. The third patient was the daughter of the first and presented with headache and dizziness. CT-scan showed a cerebellar haemangioblastoma. Epidemiological considerations on the commonest visceral and CNS lesions and a review of current diagnostic criteria are discussed.Os autores relatam os achados de autópsia de dois pacientes de uma mesma família e o diagnóstico por biópsia de hemangioblastoma de um terceiro membro desta mesma família. O primeiro paciente tinha 34 anos por ocasião do óbito e os achados de necrópsia mostraram hemangioblastoma de retina, cerebelo, bulbo e medula espinhal, além de carcinoma renal, feocromocitoma, lesões císticas de rim e pâncreas, hidromielia e meningiomas atípicos. Seu irmão morreu com 30 anos de idade e a autópsia revelou hemangioblastomas de cerebelo, carcinoma renal e cistoadenoma de células claras de epididimo. A terceira paciente era filha do primeiro paciente e apresentou cefaléia e ataxia. A tomografia computadorizada mostrou lesão cerebelar cística e a biópsia confirmou tratar-se de hemangioblastoma. São feitas considerações epidemiológicas sobre lesões viscerais e do sistema nervoso mais comumente encontradas, além de discutir critérios diagnósticos.

  19. Cauda equina hemangioblastoma: case report.

    Science.gov (United States)

    da Costa, Leodante Batista; de Andrade, Agustinho; Braga, Bruno Perocco; Ribeiro, Carlos Alberto

    2003-06-01

    Hemangioblastomas of the spinal cord are rare lesions, and those located at the cauda equina are even rarer. Most commonly these tumors are present in patients with von Hippel-Lindau (VHL) syndrome. We describe here the case of a 48 years old woman with a pure radicular hemangioblastoma, not associated with VHL, presenting with radicular pain, diagnosed with magnetic ressonance imaging (MRI) and submitted to total resection with a very good outcome. To our knownledge, this is the second report to describe the MRI aspect of histologically proved hemangioblastoma of the cauda equina in a patient without clinical criteria for VHL.

  20. Cauda equina hemangioblastoma: case report

    Directory of Open Access Journals (Sweden)

    Costa Jr Leodante Batista da

    2003-01-01

    Full Text Available Hemangioblastomas of the spinal cord are rare lesions, and those located at the cauda equina are even rarer. Most commonly these tumors are present in patients with von Hippel-Lindau (VHL syndrome. We describe here the case of a 48 years old woman with a pure radicular hemangioblastoma, not associated with VHL, presenting with radicular pain, diagnosed with magnetic ressonance imaging (MRI and submitted to total resection with a very good outcome. To our knownledge, this is the second report to describe the MRI aspect of histologically proved hemangioblastoma of the cauda equina in a patient without clinical criteria for VHL.

  1. Disease: H00559 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available description, gene) Maher ER, Neumann HP, Richard S von Hippel-Lindau disease: a clinical and scientific revi...amasaki I, Tamura K, Okuda H, Furihata M, Ashida S Von Hippel-Lindau disease: molecular pathological basis, clinic...al criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol 36:337-43 (2

  2. Dicty_cDB: VSE760 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available |pid:none) Xenopus laevis von Hippel-Lindau b... 127 2e-28 BC092334_1( BC092334 ...7 BC132169_1( BC132169 |pid:none) Mus musculus von Hippel-Lindau bin... 124 2e-27 EF087700_1( EF087700 |pid:

  3. Dicty_cDB: VSE765 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available :none) Xenopus laevis von Hippel-Lindau b... 127 3e-28 BC092334_1( BC092334 |pid:...32169_1( BC132169 |pid:none) Mus musculus von Hippel-Lindau bin... 124 2e-27 EF087700_1( EF087700 |pid:none)

  4. ANATOMÍA PATOLÓGICA Y TUMORES HEREDITARIOS

    Directory of Open Access Journals (Sweden)

    Dra. M. Teresa Vial

    2017-07-01

    Nos referiremos desde el punto de vista patológico a algunas de las neoplasias malignas incluidas en síndromes de cáncer hereditario causados por los principales y más frecuentes genes de predisposición genética. Cáncer de Mama (BRCA1/2, Cáncer Colorectal no Polipósico/Síndrome de Lynch (MMR, Cáncer Gástrico Hereditario, Poliposis adenomatosa familiar (PAF, Cáncer Renal y Síndrome de von Hippel Lindau (VHL y Cáncer Medular de Tiroides (RET.

  5. Phospholamban Is Downregulated by pVHL-Mediated Degradation through Oxidative Stress in Failing Heart

    Directory of Open Access Journals (Sweden)

    Shunichi Yokoe

    2017-10-01

    Full Text Available The E3 ubiquitin ligase, von Hippel–Lindau (VHL, regulates protein expression by polyubiquitination. Although the protein VHL (pVHL was reported to be involved in the heart function, the underlying mechanism is unclear. Here, we show that pVHL was upregulated in hearts from two types of genetically dilated cardiomyopathy (DCM mice models. In comparison with the wild-type mouse, both DCM mice models showed a significant reduction in the expression of phospholamban (PLN, a potent inhibitor of sarco(endoplasmic reticulum Ca2+-ATPase, and enhanced interaction between pVHL and PLN. To clarify whether pVHL is involved in PLN degradation in failing hearts, we used carbonylcyanide m-chlorophenylhydrazone (CCCP, a mitochondrial membrane potential (MMP-lowering reagent, to mimic the heart failure condition in PLN-expressing HEK293 cells and found that CCCP treatment resulted in PLN degradation and increased interaction between PLN and pVHL. However, these effects were reversed with the addition of N-acetyl-l-cysteine. Furthermore, the co-transfection of VHL and PLN in HEK293 cells decreased PLN expression under oxidative stress, whereas knockdown of VHL increased PLN expression both under normal and oxidative stress conditions. Together, we propose that oxidative stress upregulates pVHL expression to induce PLN degradation in failing hearts.

  6. Dicty_cDB: VHL444 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available library) VHL444 (Link to dictyBase) - - - Contig-U15033-1 VHL444P (Link to Original site) VHL444F 595 VHL444Z...VHL444Z 674 VHL444P 1249 - - Show VHL444 Library VH (Link to library) Clone ID VHL444 (Link to dictyBase)...tsukuba.ac.jp/CSM/VH/VHL4-B/VHL444Q.Seq.d/ Representative seq. ID VHL444P (Link to Original site) Representative...Representative DNA sequence >VHL444 (VHL444Q) /CSM/VH/VHL4-B/VHL444Q.Seq.d/ CACTGTTGGCCTACTGGTATAGTTACA...significant alignments: (bits) Value VHL444 (VHL444Q) /CSM/VH/VHL4-B/VHL444Q.Seq.d/ 2420 0.0 VHN389 (VHN389Q)

  7. Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas

    Directory of Open Access Journals (Sweden)

    Christ Ordookhanian

    2017-08-01

    Full Text Available Hemangioblastomas are rare and benign tumors accounting for less than 2% of all central nervous system (CNS tumors. The vast majority of hemangioblastomas occur sporadically, whereas a small number of cases, especially in younger patients, are associated with Von Hippel–Lindau (VHL syndrome. It is thought that loss of tumor suppressor function of the VHL gene results in stabilization of hypoxia-inducible factor alpha with downstream activation of cellular proliferative and angiogenic genes that promote tumorigenesis. VHL-related hemangioblastomas predominantly occur in the cerebellum and spine. Lesions are often diagnosed on contrast-enhanced craniospinal MRIs, and the diagnosis of VHL occurs through assessment for germline VHL mutations. Surgical resection remains the primary treatment modality for symptomatic or worrisome lesions, with excellent local control rates and neurological outcomes. Stereotactic radiotherapy can be employed in patients who are deemed high risk for surgery, have multiple lesions, or have non-resectable lesions. Given the tendency for development of either new or multiple lesions, close radiographic surveillance is often recommended for asymptomatic lesions.

  8. Avaliação da resistência/susceptibilidade a Leishmania amazonensis em macrófagos mutantes para o gene Von Hippel Lindau e estudo da expressão de marcadores de superfície de macrófagos frente à infecção com L. amazonensis

    OpenAIRE

    Solange dos Santos Costa

    2016-01-01

    Resumo: Leishmania spp. são parasitas obrigatórios de células fagocíticas mononucleares, responsáveis pelo aparecimento de um grupo de doenças que variam de lesões cutâneas simples, lesões mucosas e a leishmaniose visceral. As lesões causadas por L. amazonensis, espécie utilizada nestes estudos, apresentam características de tecido hipóxico, uma vez que apresentam parasitas em proliferação, migração de células inflamatórias, infecções secundárias com bactérias anaeróbias e a expressão do fato...

  9. Treatment of Exudative and Vasogenic Chorioretinal Diseases Including Variants of AMD and Other CNV Related Maculopathy

    Science.gov (United States)

    2012-10-24

    Coats' Disease; Idiopathic Retinal Telangiectasia; Retinal Angiomatous Proliferation; Polypoidal Choroidal Vasculopathy; Pseudoxanthoma Elasticum; Pathological Myopia; Multi-focal Choroiditis; Rubeosis Iridis; Von Hippel Lindau Disease; BEST VITELLIFORM MACULAR DYSTROPHY, MULTIFOCAL (Disorder)

  10. [Current strategies in the treatment of renal-cell cancer: targeted therapies].

    Science.gov (United States)

    Trigo, José Manuel; Bellmunt, Joaquim

    2008-03-22

    Renal-cell carcinoma represents 95% of all renal tumours. The Von Hippel-Lindau (VHL) tumor-suppressor gene is mutated or silenced in most clear cell renal carcinomas. pVHL loss results in the stabilization of the heterodimeric transcription factor hypoxia-inducible factor (HIF) and enhanced transactivation of HIF target genes. HIF itself has been difficult to inhibit with drug-like molecules although a number of agents that indirectly inhibit HIF, including mTOR (mammalian target of rapamycin) inhibitors, have been identified. Moreover, a number of drugs have been developed that target HIF-responsive gene products, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), implicated in tumor angiogenesis. Many of these targeted therapies, especially sunitinib, have demonstrated significant activity in kidney cancer clinical trials and represent a substantive advance in the treatment of this disease.

  11. VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma.

    Science.gov (United States)

    Lessi, Francesca; Mazzanti, Chiara Maria; Tomei, Sara; Di Cristofano, Claudio; Minervini, Andrea; Menicagli, Michele; Apollo, Alessandro; Masieri, Lorenzo; Collecchi, Paola; Minervini, Riccardo; Carini, Marco; Bevilacqua, Generoso

    2014-03-01

    Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1α (HIF-1α) expression is regulated by O2 level. In normal O2 conditions, VHL binds HIF-1α and allows HIF-1α proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1α interaction is abolished and HIF-1α activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1α gene (HIF-1α) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1α C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1α protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12% of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1α C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1α protein in the nucleus. Our results highlight the role of VHL/HIF-1α pathway in RCC and support the molecular heterogeneity of early-stage ccRCC. More important, we show the involvement of HIF-1α C1772T SNP in ccRCC progression.

  12. Nuclear expression of hypoxia-inducible factor-1alpha in clear cell renal cell carcinoma is involved in tumor progression.

    Science.gov (United States)

    Di Cristofano, Claudio; Minervini, Andrea; Menicagli, Michele; Salinitri, Giuseppe; Bertacca, Gloria; Pefanis, Gerasimos; Masieri, Lorenzo; Lessi, Francesca; Collecchi, Paola; Minervini, Riccardo; Carini, Marco; Bevilacqua, Generoso; Cavazzana, Andrea

    2007-12-01

    The most frequent genomic abnormality in clear cell renal cell carcinoma (cc-RCC) is inactivation of Von Hippel-Lindau gene (VHL). pVHL19 is a ligase promoting proteosomal degradation of hypoxia-inducible factor-1alpha (HIF-1alpha); pVHL30 is associated with microtubules. VHL exert its oncogenetic action both directly and through HIF-1alpha activation. TNM classification is unable to define a correct prognostic evaluation of intracapsular cc-RCC. The nucleo-cytoplasmic trafficking in VHL/HIF-1alpha pathway could be relevant in understanding the molecular pathogenesis of renal carcinogenesis. This study analyzes VHL/HIF-1alpha proteins in a large series of intracapsular cc-RCCs, correlating their expression and cellular localization with prognosis. Two anti-pVHL (clones Ig32 and Ig33) and 1 anti-HIF-1alpha were used on tissue microarrays from 136 intracapsular cc-RCCs (mean follow-up: 74 mo). Clone 32 recognizes both pVHLs, whereas clone 33 only pVHL30. Results were matched with clinicopathologic variables and tumor-specific survival (TSS). A strong cytoplasmic positivity was found for all antibodies in the largest part of cases, associated to a strong nuclear localization in the case of HIF-1alpha. All pVHL-negative cases were associated with high HIF-1alpha expression. pVHL negativity and HIF-1alpha nuclear positivity significantly correlated with shorter TSS. In multivariate analysis both pVHL negativity and HIF-1alpha nuclear expression were independent predictors of TSS. The localization of the proteins well matches with their role and with the supposed tumor molecular pathways. The correlation with prognosis of VHL/HIF-1alpha alterations confirms the relevance of their molecular pathway and of the cellular trafficking of their products in the pathogenesis of renal cancer.

  13. Combined Vhlh and Pten Mutation Causes Genital Tract Cystadenoma and Squamous Metaplasia▿

    Science.gov (United States)

    Frew, Ian J.; Minola, Andrea; Georgiev, Strahil; Hitz, Manuela; Moch, Holger; Richard, Stéphane; Vortmeyer, Alexander O.; Krek, Wilhelm

    2008-01-01

    Patients with von Hippel-Lindau (VHL) disease develop tumors in a range of tissues, but existing mouse models of Vhlh mutation have failed to reproduce these lesions. Epididymal cystadenomas arise frequently in VHL patients, but VHL mutation alone is believed to be insufficient for tumor formation, implying a requirement for cooperating mutations in epididymal pathogenesis. Here we show that epididymal cystadenomas from VHL patients frequently also lack expression of the PTEN tumor suppressor and display activation of phosphatidylinositol 3-kinase (PI3K) pathway signaling. Strikingly, while conditional inactivation of either Vhlh or Pten in epithelia of the mouse genital tract fails to produce a tumor phenotype, their combined deletion causes benign genital tract tumors with regions of squamous metaplasia and cystadenoma. The latter are histologically identical to lesions found in VHL patients. Importantly, these lesions are characterized by expansion of basal stem cells, high levels of expression and activity of HIF1α and HIF2α, and dysregulation of PI3K signaling. Our studies suggest a model for cooperative tumor suppression in which inactivation of PTEN facilitates epididymal cystadenoma genesis initiated by loss of VHL. PMID:18474617

  14. The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A

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    Inmaculada Segura

    2016-03-01

    Full Text Available Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs, and silencing of Phd2 induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas Flna silencing rescues the immature spine phenotype induced by PHD2 inhibition.

  15. Genetic testing by cancer site: endocrine system.

    Science.gov (United States)

    Pilarski, Robert; Nagy, Rebecca

    2012-01-01

    Numerous hereditary syndromes, caused by mutations in multiple tumor suppressor genes and oncogenes, can cause tumors in organs of the endocrine system. The primary syndromes (and genes) addressed here include multiple endocrine neoplasia types 1 and 2 (MEN1 and RET genes), Cowden syndrome (PTEN), hereditary pheochromocytoma/paraganglioma syndromes (multiple genes), and von Hippel-Lindau disease (VHL). Clinical genetic testing is available for each of these syndromes and is generally directed to individuals with endocrine or other tumors and additional features suggestive of a hereditary syndrome. However, for some endocrine tumors, the proportion because of heredity is so high that genetic testing may be appropriate for all affected individuals. Management for hereditary cases typically involves aggressive screening and/or surgical protocols, starting at young ages to minimize morbidity and mortality. Endocrine tumors can be less commonly seen in a number of other hereditary syndromes (eg, neurofibromatosis), which are not reviewed in this section.

  16. Familial Renal Cancer: Molecular Genetics and Surgical Management

    Directory of Open Access Journals (Sweden)

    Glen W. Barrisford

    2011-01-01

    Full Text Available Familial renal cancer (FRC is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL, hereditary papillary renal carcinoma (HPRC, hereditary leiomyomatosis renal cell carcinoma (HLRCC, and Birt-Hogg-Dubé (BHD are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer.

  17. The Oxygen Sensor PHD2 Controls Dendritic Spines and Synapses via Modification of Filamin A

    Science.gov (United States)

    Segura, Inmaculada; Lange, Christian; Knevels, Ellen; Moskalyuk, Anastasiya; Pulizzi, Rocco; Eelen, Guy; Chaze, Thibault; Tudor, Cicerone; Boulegue, Cyril; Holt, Matthew; Daelemans, Dirk; Matondo, Mariette; Ghesquière, Bart; Giugliano, Michele; Ruiz de Almodovar, Carmen; Dewerchin, Mieke; Carmeliet, Peter

    2016-01-01

    Summary Neuronal function is highly sensitive to changes in oxygen levels, but how hypoxia affects dendritic spine formation and synaptogenesis is unknown. Here we report that hypoxia, chemical inhibition of the oxygen-sensing prolyl hydroxylase domain proteins (PHDs), and silencing of Phd2 induce immature filopodium-like dendritic protrusions, promote spine regression, reduce synaptic density, and decrease the frequency of spontaneous action potentials independently of HIF signaling. We identified the actin cross-linker filamin A (FLNA) as a target of PHD2 mediating these effects. In normoxia, PHD2 hydroxylates the proline residues P2309 and P2316 in FLNA, leading to von Hippel-Lindau (VHL)-mediated ubiquitination and proteasomal degradation. In hypoxia, PHD2 inactivation rapidly upregulates FLNA protein levels because of blockage of its proteasomal degradation. FLNA upregulation induces more immature spines, whereas Flna silencing rescues the immature spine phenotype induced by PHD2 inhibition. PMID:26972007

  18. Deubiquitinating enzyme USP33/VDU1 is required for Slit signaling in inhibiting breast cancer cell migration.

    Science.gov (United States)

    Yuasa-Kawada, Junichi; Kinoshita-Kawada, Mariko; Rao, Yi; Wu, Jane Y

    2009-08-25

    Slit regulates migration of not only neurons, but also nonneuronal cells, such as leukocytes and cancer cells. Slit effect on cancer cell migration has not been well-characterized. In this study, we used several different assays to examine Slit effect on breast cancer cell migration in vitro. We show that ubiquitin-specific protease 33 (USP33)/VDU1, originally identified as a von Hippel-Lindau tumor suppressor (VHL) protein-interacting deubiquitinating enzyme, binds to the Robo1 receptor, and that USP33 is required for Slit responsiveness in breast cancer cells. Slit induces redistribution of Robo1 from intracellular compartments to the plasma membrane in a USP33-dependent manner. Slit impairs directional migration of breast cancer cells without affecting their migration speed. This inhibitory effect is Robo-mediated and USP33-dependent. These data uncover a previously unknown function of USP33 and reveal a new player in Slit-Robo signaling in cancer cell migration.

  19. Familial paragangliomas

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    Lips CJM

    2006-10-01

    Full Text Available Abstract Paragangliomas are rare tumours of the autonomic nervous system and occur in sporadic and hereditary forms. They are usually benign and have a low mortality. However, they cause significant morbidity related to their mass effect. Genetic predisposition can occur within the familial tumour syndromes multiple endocrine neoplasia type 2 (MEN 2, von Hippel-Lindau (VHL and neurofibromatosis type 1 (NF-1, or be due to mutations in genes specific to the development of paraganglioma only. Compared to sporadic forms, familial paragangliomas tend to present at a younger age and at multiple sites. Tumours should be diagnosed and resected as early as possible, as it has been shown that morbidity is related to tumour size. This article gives an overview of the current literature on the origin of the different forms of paragangliomas, DNA diagnosis, as well as biochemical and radiological screening guidelines.

  20. Dicty_cDB: VHL663 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available VH (Link to library) VHL663 (Link to dictyBase) - - - Contig-U15767-1 VHL663P (Link... to Original site) VHL663F 574 VHL663Z 702 VHL663P 1256 - - Show VHL663 Library VH (Link to library) Clone ID VHL663 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U15767-1 Original site URL http://dict...WPDGFKYFFVDNQAGDSESAKSGKNLPIQRDIELNWNGEAYEYSNSNYFPINGQG FNDVSYPV--- ---SYATGKCEPDSSLCNDNNICTIDICVHEGILDGLPQG...ik rqelvgqmvlsifl*itklviqnlpnlvkifqfkeiss*igmekhmniviqitsqltdkv smm*aiq--- ---SYATGKCEPDSSLCNDNNICTIDICVHEGI

  1. Dicty_cDB: VHL434 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available VH (Link to library) VHL434 (Link to dictyBase) - - - Contig-U16336-1 VHL434P (Link... to Original site) VHL434F 546 VHL434Z 778 VHL434P 1304 - - Show VHL434 Library VH (Link to library) Clone ID VHL434 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U16336-1 Original site URL http://dict...EVMSCNKFSSKRIGYLAASQSFNEGTDVIVLATHQIRKDFLS SNQSEAYLALNCLSNICTTDLARELANDILTLLSTQKTHILKRAITVLYKIFLRYPES-- - --...GFDISWASFKIVEVMSCNKFSSKRIGYLAASQSFNEGTDVIVLATHQIRKDFLS SNQSEAYLALNCLSNICTTDLARELANDILTLLSTQKTHILKRAITVLYKIFL

  2. Hif-2α promotes degradation of mammalian peroxisomes by selective autophagy.

    Science.gov (United States)

    Walter, Katharina M; Schönenberger, Miriam J; Trötzmüller, Martin; Horn, Michael; Elsässer, Hans-Peter; Moser, Ann B; Lucas, Miriam S; Schwarz, Tobias; Gerber, Philipp A; Faust, Phyllis L; Moch, Holger; Köfeler, Harald C; Krek, Wilhelm; Kovacs, Werner J

    2014-11-04

    Peroxisomes play a central role in lipid metabolism, and their function depends on molecular oxygen. Low oxygen tension or von Hippel-Lindau (Vhl) tumor suppressor loss is known to stabilize hypoxia-inducible factors alpha (Hif-1α and Hif-2α) to mediate adaptive responses, but it remains unknown if peroxisome homeostasis and metabolism are interconnected with Hif-α signaling. By studying liver-specific Vhl, Vhl/Hif1α, and Vhl/Hif2α knockout mice, we demonstrate a regulatory function of Hif-2α signaling on peroxisomes. Hif-2α activation augments peroxisome turnover by selective autophagy (pexophagy) and thereby changes lipid composition reminiscent of peroxisomal disorders. The autophagy receptor Nbr1 localizes to peroxisomes and is likewise degraded by Hif-2α-mediated pexophagy. Furthermore, we demonstrate that peroxisome abundance is reduced in VHL-deficient human clear cell renal cell carcinomas with high HIF-2α levels. These results establish Hif-2α as a negative regulator of peroxisome abundance and metabolism and suggest a mechanism by which cells attune peroxisomal function with oxygen availability. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Altered cytokine profiles in patients with Chuvash polycythemia.

    Science.gov (United States)

    Niu, Xiaomei; Miasnikova, Galina Y; Sergueeva, Adelina I; Polyakova, Lydia A; Okhotin, Daniel J; Tuktanov, Nikolai V; Nouraie, Mehdi; Ammosova, Tatiana; Nekhai, Sergei; Gordeuk, Victor R

    2009-02-01

    Chuvash polycythemia results from a homozygous 598C>T mutation in exon 3 of the von Hippel-Lindau (VHL) gene. This disrupts the normoxia pathway for degrading hypoxia inducible factor (HIF)-1alpha and HIF-2alpha causing altered expression of HIF-1 and HIF-2 inducible genes. As hypoxia induces expression of pro-inflammatory cytokines, we hypothesized that there might be an elevation of Th1 cytokines in the setting of Chuvash polycythemia. We analyzed plasma concentrations of Th1 (interleukins-2 and 12, interferon-gamma, granulocyte-monocyte colony-stimulating factor, tumor necrosis factor-alpha) and Th2 cytokines (interleukins-4, 5, 10, and 13) using the Bio-Plex multiplex suspension array system in 34 VHL598C>T homozygotes and 32 VHL wild-type participants from Chuvashia. Concentrations of all the Th1 and Th2 cytokines measured were elevated in the VHL598C>T homozygotes compared with the control wild-type participants, but the ratios of Th1 to Th2 cytokines did not differ by genotype. In parallel, peripheral blood concentrations of CD4 positive T-helper cells and CD4/CD8 ratio were lower in the VHL598C>T homozygotes. In conclusion, the up-regulated hypoxic response in Chuvash polycythemia is associated with increased plasma products of both the Th1 and Th2 pathways, but the balance between the two pathways seems to be preserved.

  4. Role of the NEDD8 modification of Cul2 in the sequential activation of ECV complex.

    Science.gov (United States)

    Sufan, Roxana I; Ohh, Michael

    2006-11-01

    ECV is an E3 ubiquitin ligase complex, which is composed of elongins B and C, Rbx1, Cul2, and the substrate-conferring von Hippel-Lindau (VHL) tumor-suppressor protein that targets the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-dependent ubiquitin-mediated destruction. Mutations in VHL that compromise proper HIFalpha regulation through ECV have been documented in the majority of renal cell carcinomas, underscoring the significance of the VHL-HIF pathway in renal epithelial oncogenesis. Recent evidence has shown that the modification of Cul2 by the ubiquitin-like molecule NEDD8 increases the activity of ECV to ubiquitylate HIFalpha. However, the underlying mechanism responsible for the NEDD8-mediated induction of ECV function is unknown. Here, we demonstrate that oxygen-dependent recognition of HIFalpha by VHL triggers Rbx1-dependent neddylation of Cul2, which preferentially engages the E2 ubiquitin-conjugating enzyme UbcH5a. These events establish a central role for the neddylation of Cul2 in a previously unrecognized, temporally coordinated activation of ECV with the recruitment of its substrate HIFalpha.

  5. Clin Cancer Res. 2004 Sep 15; 10(18 Pt 2):6371S-6376S.

    Science.gov (United States)

    Meng, Max

    2017-05-01

    Current standard treatments for patients with metastatic (stage IV) renal cell carcinoma involve both surgical removal of tumors and treatment with biological agents such as interleukin 2 or IFN-α. Unfortunately, such approaches are inadequate for most patients with stage IV disease; the result is a median time to progression of 2 to 4 months and an overall survival of 6 to 17 months. Standard chemotherapy has been uniformly disappointing in this disorder. It is clear that new therapies are needed to approach these patients. Recently, a greater understanding of cancer genetics has led to the successful development of novel therapeutics directed against targets linked to specific types of cancer. During the past decade, researchers have identified the von Hippel-Lindau (VHL) gene as an important tumor suppressor in clear cell carcinoma of the kidney. Elucidation of the VHL gene product (pVHL) and its regulation of hypoxia-inducible factor signaling have created a potential genetic basis for growth factor-targeted strategies in this disease. This review will focus on the potential growth factor targets in clear cell carcinoma, their relation to VHL and hypoxia-inducible factor, and the clinical challenges that face their development. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Role of the NEDD8 Modification of Cul2 in the Sequential Activation of ECV Complex

    Directory of Open Access Journals (Sweden)

    Roxana I. Sufan

    2006-11-01

    Full Text Available ECV is an E3 ubiquitin ligase complex, which is composed of elongins B and C, Rbxi, Cul2, the substrate-conferring von Hippel-Lindau (VHL tumorsuppressor protein that targets the catalytic α subunit of hypoxia-inducible factor (HI F for oxygen-dependent ubiquitin-mediated destruction. Mutations in VHL that compromise proper HIFα regulation through ECV have been documented in the majority of renal cell carcinomas, underscoring the significance of the VHL-HIF pathway in renal epithelial oncogenesis. Recent evidence has shown that the modification of Cul2 by the ubiquitin-like molecule NEDD8 increases the activity of ECV to ubiquitylate HIFα. However, the underlying mechanism responsible for the NEDD8-mediated induction of ECV function is unknown. Here, we demonstrate that oxygen-dependent recognition of HIFα by VHL triggers Rbxi-dependent neddylation of Cul2, which preferentially engages the E2 ubiquitin-conjugating enzyme UbcH5a. These events establish a central role for the neddylation of Cul2 in a previously unrecognized, temporally coordinated activation of ECV with the recruitment of its substrate HIFα.

  7. Hypoxia, Hypoxia-inducible Transcription Factors, and Renal Cancer.

    Science.gov (United States)

    Schödel, Johannes; Grampp, Steffen; Maher, Eamonn R; Moch, Holger; Ratcliffe, Peter J; Russo, Paul; Mole, David R

    2016-04-01

    Renal cancer is a common urologic malignancy, and therapeutic options for metastatic disease are limited. Most clear cell renal cell carcinomas (ccRCC) are associated with loss of von Hippel-Lindau tumor suppressor (pVHL) function and deregulation of hypoxia pathways. This review summarizes recent evidence from genetic and biological studies showing that hypoxia and hypoxia-related pathways play critical roles in the development and progress of renal cancer. We used a systematic search for articles using the keywords hypoxia, HIF, renal cancer, and VHL. Identification of the tumor suppressor pVHL has allowed the characterization of important ccRCC-associated pathways. pVHL targets α-subunits of hypoxia-inducible transcription factors (HIF) for proteasomal degradation. The two main HIF-α isoforms have opposing effects on RCC biology, possibly through distinct interactions with additional oncogenes. Furthermore, HIF-1α activity is commonly diminished by chromosomal deletion in ccRCCs, and increased HIF-1 activity reduces tumor burden in xenograft tumor models. Conversely, polymorphisms at the HIF-2α gene locus predispose to the development of ccRCCs, and HIF-2α promotes tumor growth. Genetic studies have revealed a prominent role for chromatin-modifying enzyme genes in ccRCC, and these may further modulate specific aspects of the HIF response. This suggests that, rather than global activation of HIF, specific components of the response are important in promoting kidney cancer. Some of these processes are already targets for current therapeutic strategies, and further dissection of this pathway might yield novel methods of treating RCC. In contrast to many tumor types, HIF-1α and HIF-2α have opposing effects in ccRCC biology, with HIF-1α acting as a tumor suppressor and HIF-2α acting as an oncogene. The overall effect of VHL inactivation will depend on fine-tuning of the HIF response. High levels of hypoxia-inducible transcription factors (HIF) are

  8. Proteomic analysis of signaling network regulation in renal cell carcinomas with differential hypoxia-inducible factor-2α expression.

    Directory of Open Access Journals (Sweden)

    Lokesh Dalasanur Nagaprashantha

    Full Text Available BACKGROUND: The loss of von Hippel-Lindau (VHL protein function leads to highly vascular renal tumors characterized by an aggressive course of disease and refractoriness to chemotherapy and radiotherapy. Loss of VHL in renal tumors also differs from tumors of other organs in that the oncogenic cascade is mediated by an increase in the levels of hypoxia-inducible factor-2α (HIF2α instead of hypoxia-inducible factor-1α (HIF1α. METHODS AND PRINCIPAL FINDINGS: We used renal carcinoma cell lines that recapitulate the differences between mutant VHL and wild-type VHL genotypes. Utilizing a method relying on extracted peptide intensities as a label-free approach for quantitation by liquid chromatography-mass spectrometry, our proteomics study revealed regulation of key proteins important for cancer cell survival, proliferation and stress-resistance, and implicated differential regulation of signaling networks in VHL-mutant renal cell carcinoma. We also observed upregulation of cellular energy pathway enzymes and the stress-responsive mitochondrial 60-kDa heat shock protein. Finding reliance on glutaminolysis in VHL-mutant renal cell carcinoma was of particular significance, given the generally predominant dependence of tumors on glycolysis. The data have been deposited to the ProteomeXchange with identifier PXD000335. CONCLUSIONS AND SIGNIFICANCE: Pathway analyses provided corroborative evidence for differential regulation of molecular and cellular functions influencing cancer energetics, metabolism and cell proliferation in renal cell carcinoma with distinct VHL genotype. Collectively, the differentially regulated proteome characterized by this study can potentially guide translational research specifically aimed at effective clinical interventions for advanced VHL-mutant, HIF2α-over-expressing tumors.

  9. Inactivation of Vhl in Osteochondral Progenitor Cells Causes High Bone Mass Phenotype and Protects Against Age-Related Bone Loss in Adult Mice

    Science.gov (United States)

    Weng, Tujun; Xie, Yangli; Huang, Junlan; Luo, Fengtao; Yi, Lingxian; He, Qifen; Chen, Di; Chen, Lin

    2014-01-01

    Previous studies have shown that disruption of von Hippel–Lindau gene (Vhl) coincides with activation of hypoxia-inducible factor α (HIFα) signaling in bone cells and plays an important role in bone development, homeostasis, and regeneration. It is known that activation of HIF1α signaling in mature osteoblasts is central to the coupling between angiogenesis and bone formation. However, the precise mechanisms responsible for the coupling between skeletal angiogenesis and osteogenesis during bone remodeling are only partially elucidated. To evaluate the role of Vhl in bone homeostasis and the coupling between vascular physiology and bone, we generated mice lacking Vhl in osteochondral progenitor cells (referred to as Vhl cKO mice) at postnatal and adult stages in a tamoxifen-inducible manner and changes in skeletal morphology were assessed by micro–computed tomography (µCT), histology, and bone histomorphometry. We found that mice with inactivation of Vhl in osteochondral progenitor cells at the postnatal stage largely phenocopied that of mice lacking Vhl in mature osteoblasts, developing striking and progressive accumulation of cancellous bone with increased microvascular density and bone formation. These were accompanied with a significant increase in osteoblast proliferation, upregulation of differentiation marker Runx2 and osteocalcin, and elevated expression of vascular endothelial growth factor (VEGF) and phosphorylation of Smad1/5/8. In addition, we found that Vhl deletion in osteochondral progenitor cells in adult bone protects mice from aging-induced bone loss. Our data suggest that the VHL-mediated signaling in osteochondral progenitor cells plays a critical role in bone remodeling at postnatal/adult stages through coupling osteogenesis and angiogenesis. © 2014 American Society for Bone and Mineral Research. PMID:23999831

  10. Dicty_cDB: SSE728 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available cromonas sp. RCC299 chromosome... 131 2e-29 BC054252_1( BC054252 |pid:none) Xenopus laevis von Hippel-Lind...4 2e-27 BC132169_1( BC132169 |pid:none) Mus musculus von Hippel-Lindau bin... 124 2e-27 protein update 2009.

  11. Central nervous system gadolinium accumulation in patients undergoing periodical contrast MRI screening for hereditary tumor syndromes.

    Science.gov (United States)

    Vergauwen, Evelynn; Vanbinst, Anne-Marie; Brussaard, Carola; Janssens, Peter; De Clerck, Dieter; Van Lint, Michel; Houtman, Anne C; Michel, Olaf; Keymolen, Kathelijn; Lefevere, Bieke; Bohler, Susanne; Michielsen, Dirk; Jansen, Anna C; Van Velthoven, Vera; Gläsker, Sven

    2018-01-01

    Patients with hereditary tumor syndromes undergo periodical magnetic resonance imaging (MRI) screening with Gadolinium contrast. Gadolinium accumulation has recently been described in the central nervous system after repeated administrations. The prevalence and rate of accumulation in different subgroups of patients are unknown. Neither are the mechanism nor clinical impact. This may cause uncertainty about the screening. To explore the prevalence and rate of Gadolinium accumulation in different subgroups, we retrospectively analyzed MRIs of patients with von Hippel-Lindau disease (VHL) and Tuberous Sclerosis Complex (TSC). We determined the prevalence and rate of accumulation in the dentate nucleus and globus pallidus on unenhanced T1-weighted MRI from VHL and TSC patients. We compared the signal intensities of these regions to the signal intensity of the pons. We evaluated the impact of number of MRIs, kidney function and liver function on Gadolinium accumulation. Twenty eight VHL patients and 24 TSC patients were included. The prevalence of accumulation in the dentate nucleus and globus pallidus increased linearly according to number of Gadolinium enhanced MRIs and was higher in the VHL group (100%). A significant linear correlation between number of MRIs and increased signal intensity was observed in the VHL group. Gadolinium accumulation occurs in almost all patients undergoing contrast MRI screening after >5 MRIs. We advocate a screening protocol for patients with hereditary tumor syndromes that minimizes the Gadolinium dose. This can be accomplished by using a single administration to simultaneously screen for brain, spine and/or abdominal lesions, using an MRI protocol focused on either VHL- or TSC-specific lesions. Higher prevalence and rate of accumulation in VHL patients may be explained by the typical vascular leakage accompanying central nervous system hemangioblastomas.

  12. Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth.

    Science.gov (United States)

    Vindrieux, David; Devailly, Guillaume; Augert, Arnaud; Le Calvé, Benjamin; Ferrand, Mylène; Pigny, Pascal; Payen, Léa; Lambeau, Gérard; Perrais, Michael; Aubert, Sébastien; Simonnet, Hélène; Dante, Robert; Bernard, David

    2014-02-28

    Loss of secreted phospholipase A2 receptor (PLA2R1) has recently been found to render human primary cells more resistant to senescence whereas increased PLA2R1 expression is able to induce cell cycle arrest, cancer cell death or blockage of cancer cell transformation in vitro, suggesting that PLA2R1 displays tumor suppressive activities. Here we report that PLA2R1 expression strongly decreases in samples of human renal cell carcinoma (RCC). Knockdown of PLA2R1 increases renal cancer cell tumorigenicity supporting a role of PLA2R1 loss to promote in vivo RCC growth. Most RCC result from Von Hippel-Lindau (VHL) tumor suppressor loss-of-function and subsequent gain-of-function of the oncogenic HIF-2alpha/c-MYC pathway. Here, by genetically manipulating VHL, HIF-2alpha and c-MYC, we demonstrate that loss of VHL, stabilization of HIF-2alpha and subsequent increased c-MYC activity, binding and transcriptional repression, through induction of PLA2R1 DNA methylation closed to PLA2R1 transcriptional start site, results in decreased PLA2R1 transcription. Our results describe for the first time an oncogenic pathway leading to PLA2R1 transcriptional repression and the importance of this repression for tumor growth.

  13. UV-induced proteolysis of RNA polymerase II is mediated by VCP/p97 segregase and timely orchestration by Cockayne syndrome B protein.

    Science.gov (United States)

    He, Jinshan; Zhu, Qianzheng; Wani, Gulzar; Wani, Altaf A

    2017-02-14

    RNA polymerase II (RNAPII) acts as a damage sensor for transcription-coupled nucleotide excision repair (TC-NER) and undergoes proteolytic clearance from damaged chromatin by the ubiquitin-proteasome system (UPS). Here, we report that Valosin-containing protein (VCP)/p97, a druggable oncotarget, is essential for RNAPII's proteolytic clearance in mammalian cells. We show that inhibition of VCP/p97, or siRNA-mediated ablation of VCP/p97 and its cofactors UFD1 and UBXD7 severely impairs ultraviolet radiation (UVR)-induced RNAPII degradation. VCP/p97 interacts with RNAPII, and the interaction is enhanced by Cockayne syndrome B protein (CSB). However, the VCP/p97-mediated RNAPII proteolysis occurs independent of CSB. Surprisingly, CSB enhances UVR-induced RNAPII ubiquitination but delays its turnover. Additionally, VCP/p97-mediated RNAPII turnover occurs with and without Von Hippel-Lindau tumor suppressor protein (pVHL), a known substrate receptor of Elongin E3 ubiquitin ligase for RNAPII. Moreover, pVHL re-expression improves cell viability following UVR. Whereas, VCP/p97 inhibition decreases cell viability and enhances a low-dose UVR killing in presence of pVHL. These findings reveal a function of VCP/p97 segregase in UVR-induced RNAPII degradation in mammalian cells, and suggest a role of CSB in coordinating VCP/p97-mediated extraction of ubiquitinated RNAPII and CSB itself from chromatin.

  14. Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma

    Science.gov (United States)

    Gatto, Francesco; Nookaew, Intawat; Nielsen, Jens

    2014-01-01

    Several common oncogenic pathways have been implicated in the emergence of renowned metabolic features in cancer, which in turn are deemed essential for cancer proliferation and survival. However, the extent to which different cancers coordinate their metabolism to meet these requirements is largely unexplored. Here we show that even in the heterogeneity of metabolic regulation a distinct signature encompassed most cancers. On the other hand, clear cell renal cell carcinoma (ccRCC) strongly deviated in terms of metabolic gene expression changes, showing widespread down-regulation. We observed a metabolic shift that associates differential regulation of enzymes in one-carbon metabolism with high tumor stage and poor clinical outcome. A significant yet limited set of metabolic genes that explained the partial divergence of ccRCC metabolism correlated with loss of von Hippel-Lindau tumor suppressor (VHL) and a potential activation of signal transducer and activator of transcription 1. Further network-dependent analyses revealed unique defects in nucleotide, one-carbon, and glycerophospholipid metabolism at the transcript and protein level, which contrasts findings in other tumors. Notably, this behavior is recapitulated by recurrent loss of heterozygosity in multiple metabolic genes adjacent to VHL. This study therefore shows how loss of heterozygosity, hallmarked by VHL deletion in ccRCC, may uniquely shape tumor metabolism. PMID:24550497

  15. Neurofibromatosis 1 with pheochromocytoma

    Directory of Open Access Journals (Sweden)

    K. V. S Hari Kumar

    2011-01-01

    Full Text Available Von Hippel-Lindau (VHL disease includes a wide spectrum of highly vascular tumors like pheochromocytoma, cysts and adenomas of the pancreas and kidney, endolymphatic sac and renal cell carcinoma. Molecular analysis of the VHL gene is vital in these patients and their kindred. Neuroendocrine pancreatic tumors are rare and are known for their malignant and metastatic potential. We discuss an interesting case of a young lady who had a strong family history of central nervous system and spinal tumors. Our patient presented with recently detected severe hypertension. She was found to have elevated urinary normetanephrine levels; radiological imaging revealed bilateral pheochromocytomas with a pancreatic lesion. On genetic analysis, a variation, c.IVS 2 + 3 A > G, was found in the intronic region following exon 2 of the VHL gene. This variant appears novel. This patient underwent bilateral adrenalectomy (right total and left cortical sparing, distal pancreatectomy and splenectomy. Histology was diagnostic for pheochromocytoma with a neuroendocrine tumor of the pancreas. The postoperative period was uneventful. She was advised genetic screening of all her first-degree relatives.

  16. Chronic hypoxia-inducible transcription factor-2 activation stably transforms juxtaglomerular renin cells into fibroblast-like cells in vivo.

    Science.gov (United States)

    Kurt, Birguel; Gerl, Katharina; Karger, Christian; Schwarzensteiner, Ilona; Kurtz, Armin

    2015-03-01

    On the basis of previous observations that deletion of the von Hippel-Lindau protein (pVHL) in juxtaglomerular (JG) cells of the kidney suppresses renin and induces erythropoietin expression, this study aimed to characterize the events underlying this striking change of hormone expression. We found that renin cell-specific deletion of pVHL in mice leads to a phenotype switch in JG cells, from a cuboid and multiple vesicle-containing form into a flat and elongated form without vesicles. This shift of cell phenotype was accompanied by the disappearance of marker proteins for renin cells (e.g., aldo-keto reductase family 1, member 7 and connexin 40) and by the appearance of markers of fibroblast-like cells (e.g., collagen I, ecto-5'-nucleotidase, and PDGF receptor-β). Furthermore, hypoxia-inducible transcription factor-2α (HIF-2α) protein constitutively accumulated in these transformed cells. Codeletion of pVHL and HIF-2α in JG cells completely prevented the phenotypic changes. Similar to renin expression in normal JG cells, angiotensin II negatively regulated erythropoietin expression in the transformed cells. In summary, chronic activation of HIF-2 in renal JG cells leads to a reprogramming of the cells into fibroblast-like cells resembling native erythropoietin-producing cells located in the tubulointerstitium. Copyright © 2015 by the American Society of Nephrology.

  17. Hereditary kidney cancer syndromes: Genetic disorders driven by alterations in metabolism and epigenome regulation.

    Science.gov (United States)

    Hasumi, Hisashi; Yao, Masahiro

    2018-01-11

    Although hereditary kidney cancer syndrome accounts for around five percent of all kidney cancers, the mechanistic insight into tumor development in these rare conditions has provided the foundation for the development of molecular targeting agents currently used for sporadic kidney cancer. In the late 1980s, the comprehensive study for hereditary kidney cancer syndrome was launched in the National Cancer Institute, U.S.A. and the first kidney cancer associated gene, VHL was identified through kindred analysis of von Hippel-Lindau syndrome in 1993. Subsequent molecular studies on VHL function have elucidated that the VHL protein is a component of E3 ubiquitin ligase complex for hypoxia-inducible factor (HIF), which provided basis for the development of tyrosine kinase inhibitors targeting the HIF-VEGF/PDGF pathway. Recent whole-exome sequencing analysis of sporadic kidney cancer exhibited the recurrent mutations in chromatin remodeling genes and the later study has revealed that several chromatin remodeling genes are altered in kidney cancer kindred at germline level. To date, more than 10 hereditary kidney cancer syndromes together with each responsible gene have been characterized and most of causative genes for these genetic disorders are associated with either metabolism or epigenome regulation. In this review article, we describe the molecular mechanisms how an alteration of each kidney cancer associated gene leads to renal tumorigenesis as well as denote therapeutic targets elicited by studies on hereditary kidney cancer. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  18. Diagnostic value of maspin in distinguishing adenocarcinoma from benign biliary epithelium on endoscopic bile duct biopsy.

    Science.gov (United States)

    Chen, Lihong; Huang, Kevin; Himmelfarb, Eric A; Zhai, Jing; Lai, Jin-Ping; Lin, Fan; Wang, Hanlin L

    2015-11-01

    Histopathologic distinction between benign and malignant epithelia on endoscopic bile duct biopsy can be extremely challenging due to small sample size, crush artifact, and a propensity for marked inflammatory and reactive changes after stent placement. Our previous studies have shown that the insulin-like growth factor II mRNA-binding protein 3, S100P, and the von Hippel-Lindau gene product (pVHL) can help the distinction. This study analyzed 134 endoscopic bile duct biopsy specimens (adenocarcinoma 45, atypical 31, and benign 58) by immunohistochemistry for the expression of maspin, a serine protease inhibitor. The results demonstrated that (1) maspin expression was more frequently detected in malignant than in benign biopsies; (2) malignant biopsies frequently showed diffuse, strong/intermediate, and combined nuclear/cytoplasmic staining patterns for maspin, which were much less commonly seen in benign biopsies; (3) the malignant staining patterns for maspin observed in atypical biopsies were consistent with follow-up data showing that 67% of these patients were subsequently diagnosed with adenocarcinoma; (4) a maspin+/S100P+/pVHL- staining profile was seen in 75% of malignant biopsies but in none of the benign cases. These observations demonstrate that maspin is a useful addition to the diagnostic immunohistochemical panel (S100P, pVHL, and insulin-like growth factor II mRNA-binding protein 3) to help distinguish malignant from benign epithelia on challenging bile duct biopsies. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Polycystic kidney disease in a patient with achondroplasia ...

    African Journals Online (AJOL)

    Autosomal dominant polycystic kidney disease is a multisystem disease involving many organs. An association with other diseases such as tuberous sclerosis, von Hippel-Lindau disease and Marfan syndrome have been previously described. We describe a 35 year old female with achondroplasia who developed ...

  20. Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)—Health Professional Version

    Science.gov (United States)

    Hereditary kidney cancer (renal cell cancer) syndromes include von Hippel-Lindau disease, hereditary leiomyomatosis and renal cell cancer, Birt-Hogg-Dubé syndrome, and hereditary papillary renal carcinoma. Learn about the genetics, clinical manifestations, and management of these hereditary cancer syndromes in this expert-reviewed summary.

  1. POLYCYSTIC KIDNEY DISEASE IN A PATIENT WITH ...

    African Journals Online (AJOL)

    hi-tech

    2003-01-01

    Jan 1, 2003 ... Autosomal dominant polycystic kidney disease is a multisystem disease involving many organs. An association with other diseases such as tuberous sclerosis, von Hippel-Lindau disease and Marfan syndrome have been previously described. We describe a 35 year old female with achondroplasia who ...

  2. Endolymphatic sac tumor: case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Sun Yan-Hua

    2012-04-01

    Full Text Available Abstract Endolymphatic sac tumor (ELST is a rare neoplasm which can be encountered sporadically or in Von Hippel-Lindau (VHL disease. Here we report a sporadic case of ELST in 31-year-old man. Neither the symptoms nor a family history of VHL disease were found in the patient. CT imaging demonstrated an expansile lytic lesion of the mastoid process of the left petrous bone. MR scanning revealed a 5.2 cm × 4.7 cm × 4.2 cm mass which showed hyperintensity on T1- and T2-weighted images. Histologic sections showed a papillary, cystic or glandular architecture. The papillary and glandular structures were lined by a single layer of flattened cuboidal-to-columnar cells. The stroma of the papillary fronds was richly vascularized and chronically inflamed. The tumor showed diffusely positive reactivity with cytokeratin (Pan, cytokeratin 19, cytokeratin 5/6, cytokeratin 7, EMA, vimentin, CD56, and NSE and also showed variable reactivity with glial fibrillary acidic protein (GFAP and VEGF. The Ki-67 immunostain showed a proliferation index of Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7973320646763012

  3. Nitric oxide and superoxide: interference with hypoxic signaling.

    Science.gov (United States)

    Brüne, Bernhard; Zhou, Jie

    2007-07-15

    Sensing and responding to changes in oxygen partial pressure assures that the cellular oxygen supply is tightly controlled in order to balance the risks of oxidative damage vs. oxygen deficiency. The hypoxia inducible factor (HIF) regulatory system is controlled by prolyl hydroxylases (PHDs), the von Hippel Lindau protein (pVHL), and the 26S proteasome and transduces changes in oxygenation to adequate intracellular adaptive responses. A functional HIF response requires stabilization of the alpha-subunit, e.g. HIF-1alpha, during hypoxia and dimerization with HIF-1beta, to drive target gene activation. Intriguingly, high concentrations of nitric oxide (NO) stabilize HIF-1alpha and thus mimic a hypoxic response under normoxia. Mechanistically, NO blocks PHD activity and attenuates proline hydroxylation of HIF-1alpha. This causes dissociation of pVHL from HIF-1alpha and, consequently, HIF-1alpha accumulates because proteasomal destruction is impaired. However, during hypoxia low concentrations of NO facilitate destruction of HIF-1alpha and thus reverse HIF signaling. Under these conditions, NO impairs respiration and avoids oxygen gradients that limit PHD activity. An additional layer of complexity comprises the interaction of NO with O(2)(-). Signaling qualities attributed to NO are antagonized by compensatory flux rates of O(2)(-) and vice versa to adjust levels of HIF-1alpha under normoxia and hypoxia. The liaison of NO and hypoxia is versatile and ranges from courting to matrimony and divorce.

  4. Oncotargets in different renal cancer subtypes.

    Science.gov (United States)

    Moch, Holger; Montironi, Rodolfo; Lopez-Beltran, Antonio; Cheng, Liang; Mischo, Axel

    2015-01-01

    Renal cell cancer is a heterogeneous group of cancers with different histologic subtypes. The majority of renal tumors in adults are clear cell renal cell carcinomas, which are characterized by von Hippel- Lindau (VHL) gene alterations. Recent advances in defining the genetic landscape of renal cancer has shown the genetic heterogeneity of clear cell renal cell carcinomas (ccRCC) and the presence of at least 3 additional ccRCC tumor suppressor genes on chromosome 3p. Due to inactivation of VHL, renal cancer cells produce the HIF-responsive growth factor VEGF. The PI3K--mTORC1 signaling axis also represents a target for therapy. The new systemic therapies, including tyrosine kinase inhibitors, monoclonal antibodies, and mTOR inhibitors, aim to suppress angiogenesis with vascular endothelial growth factor as a target. Various VEGF-inhibitors are approved for the treatment of ccRCC and we discuss recent advancements in the treatment of metastatic ccRCC. Other gene alterations have been identified in hereditary cancer syndromes, e.g. FLCN, TSC1, TSC2, TFE3, TFEB, MITF, FH, SDHB, SDHD, MET, and PTEN and we review their role in renal tumor carcinogenesis, prognosis, and targeted therapy. By reviewing the associations between morphologic features and molecular genetics of renal cancer we provide insight into the basis for targeted renal cancer therapy.

  5. Endolymphatic sac tumors: experience of three cases.

    Science.gov (United States)

    Bastier, Pierre-Louis; de Mones, Erwan; Marro, Magali; Elkhatib, Wael; Franco-Vidal, Valérie; Liguoro, Dominique; Darrouzet, Vincent

    2013-03-01

    To describe the clinical features, radiological findings, treatment and outcomes of three cases of endolymphatic sac tumors (ELST). Retrospective analysis of three cases of ELST. The first patient had a large ELST invading the labyrinth after a long history of vertigo. He was recurrence-free 1 year after retrolabyrinthine surgical removal. In the second case, an acute peripheral facial nerve paralysis associated with ipsilateral sensorineural hearing loss led to the diagnosis. A translabyrinthine approach was used to remove the tumor, which recurred three times over 10 years. The third patient was a young woman suffering from von Hippel-Lindau (VHL) disease and referred for a sudden sensorineural hearing loss due to an intralabyrinthine hemorrhage secondary to a 2 mm-large endolymphatic sac-confined ELST. Her hearing was totally lost after the deafness recurred 1 month after this first episode. MRI demonstrated a small bilateral ELST. The patient refused surgery on the deaf side. ELST are difficult to diagnose due to the wide variety of their presentations. Patients with ELST should be screened for VHL disease. Dural invasion and tumor hypervascularization increase the risk of local recurrences after surgery. Early surgical resection may lead to complete tumor removal and inner ear preservation.

  6. Phosphorylation and Ubiquitination Regulate Protein Phosphatase 5 Activity and Its Prosurvival Role in Kidney Cancer

    Directory of Open Access Journals (Sweden)

    Natela Dushukyan

    2017-11-01

    Full Text Available The serine/threonine protein phosphatase 5 (PP5 regulates multiple cellular signaling networks. A number of cellular factors, including heat shock protein 90 (Hsp90, promote the activation of PP5. However, it is unclear whether post-translational modifications also influence PP5 phosphatase activity. Here, we show an “on/off switch” mechanism for PP5 regulation. The casein kinase 1δ (CK1δ phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90. Overexpression of the phosphomimetic T362E-PP5 mutant hyper-dephosphorylates substrates such as the co-chaperone Cdc37 and glucocorticoid receptor in cells. Our proteomic approach revealed that the tumor suppressor von Hippel-Lindau protein (VHL interacts with and ubiquitinates K185/K199-PP5 for proteasomal degradation in a hypoxia- and prolyl-hydroxylation-independent manner. Finally, VHL-deficient clear cell renal cell carcinoma (ccRCC cell lines and patient tumors exhibit elevated PP5 levels. Downregulation of PP5 causes ccRCC cells to undergo apoptosis, suggesting a prosurvival role for PP5 in kidney cancer.

  7. Uptake of prenatal diagnostic testing for retinoblastoma compared to other hereditary cancer syndromes in the Netherlands.

    Science.gov (United States)

    Dommering, Charlotte J; Henneman, Lidewij; van der Hout, Annemarie H; Jonker, Marianne A; Tops, Carli M J; van den Ouweland, Ans M W; van der Luijt, Rob B; Mensenkamp, Arjen R; Hogervorst, Frans B L; Redeker, Egbert J W; de Die-Smulders, Christine E M; Moll, Annette C; Meijers-Heijboer, Hanne

    2017-04-01

    Since the 1980s the genetic cause of many hereditary tumor syndromes has been elucidated. As a consequence, carriers of a deleterious mutation in these genes may opt for prenatal diagnoses (PND). We studied the uptake of prenatal diagnosis for five hereditary cancer syndromes in the Netherlands. Uptake for retinoblastoma (Rb) was compared with uptake for Von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome (LFS), familial adenomatous polyposis (FAP), and hereditary breast ovarian cancer (HBOC). A questionnaire was completed by all nine DNA-diagnostic laboratories assessing the number of independent mutation-positive families identified from the start of diagnostic testing until May 2013, and the number of PNDs performed for these syndromes within these families. Of 187 families with a known Rb-gene mutation, 22 had performed PND (11.8%), this was significantly higher than uptake for FAP (1.6%) and HBOC (cancer syndromes PND started 10-15 years after the introduction and uptake for PND showed an increase after 2009. We conclude that uptake of PND for Rb was significantly higher than for FAP and HBOC, but not different from VHL and LFS. Early onset, high penetrance, lack of preventive surgery and perceived burden of disease may explain these differences.

  8. Mice with increased angiogenesis and osteogenesis due to conditional activation of HIF pathway in osteoblasts are protected from ovariectomy induced bone loss.

    Science.gov (United States)

    Zhao, Qiang; Shen, Xing; Zhang, Wei; Zhu, Guochun; Qi, Jin; Deng, Lianfu

    2012-03-01

    Postmenopausal osteoporosis is characterized by a reduction in the numbers of sinusoidal and arterial capillaries in the bone marrow and reduced bone perfusion suggesting a role of vascular component in the pathogenesis of osteoporosis. Previous studies have shown that bone formation and angiogenesis are positively coupled through activation of the hypoxia inducible factor (HIF1α) signaling pathway. Therefore, we hypothesized that mice with increased angiogenesis and osteogenesis due to activation of the HIF signaling pathway in osteoblasts, via osteoblast specific disruption of HIF degrading protein von Hippel-Lindau (VHL) (ΔVhl), are protected from ovariectomy induced bone loss. ΔVhl mice and control littermates were ovariectomized or sham operated and four weeks later bone quality was evaluated along with blood vessel formation. Trabecular and cortical bone volume was strikingly increased in ΔVhl mice along with blood vessel formation as compared to control littermates. In control mice, ovariectomy significantly decreased bone mineral density, deteriorated bone microarchitecture, and decreased mechanical strength compared to the sham operated control mice. This was accompanied with a significant decrease in blood vessel volume and expressions of HIF1α, HIF2α, and VEGF proteins at the distal femur in ovariectomized control mice. In contrast, ovariectomy in ΔVhl mice had absolutely no effect on either the blood vessel formation or the bone structural and mechanical quality parameters. These data indicate that activation of HIF signaling pathway in osteoblasts may prevent estrogen deficiency-induced bone loss and decrease in blood vessels in bone marrow. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Nuclear molecular imaging of paragangliomas; Imagerie moleculaire nucleaire des paragangliomes

    Energy Technology Data Exchange (ETDEWEB)

    Taieb, D.; Tessonnier, L.; Mundler, O. [Service central de biophysique et de medecine nucleaire, CHU de la Timone, 13 - Marseille (France)

    2010-08-15

    Paragangliomas (PGL) are relatively rare neural crest tumors originating in the adrenal medulla (usually called pheochromocytoma), chemoreceptors (i.e., carotid and aortic bodies) or autonomic ganglia. These tumors are highly vascular, usually benign and slow-growing. PGL may occur as sporadic or familial entities, the latter mostly in association with germline mutations of the succinate dehydrogenase (SDH) B, SDHC, SDHD, SDH5, von Hippel-Lindau (VHL), ret proto-oncogene (RET), neurofibromatosis 1 (NF1) (von Recklinghausen's disease), prolyl hydroxylase domain protein 2 (PHD2) genes and TMEM127. Molecular nuclear imaging has a central role in characterization of PGL and include: somatostatin receptor imaging ({sup 111}In, {sup 68}Ga), MIBG scintigraphy ({sup 131}I, {sup 123}I), {sup 18}F-dihydroxy-phenylalanine ({sup 18}F-DOPA) positron emission tomography (PET), and {sup 18}F-deoxyglucose ({sup 18}F-FDG) PET. The choice of the tracer is not yet fully established but the work-up of familial forms often require the combination of multiple approaches. (authors)

  10. Histomorphological spectrum and immunohistochemical characterization of hemangioblastomas: An entity of unclear histogenesis

    Directory of Open Access Journals (Sweden)

    Sridhar Epari

    2014-01-01

    Full Text Available Introduction: Hemangioblastomas (HBs are rare WHO grade I neoplasms of uncertain histogenesis. Most are sporadic and association with von Hippel-Lindau disease (VHL is uncommon. Materials and Methods: Histomorphological and immunohistochemical evaluation of 24 cases of HBs was done. Results: Age range was 15-68 yrs (median: 30 yrs with male:Female of 1.2:1 (M-13; F-11. Cerebellum was commonest location (n = 20, one each was seen in brain stem, cervical spinal cord, fourth ventricle and frontal lobe, respectively. VHL association was noted in 5 cases. Four cases were recurrent in nature of which 3 were in association with vHL. Histologically, reticular variant was the predominant subtype (n = 15, 5 were of cellular variant and 4 were mixed. Nuclear pleomorphism, nuclear cytoplasmic inclusions, cytoplasmic vacuolation were noted in the stromal cells in varying proportions. Immunohistochemical evaluation was successful in only 11 cases and of which 8 showed stromal cell positivity for alpha-inhibin. CD56 (NCAM, Nestin and synaptophysin positivity was seen in 6, 7 and 4 cases, respectively. Nestin positivity was noted in stromal cells only and no reactivity with the endothelial cells seen. S-100 protein and NSE positivity was seen in 8 and 10 cases, respectively. Glial fibrillary acidic protein (GFAP showed two distinct patterns of immunoreactivity - scattered stromal cell positivity (n:5 and pattern of reactive astrogliosis positivity (n:10. CD44 positivity was noted in 5 cases. VEGF and EGFR positivity was seen in 5 cases each. None of the cases showed positivity for epithelial membrane antigen and no stromal cells in any of the cases showed positivity for CD34 and CD31. Conclusion: HBs can occur in throughout the neuroaxis. Cerebellum is the commonest site of occurrence for HBs and uncommonly can occur in the supratentorial compartment and spinal cord. Its association with vHL is uncommon and no histological or immunohistochemical correlation was

  11. Decreased serum glucose and glycosylated hemoglobin levels in patients with Chuvash polycythemia: a role for HIF in glucose metabolism

    Science.gov (United States)

    McClain, Donald A.; Abuelgasim, Khadega A.; Nouraie, Mehdi; Salomon-Andonie, Juan; Niu, Xiaomei; Miasnikova, Galina; Polyakova, Lydia A.; Sergueeva, Adelina; Okhotin, Daniel J.; Cherqaoui, Rabia; Okhotin, David; Cox, James E.; Swierczek, Sabina; Song, Jihyun; Simon, M.Celeste; Huang, Jingyu; Simcox, Judith A.; Yoon, Donghoon; Prchal, Josef T.; Gordeuk, Victor R.

    2012-01-01

    In Chuvash polycythemia, a homozygous 598C>T mutation in the von Hippel-Lindau gene (VHL) leads to an R200W substitution in VHL protein, impaired degradation of α-subunits of hypoxia inducible factor (HIF)-1 and HIF-2, and augmented hypoxic responses during normoxia. Chronic hypoxia of high altitude is associated with decreased serum glucose and insulin concentrations. Other investigators reported that HIF-1 promotes cellular glucose uptake by increased expression of GLUT1 and increased glycolysis by increased expression of enzymes such as PDK. On the other hand, inactivation of Vhl in murine liver leads to hypoglycemia associated with a HIF-2-related decrease in the expression of the gluconeogenic enzymes genes Pepck, G6pc, and Glut2. We therefore hypothesized that glucose concentrations are decreased in individuals with Chuvash polycythemia. We found that 88 Chuvash VHLR200W homozygotes had lower random glucose and glycosylated hemoglobin A1c levels than 52 Chuvash subjects with wildtype VHL alleles. Serum metabolomics revealed higher glycerol and citrate levels in the VHLR200W homozygotes. We expanded these observations in VHLR200W homozygote mice and found that they had lower fasting glucose values and lower glucose excursions than wild-type control mice but no change in fasting insulin concentrations. Hepatic expression of Glut2 and G6pc but not Pdk2 was decreased and skeletal muscle expression of Glut1, Pdk1 and Pdk4 was increased. These results suggest that both decreased hepatic gluconeogenesis and increased skeletal uptake and glycolysis contribute to the decreased glucose concentrations. Further study is needed to determine whether pharmacologically manipulating HIF expression might be beneficial for treatment of diabetic patients. PMID:23015148

  12. Fructose-1,6-bisphosphatase opposes renal carcinoma progression.

    Science.gov (United States)

    Li, Bo; Qiu, Bo; Lee, David S M; Walton, Zandra E; Ochocki, Joshua D; Mathew, Lijoy K; Mancuso, Anthony; Gade, Terence P F; Keith, Brian; Nissim, Itzhak; Simon, M Celeste

    2014-09-11

    Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is characterized by elevated glycogen levels and fat deposition. These consistent metabolic alterations are associated with normoxic stabilization of hypoxia-inducible factors (HIFs) secondary to von Hippel-Lindau (VHL) mutations that occur in over 90% of ccRCC tumours. However, kidney-specific VHL deletion in mice fails to elicit ccRCC-specific metabolic phenotypes and tumour formation, suggesting that additional mechanisms are essential. Recent large-scale sequencing analyses revealed the loss of several chromatin remodelling enzymes in a subset of ccRCC (these included polybromo-1, SET domain containing 2 and BRCA1-associated protein-1, among others), indicating that epigenetic perturbations are probably important contributors to the natural history of this disease. Here we used an integrative approach comprising pan-metabolomic profiling and metabolic gene set analysis and determined that the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) is uniformly depleted in over six hundred ccRCC tumours examined. Notably, the human FBP1 locus resides on chromosome 9q22, the loss of which is associated with poor prognosis for ccRCC patients. Our data further indicate that FBP1 inhibits ccRCC progression through two distinct mechanisms. First, FBP1 antagonizes glycolytic flux in renal tubular epithelial cells, the presumptive ccRCC cell of origin, thereby inhibiting a potential Warburg effect. Second, in pVHL (the protein encoded by the VHL gene)-deficient ccRCC cells, FBP1 restrains cell proliferation, glycolysis and the pentose phosphate pathway in a catalytic-activity-independent manner, by inhibiting nuclear HIF function via direct interaction with the HIF inhibitory domain. This unique dual function of the FBP1 protein explains its ubiquitous loss in ccRCC, distinguishing FBP1 from previously identified tumour suppressors that are not consistently mutated in all tumours.

  13. Dicty_cDB: Contig-U04465-1 [Dicty_cDB

    Lifescience Database Archive (English)

    Full Text Available 01333 |pid:none) Micromonas sp. RCC299 chromosome... 114 5e-24 BC054252_1( BC054252 |pid:none) Xenopus laevis von Hippel-Linda...ein-1 (VBP-1) mR... 110 7e-23 BC132169_1( BC132169 |pid:none) Mus musculus von Hippel-Linda...70_1( BC095370 |pid:none) Danio rerio von Hippel-Lindau bind... 105 1e-21 ( O1805

  14. Polymorphism and genetic mapping of the human oxytocin receptor gene on chromosome 3

    Energy Technology Data Exchange (ETDEWEB)

    Michelini, S.; Urbanek, M.; Goldman, D. [National Institute of Health-National Institute of Alcohol Abuse and Alcoholism, Rockville, MD (United States)] [and others

    1995-06-19

    Centrally administered oxytocin has been reported to facilitate affiliative and social behaviors, in functional harmony with its well-known peripheral effects on uterine contraction and milk ejection. The biological effects of oxytocin could be perturbed by mutations occurring in the sequence of the oxytocin receptor gene, and it would be of interest to establish the position of this gene on the human linkage map. Therefore we identified a polymorphism at the human oxytocin receptor gene. A portion of the 3{prime} untranslated region containing a 30 bp CA repeat was amplified by polymerase chain reaction (PCR), revealing a polymorphism with two alleles occurring with frequencies of 0.77 and 0.23 in a sample of Caucasian CEPH parents (n = 70). The CA repeat polymorphism we detected was used to map the human oxytocin receptor to chromosome 3p25-3p26, in a region which contains several important genes, including loci for Von Hippel-Lindau disease (VHL) and renal cell carcinoma. 53 refs., 2 figs., 1 tab.

  15. Stereotactic radiosurgery versus surgical resection for spinal hemangioblastoma: A systematic review.

    Science.gov (United States)

    Bridges, Kelly J; Jaboin, Jerry J; Kubicky, Charlotte D; Than, Khoi D

    2017-03-01

    Spinal cord hemangioblastomas are benign vascular tumors arising sporadically in approximately 70-80% of cases. They can also be manifestations of von Hippel-Lindau (VHL) disease, as these patients will often have multiple spinal hemangioblastomas. Historically, surgical management of symptomatic intramedullary hemangioblastomas has been considered the treatment of choice. However, recently, stereotactic radiosurgery has been utilized as an adjuvant therapeutic modality, and some have suggested it may have utility as the primary treatment option for these tumors. Because of the rarity of spinal hemangioblastomas, management options, clinical outcomes, and prognostic factors have not yet been fully elucidated. The National Institutes of Health (PubMed) was queried to identify all studies describing treatment of spinal hemangioblastomas. Focus was narrowed to institutional retrospective reviews, and comparisons were drawn regarding outcomes of both stereotactic radiosurgery and surgical resection. Stereotactic radiosurgery achieves stable or reduced tumor size with relatively little adverse clinical outcome long-term. Meanwhile, surgical resection results in successful removal of the tumor with approximately 96% stable or improved long-term clinical effect. Cross-platform analysis has been challenging when comparing efficacy amongst treatment modalities for this rare tumor. For the institutional retrospective reviews that exist, researchers tend to collect and record data in a multitude of fashions, making direct comparisons problematic. As such, the authors propose use of a national registry to input data prospectively about spinal cord hemangioblastomas. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Genetics of hereditary head and neck paragangliomas.

    Science.gov (United States)

    Boedeker, Carsten C; Hensen, Erik F; Neumann, Hartmut P H; Maier, Wolfgang; van Nederveen, Francien H; Suárez, Carlos; Kunst, Henricus P; Rodrigo, Juan P; Takes, Robert P; Pellitteri, Phillip K; Rinaldo, Alessandra; Ferlito, Alfio

    2014-06-01

    The purpose of this study was to give an overview on hereditary syndromes associated with head and neck paragangliomas (HNPGs). Our methods were the review and discussion of the pertinent literature. About one third of all patients with HNPGs are carriers of germline mutations. Hereditary HNPGs have been described in association with mutations of 10 different genes. Mutations of the genes succinate dehydrogenase subunit D (SDHD), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit B (SDHB) are the cause of paraganglioma syndromes (PGLs) 1, 2, 3, and 4. Succinate dehydrogenase subunit A (SDHA), von Hippel-Lindau (VHL), and transmembrane protein 127 (TMEM127) gene mutations also harbor the risk for HNPG development. HNPGs in patients with rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and MYC-associated factor X (MAX) gene mutations have been described very infrequently. All patients with HNPGs should be offered a molecular genetic screening. This screening may usually be restricted to mutations of the genes SDHD, SDHB, and SDHC. Certain clinical parameters can help to set up the order in which those genes should be tested. © 2013 Wiley Periodicals, Inc.

  17. Clinical and Genetic Aspects of Sporadic Non-Medullar Thyroid Cancer

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    U Rumjanzeva

    2006-03-01

    Full Text Available The role of somatic mutations in sporadic thyroid cancer is unclear today. Probably they coming out as aetiological factors in carcinogenesis as well as, respectfully to many authors, can to participate in TC pathogenesis and to determine the clinical course and prognosis of the disease. For today as main oncogenes taking part in initiation of thyroid malignant tumors are considered: RET/PTC, TRK, PTEN, P53, RAS, MET, PPARγ. By means of genetic investigations scientists are trying to solve problems with thyroid cancer differentiated diagnostics (cytokeratin-19, cytokeratin-20, mesothelial cells antigen (Hector Battifora MEsotelial (cell or HBME-1, loss of heterozigitoty (LOH in short arm of 3 chromosome (gene VHL -von Hippel Lindau, 3р26. Recently in foreign literature appeared reports of activated mutations in gene BRAF which most frequently are occurred in melanoma and papillary TC. Prognosis of thyroid cancer may reflected by the LOH as a biological breakage as well as changes of tumor suppressive gene P53 which fraught with decrease of disease prognosis. Thus, both researchers and clinicians have many questions concerning the role of genome, particularly in order to precise of genetic abnormality influence on tumor growth and therefore for assessment of clinical prognosis and with aim to chose adequate treatment tactic in each case.

  18. An Elongin-Cullin-SOCS Box Complex Regulates Stress-Induced Serotonergic Neuromodulation

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    Xicotencatl Gracida

    2017-12-01

    Full Text Available Neuromodulatory cells transduce environmental information into long-lasting behavioral responses. However, the mechanisms governing how neuronal cells influence behavioral plasticity are difficult to characterize. Here, we adapted the translating ribosome affinity purification (TRAP approach in C. elegans to profile ribosome-associated mRNAs from three major tissues and the neuromodulatory dopaminergic and serotonergic cells. We identified elc-2, an Elongin C ortholog, specifically expressed in stress-sensing amphid neuron dual ciliated sensory ending (ADF serotonergic sensory neurons, and we found that it plays a role in mediating a long-lasting change in serotonin-dependent feeding behavior induced by heat stress. We demonstrate that ELC-2 and the von Hippel-Lindau protein VHL-1, components of an Elongin-Cullin-SOCS box (ECS E3 ubiquitin ligase, modulate this behavior after experiencing stress. Also, heat stress induces a transient redistribution of ELC-2, becoming more nuclearly enriched. Together, our results demonstrate dynamic regulation of an E3 ligase and a role for an ECS complex in neuromodulation and control of lasting behavioral states.

  19. Progress of Molecular Targeted Therapies for Advanced Renal Cell Carcinoma

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    Alessandro Conti

    2013-01-01

    Full Text Available Vascular endothelial growth factor (VEGF plays a crucial role in tumor angiogenesis. VEGF expression in metastatic renal cell carcinoma (mRCC is mostly regulated by hypoxia, predominantly via the hypoxia-induced factor (HIF/Von Hippel-Lindau (VHL pathway. Advances in our knowledge of VEGF role in tumor angiogenesis, growth, and progression have permitted development of new approaches for the treatment of mRCC, including several agents targeting VEGF and VEGF receptors: tyrosine kinase pathway, serine/threonine kinases, α5β1-integrin, deacetylase, CD70, mammalian target of rapamycin (mTOR, AKT, and phosphatidylinositol 3′-kinase (PI3K. Starting from sorafenib and sunitinib, several targeted therapies have been approved for mRCC treatment, with a long list of agents in course of evaluation, such as tivozanib, cediranib, and VEGF-Trap. Here we illustrate the main steps of tumor angiogenesis process, defining the pertinent therapeutic targets and the efficacy and toxicity profiles of these new promising agents.

  20. Anti-angiogenic and anti-tumor activity of Bavachinin by targeting hypoxia-inducible factor-1α.

    Science.gov (United States)

    Nepal, Manoj; Choi, Hwa Jung; Choi, Bo-Yun; Kim, Se Lim; Ryu, Jae-Ha; Kim, Do Hee; Lee, Young-Hoon; Soh, Yunjo

    2012-09-15

    Hypoxia-inducible factor-1 (HIF-1) consists of two subunits, the HIF-1β, which is constitutively expressed, and HIF-1α, which is oxygen-responsive. HIF-1α is over-expressed in response to hypoxia, increasing transcriptional activity linked to tumor progression, angiogenesis, metastasis, and invasion. This study aimed to demonstrate that the natural compound, Bavachinin, has potent anti-angiogenic activity in vitro and in vivo. Bavachinin inhibited increases in HIF-1α activity in human KB carcinoma (HeLa cell derivative) and human HOS osteosarcoma cells under hypoxia in a concentration-dependent manner, probably by enhancing the interaction between von Hippel-Lindau (VHL) and HIF-1α. Furthermore, Bavachinin decreased transcription of genes associated with angiogenesis and energy metabolism that are regulated by HIF-1, such as vascular endothelial growth factors (VEGF), Glut 1 and Hexokinase 2. Bavachinin also inhibited tube formation in human umbilical vein endothelial cells (HUVECs) as well as in vitro migration of KB cells. In vivo studies showed that injecting Bavachinin thrice weekly for four weeks significantly reduced tumor volume and CD31 expression in nude mice with KB xenografts. These data indicate that Bavachinin could be used as a therapeutic agent for inhibiting tumor angiogenesis. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation.

    Science.gov (United States)

    Jang, Yunseon; Han, Jeongsu; Kim, Soo Jeong; Kim, Jungim; Lee, Min Joung; Jeong, Soyeon; Ryu, Min Jeong; Seo, Kang-Sik; Choi, Song-Yi; Shong, Minho; Lim, Kyu; Heo, Jun Young; Kweon, Gi Ryang

    2015-11-10

    Renal cell carcinoma (RCC) progression resulting from the uncontrolled migration and enhanced angiogenesis is an obstacle to effective therapeutic intervention. Tumor metabolism has distinctive feature called Warburg effect, which enhances the aerobic glycolysis rapidly supplying the energy for migration of tumor. To manipulate this metabolic change characteristic of aggressive tumors, we utilized the citrus extract, auraptene, known as a mitochondrial inhibitor, testing its anticancer effects against the RCC4 cell line. We found that auraptene impaired RCC4 cell motility through reduction of mitochondrial respiration and glycolytic pathway-related genes. It also strongly disrupted VEGF-induced angiogenesis in vitro and in vivo. Hypoxia-inducible factor 1a (HIF-1a), a key regulator of cancer metabolism, migration and angiogenesis that is stably expressed in RCCs by virtue of a genetic mutation in the von Hippel-Lindau (VHL) tumor-suppressor protein, was impeded by auraptene, which blocked HIF-1a translation initiation without causing cytotoxicity. We suggest that blockade HIF-1a and reforming energy metabolism with auraptene is an effective approach for suspension RCC progression.

  2. Simultaneous adrenal pheochromocytoma and carotid body paraganglioma in a woman

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    Han, Eun Ji; Lee, Sang Hoon; Song, In Uk; Chung, Yong An; Maeng, Lee So [The Catholic Univ. of Korea, Incheon (Korea, Republic of)

    2012-03-15

    Simultaneous occurrence of carotid body tumor and pheochromocytoma is rare. Most pheochromocytomas have grown on adrenal medulla, but some of the pheochromocytoma patients have multifocal paragangliomas arising from extraaderenal tissues. Pheochromocytomas and paragangliomas occur as sporadic tumors or they can be associated with several hereditary syndromes such as (1) multiple endocrine neoplasia type 2 (MEN 2), (2) Von Hippel Lindau disease (VHL) and (3) neurofibromatosis type 1 as an unusual genetic cause of pheochromocytomas. Genetic testing is recommended for patients with an apparently sporadic pheochromocytoma under the age of 20 years with a family history or features suggestive of hereditary pheochromocytoma or for patients with sympathetic paragangliomas. For individuals who do not meet these criteria, genetic testing is optional. Discovery of pheochromocytoma or paraganglioma in a patient should lead to a careful search to rule out multifocal lesions and/or hereditary syndromes. The diagnosis of pheochromocytoma and paraganglioma is made by biochemical testing, and imaging is done to localize the tumor for surgical planning. F 18 FDG PET has proved to be an effective tool in the localization of pheochromocytomas and paragangliomas.

  3. Epidemiology, molecular epidemiology, and risk factors for renal cell carcinoma

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    Chiara Paglino

    2011-12-01

    Full Text Available Despite only accounting for approximately 2% of all new primary cancer cases, renal cell carcinoma (RCC incidence has dramatically increased over time. Incidence rates vary greatly according to geographic areas, so that it is extremely likely that exogenous risk factors could play an important role in the development of this cancer. Several risk factors have been linked with RCC, including cigarette smoking, obesity, hypertension (and antihypertensive drugs, chronic kidney diseases (also dialysis and transplantation, as well as the use of certain analgesics. Furthermore, although RCC has not generally been considered an occupational cancer, several types of occupationally-derived exposures have been implicated in its pathogenesis. These include exposure to asbestos, chlorinated solvents, gasoline, diesel exhaust fumes, polycyclic aromatic hydrocarbons, printing inks and dyes, cadmium and lead. Finally, families with a predisposition to the development of renal neoplasms were identified and the genes involved discovered and characterized. Therefore, there are now four well-characterized, genetically determined syndromes associated with an increased incidence of kidney tumors, i.e., Von Hippel Lindau (VHL, Hereditary Papillary Renal Carcinoma (HPRC, Birt-Hogg-Dubé Syndrome (BHD, and Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC. This review will address present knowledge about the epidemiology, molecular epidemiology and risk factors of RCC.

  4. Capture-C reveals preformed chromatin interactions between HIF-binding sites and distant promoters.

    Science.gov (United States)

    Platt, James L; Salama, Rafik; Smythies, James; Choudhry, Hani; Davies, James Oj; Hughes, Jim R; Ratcliffe, Peter J; Mole, David R

    2016-10-01

    Hypoxia-inducible factor (HIF) directs an extensive transcriptional cascade that transduces numerous adaptive responses to hypoxia. Pan-genomic analyses, using chromatin immunoprecipitation and transcript profiling, have revealed large numbers of HIF-binding sites that are generally associated with hypoxia-inducible transcripts, even over long chromosomal distances. However, these studies do not define the specific targets of HIF-binding sites and do not reveal how induction of HIF affects chromatin conformation over distantly connected functional elements. To address these questions, we deployed a recently developed chromosome conformation assay that enables simultaneous high-resolution analyses from multiple viewpoints. These assays defined specific long-range interactions between intergenic HIF-binding regions and one or more promoters of hypoxia-inducible genes, revealing the existence of multiple enhancer-promoter, promoter-enhancer, and enhancer-enhancer interactions. However, neither short-term activation of HIF by hypoxia, nor long-term stabilization of HIF in von Hippel-Lindau (VHL)-defective cells greatly alters these interactions, indicating that at least under these conditions, HIF can operate on preexisting patterns of chromatin-chromatin interactions that define potential transcriptional targets and permit rapid gene activation by hypoxic stress. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  5. Analyses of Potential Predictive Markers and Response to Targeted Therapy in Patients with Advanced Clear-cell Renal Cell Carcinoma

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    Yan Song

    2015-01-01

    Full Text Available Background: Vascular endothelial growth factor-targeted agents are standard treatments in advanced clear-cell renal cell carcinoma (ccRCC, but biomarkers of activity are lacking. The aim of this study was to investigate the association of Von Hippel-Lindau (VHL gene status, vascular endothelial growth factor receptor (VEGFR or stem cell factor receptor (KIT expression, and their relationships with characteristics and clinical outcome of advanced ccRCC. Methods: A total of 59 patients who received targeted treatment with sunitinib or pazopanib were evaluated for determination at Cancer Hospital and Institute, Chinese Academy of Medical Sciences between January 2010 and November 2012. Paraffin-embedded tumor samples were collected and status of the VHL gene and expression of VEGFR and KIT were determined by VHL sequence analysis and immunohistochemistry. Clinical-pathological features were collected and efficacy such as response rate and Median progression-free survival (PFS and overall survival (OS were calculated and then compared based on expression status. The Chi-square test, the Kaplan-Meier method, and the Lon-rank test were used for statistical analyses. Results: Of 59 patients, objective responses were observed in 28 patients (47.5%. The median PFS was 13.8 months and median OS was 39.9 months. There was an improved PFS in patients with the following clinical features: Male gender, number of metastatic sites 2 or less, VEGFR-2 positive or KIT positive. Eleven patients (18.6% had evidence of VHL mutation, with an objective response rate of 45.5%, which showed no difference with patients with no VHL mutation (47.9%. VHL mutation status did not correlate with either overall response rate (P = 0.938 or PFS (P = 0.277. The PFS was 17.6 months and 22.2 months in VEGFR-2 positive patients and KIT positive patients, respectively, which was significantly longer than that of VEGFR-2 or KIT negative patients (P = 0.026 and P = 0.043. Conclusion

  6. BC-Box Motif-Mediated Neuronal Differentiation of Somatic Stem Cells

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    Hiroshi Kanno

    2018-02-01

    Full Text Available Von Hippel-Lindau tumor suppressor protein (pVHL functions to induce neuronal differentiation of neural stem/progenitor cells (NSCs and skin-derived precursors (SKPs. Here we identified a neuronal differentiation domain (NDD in pVHL. Neuronal differentiation of SKPs was induced by intracellular delivery of a peptide composed of the amino-acid sequences encoded by the NDD. Neuronal differentiation mediated by the NDD was caused by the binding between it and elongin C followed by Janus kinase-2 (JAK2 ubiquitination of JAK2 and inhibition of the JAK2/the signal transducer and activator of transcription-3(STAT3 pathway. The NDD in pVHL contained the BC-box motif ((A,P,S,TLXXX (A,C XXX(A,I,L,V corresponding to the binding site of elongin C. Therefore, we proposed that other BC-box proteins might also contain an NDD; and subsequently also identified in them an NDD containing the amino-acid sequence encoded by the BC-box motif in BC-box proteins. Furthermore, we showed that different NDD peptide-delivered cells differentiated into different kinds of neuron-like cells. That is, dopaminergic neuron-like cells, cholinergic neuron-like cells, GABAnergic neuron-like cells or rhodopsin-positive neuron-like cells were induced by different NDD peptides. These novel findings might contribute to the development of a new method for promoting neuronal differentiation and shed further light on the mechanism of neuronal differentiation of somatic stem cells.

  7. Synchronous adrenocortical neoplasms, paragangliomas, and pheochromocytomas: syndromic considerations regarding an unusual constellation of endocrine tumors.

    Science.gov (United States)

    LeBlanc, Melissa; Tabrizi, Mohsen; Kapsner, Patricia; Hanson, Joshua Anspach

    2014-12-01

    The most common clinical syndromes presenting with paragangliomas and/or pheochromocytomas as their endocrine components are multiple endocrine neoplasia type 2, neurofibromatosis, Von Hippel-Lindau syndrome, Carney-Stratakis syndrome, Carney triad, and the recently described hereditary paraganglioma syndrome. Only Carney triad is known to also present with adrenocortical adenomas, currently representing the only described syndrome in which all 3 of the aforementioned tumors are found together. In most cases, prototypical lesions of the triad such as gastrointestinal stromal tumor and pulmonary chondromas are also seen. We present a case of a young woman with synchronous paragangliomas, adrenal/extra-adrenal cortical neoplasms, and pheochromocytoma without genetic mutations for multiple endocrine neoplasia 2, Von Hippel-Lindau syndrome, neurofibromatosis, and succinate dehydrogenase. We speculate that this represents a previously undescribed presentation of Carney triad and, at the very least, indicates the need for monitoring for the development of other tumors of the triad. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Pediatric genetic ocular tumors

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    Rouhani, Behnaz; Ramasubramanian, Aparna

    2014-01-01

    Pediatric genetic ocular tumors include malignancies like retinoblastoma and phakomatosis like neurofibromatosis, tuberous sclerosis, von Hippel-Lindau syndrome, and nevoid basal cell carcinoma syndrome. It is important to screen for ocular tumors both for visual prognosis and also for systemic implications. The phakomatosis comprise of multitude of benign tumors that are aysmptomatic but their detection can aid in the diagnosis of the syndrome. Retinoblastoma is the most common malignant int...

  9. Case series

    African Journals Online (AJOL)

    ebutamanya

    3 nov. 2015 ... cas de rein unique fonctionnel ou anatomique ou en cas de tumeurs bilatérales, relatives en cas d'insuffisance rénale débutante et en cas de maladie de Von Hippel Lindau [5]. Pour les indications électives. (rein controlatéral et fonction rénale normaux), la NP peut être proposée pour des tumeurs de 4 à 7 ...

  10. Pancreatic serous cystic neoplasms accompanying other pancreatic tumors.

    Science.gov (United States)

    Kim, So-Woon; Song, In Hye; An, Soyeon; Kim, So Yeon; Kim, Hyoung Jung; Song, Ki-Byung; Hwang, Dae Wook; Lee, Sang Soo; Byun, Jae Ho; Seo, Dong-Wan; Kim, Song Cheol; Yu, Eunsil; Hong, Seung-Mo

    2017-02-01

    Serous cystic neoplasms (SCNs) are benign cystic neoplasms that predominantly occur in the tail of the pancreas in elderly women. It is well known that patients with von Hippel-Lindau syndrome can develop SCNs and neuroendocrine tumors in the pancreas. However, our understanding on SCNs accompanying other pancreatic tumors (SCNAOPTs) is limited. We compared the clinicopathological features of 15 surgically resected SCNAOPTs with 259 conventional SCNs. The prevalence of SCNAOPT was 5%. The SCNAOPTs were significantly smaller than conventional solitary SCNs, and they were more commonly observed in the head of the pancreas, whereas conventional solitary SCNs were more frequently noted in the body and tail. However, no differences were found in terms of sex, patient age, or the gross patterns of the SCNs. Accompanying neoplasms included 7 intraductal papillary mucinous neoplasms, 1 colloid carcinoma arising from intraductal papillary mucinous neoplasm, 6 neuroendocrine tumors, and 1 solid pseudopapillary neoplasm. Four neuroendocrine tumors associated with von Hippel-Lindau syndrome occurred as multiples, whereas 2 neuroendocrine tumors without von Hippel-Lindau syndrome were solitary. In summary, SCNAOPTs comprise 5% of all SCNs and tend to be smaller and located in the head of the pancreas. Common accompanying tumors include intraductal papillary mucinous neoplasms, neuroendocrine tumors, and other neoplasms such as colloid carcinoma and solid pseudopapillary neoplasm. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. [Hemangioblastomas of the central nervous system in Camagüey (Cuba)].

    Science.gov (United States)

    Vega-Basulto, S; Silva-Adán, S; Peñones-Montero, R; Mosqueda-Betancourt, G

    Hemangioblastomas of the central nervous system are the most frequent vascular tumours. They are 1 2% of primary nervous system tumours and 8 12% of the posterior fossa neoplasms. The objective is to analize clinical behaviour and long term results of sporadic and Von Hippel Lindau linked hemangioblastomas. It was searched the vacular Neurosurgical Data Bank at Manuel Ascunce Dom nech Hospital between January 1981 and January 2001 to select patients harvoring central nervous system hemangioblastomas histological confirmed. Melmo and Rosen criteria were utilized in Von Hippel Lindau syndrome. We performed a twenty years follow up of this patients. There were 12 patients with central nervous system hemangioblastomas. Average age of presentation was 41 years old. The first case had twenty years since the operation and the last, eight months. 83% were cystic and 17% were solids. There was not surgical mortality. One patient died of renal carcinoma 15 years after the operation on craneal fossa. Central nervous system hemangioblastomas are a cluster of challenge tumours. They are intraxial benign tumours with potential good outcome. We observed sporadic and Von Hippel Lindau linked hemangioblastomas. Patients with this syndrome need clinico imagenological screening to identify new associated lesions.

  12. Warburg effect's manifestation in aggressive pheochromocytomas and paragangliomas: insights from a mouse cell model applied to human tumor tissue.

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    Stephanie M J Fliedner

    Full Text Available A glycolytic profile unifies a group of pheochromocytomas and paragangliomas (PHEOs/PGLs with distinct underlying gene defects, including von Hippel-Lindau (VHL and succinate dehydrogenase B (SDHB mutations. Nevertheless, their tumor aggressiveness is distinct: PHEOs/PGLs metastasize rarely in VHL-, but frequently in SDHB-patients. To date, the molecular mechanisms causing the more aggressive phenotype in SDHB-PHEOs/PGLs remain largely unknown. Recently, however, an excellent model to study aggressive PHEOs (mouse tumor tissue (MTT cells has been developed from mouse PHEO cells (MPC. We employed this model for a proteomics based approach to identify changes characteristic for tumor aggressiveness, which we then explored in a homogeneous set of human SDHB- and VHL-PHEOs/PGLs. The increase of glucose transporter 1 in VHL, and of hexokinase 2 in VHL and SDHB, confirmed their glycolytic profile. In agreement with the cell model and in support of decoupling of glycolysis, the Krebs cycle and oxidative phosphorylation (OXPHOS, SDHB tumors showed increased lactate dehydrogenase levels. In SDHB-PGLs OXPHOS complex activity was increased at complex III and, as expected, decreased at complex II. Moreover, protein and mRNA expression of all tested OXPHOS-related genes were higher in SDHB- than in VHL-derived tumors. Although there was no direct evidence for increased reactive oxygen species production, elevated superoxide dismutase 2 expression may reflect elevated oxidative stress in SDHB-derived PHEOs/PGLs. For the first time, we show that despite dysfunction in complex II and evidence for a glycolytic phenotype, the Warburg effect does not seem to fully apply to SDHB-PHEOs/PGLs with respect to decreased OXPHOS. In addition, we present evidence for increased LDHA and SOD2 expression in SDHB-PHEOs/PGLs, proteins that have been proposed as promising therapeutic targets in other cancers. This study provides new insight into pathogenic mechanisms in

  13. The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling.

    Science.gov (United States)

    Sankin, Alexander; Hakimi, Abraham A; Mikkilineni, Nina; Ostrovnaya, Irina; Silk, Mikhail T; Liang, Yupu; Mano, Roy; Chevinsky, Michael; Motzer, Robert J; Solomon, Stephen B; Cheng, Emily H; Durack, Jeremy C; Coleman, Jonathan A; Russo, Paul; Hsieh, James J

    2014-12-01

    Primary clear cell renal cell carcinoma (ccRCC) genetic heterogeneity may lead to an underestimation of the mutational burden detected from a single site evaluation. We sought to characterize the extent of clonal branching involving key tumor suppressor mutations in primary ccRCC and determine if genetic heterogeneity could limit the mutation profiling from a single region assessment. Ex vivo core needle biopsies were obtained from three to five different regions of resected renal tumors at a single institution from 2012 to 2013. DNA was extracted and targeted sequencing was performed on five genes associated with ccRCC (von-Hippel Lindau [VHL], PBRM1, SETD2, BAP1, and KDM5C). We constructed phylogenetic trees by inferring clonal evolution based on the mutations present within each core and estimated the predictive power of detecting a mutation for each successive tumor region sampled. We obtained 47 ex vivo biopsy cores from 14 primary ccRCC's (median tumor size 4.5 cm, IQR 4.0-5.9 cm). Branching patterns of various complexities were observed in tumors with three or more mutations. A VHL mutation was detected in nine tumors (64%), each time being present ubiquitously throughout the tumor. Other genes had various degrees of regional mutational variation. Based on the mutations' prevalence we estimated that three different tumor regions should be sampled to detect mutations in PBRM1, SETD2, BAP1, and/or KDM5C with 90% certainty. The mutational burden of renal tumors varies by region sampled. Single site assessment of key tumor suppressor mutations in primary ccRCC may not adequately capture the genetic predictors of tumor behavior. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  14. Pin1, a new player in the fate of HIF-1α degradation: an hypothetical mechanism inside vascular damage as Alzheimer’s disease risk factor.

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    Elena eLonati

    2014-01-01

    Full Text Available Aetiology of neurodegenerative mechanisms underlying Alzheimer's disease (AD are still under elucidation. The contribution of cerebrovascular deficiencies (such as cerebral ischemia/stroke has been strongly endorsed in recent years. Reduction of blood supply leading to hypoxic condition is known to activate cellular responses mainly controlled by hypoxia-inducible transcription factor-1 (HIF-1. Thus alterations of oxygen responsive HIF-1α subunit in the central nervous system may contribute to the cognitive decline, especially influencing mechanisms associated to APP (amyloid precursor protein amyloidogenic metabolism. Although HIF-1α protein level is known to be regulated by von Hippel-Lindau (VHL ubiquitin-proteasome system, it has been recently suggested that Gsk-3β (glycogen synthase kinase-3β promotes a VHL-independent HIF-1α degradation. Here we provide evidences that in rat primary hippocampal cell cultures, HIF-1α degradation might be mediated by a synergic action of Gsk-3β and Pin1 (peptidyl-prolyl cis/trans isomerase. In post-ischemic conditions, such as those mimicked with oxygen glucose deprivation (OGD, HIF-1α protein level increases remaining unexpectedly high for long time after normal condition restoration jointly with the increase of LDH (lactate dehydrogenase and BACE1 (β-secretase 1 protein expression (70% and 140% respectively. Interestingly the Pin1 activity decreases about 40%-60% and Pin1S16 inhibitory phosphorylation significantly increases, indicating that Pin1 binding to its substrate and enzymatic activity are reduced by treatment. Co-immunoprecipitation experiments demonstrate that HIF-1α/Pin1 in normoxia are associated, and that in presence of specific Pin1 and Gsk-3β inhibitors their interaction is reduced in parallel to an increase of HIF-1α protein level. Thus we suggest that in post-OGD neurons the high level of HIF-1α might be due to Pin1 binding ability and activity reduction which affects HIF-1

  15. Large-scale identification of human cerebrovascular proteins: Inter-tissue and intracerebral vascular protein diversity.

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    Soo Jung Lee

    Full Text Available The human cerebrovascular system is responsible for regulating demand-dependent perfusion and maintaining the blood-brain barrier (BBB. In addition, defects in the human cerebrovasculature lead to stroke, intracerebral hemorrhage, vascular malformations, and vascular cognitive impairment. The objective of this study was to discover new proteins of the human cerebrovascular system using expression data from the Human Protein Atlas, a large-scale project which allows public access to immunohistochemical analysis of human tissues. We screened 20,158 proteins in the HPA and identified 346 expression patterns correlating to blood vessels in human brain. Independent experiments showed that 51/52 of these distributions could be experimentally replicated across different brain samples. Some proteins (40% demonstrated endothelial cell (EC-enriched expression, while others were expressed primarily in vascular smooth muscle cells (VSMC; 18%; 39% of these proteins were expressed in both cell types. Most brain EC markers were tissue oligospecific; that is, they were expressed in endothelia in an average of 4.8 out of 9 organs examined. Although most markers expressed in endothelial cells of the brain were present in all cerebral capillaries, a significant number (21% were expressed only in a fraction of brain capillaries within each brain sample. Among proteins found in cerebral VSMC, virtually all were also expressed in peripheral VSMC and in non-vascular smooth muscle cells (SMC. Only one was potentially brain specific: VHL (Von Hippel-Lindau tumor suppressor. HRC (histidine rich calcium binding protein and VHL were restricted to VSMC and not found in non-vascular tissues such as uterus or gut. In conclusion, we define a set of brain vascular proteins that could be relevant to understanding the unique physiology and pathophysiology of the human cerebrovasculature. This set of proteins defines inter-organ molecular differences in the vasculature and

  16. Prognostic role of histological necrosis for nonmetastatic clear cell renal cell carcinoma: correlation with pathological features and molecular markers.

    Science.gov (United States)

    Minervini, Andrea; Di Cristofano, Claudio; Gacci, Mauro; Serni, Sergio; Menicagli, Michele; Lanciotti, Michele; Salinitri, Giuseppe; Rocca, Carlo Della; Lapini, Alberto; Nesi, Gabriella; Bevilacqua, Generoso; Minervini, Riccardo; Carini, Marco

    2008-10-01

    We defined the prognostic role of tumor necrosis and its extent in nonmetastatic clear cell renal cell carcinoma. Also, we further investigated its pathogenesis by correlating this tumor feature with other pathological characteristics and molecular markers related to the von Hippel Lindau-hypoxia inducible factor pathway and to tumor proliferation. A total of 213 patients with nonmetastatic clear cell renal cell carcinoma were evaluated. Mean followup was 66 months. The presence and extent of histological necrosis were correlated with clinicopathological factors, Ki-67 antigen expression calculated by the MIB-1 (Ki-67 antibody) index, pVHL, HIF-1alpha, the tumor infiltrating lymphocyte subset and cancer specific survival. Histological necrosis was present in 63.8% of clear cell renal cell carcinoma cases. Necrosis was significantly associated with grade and the degree of tumor infiltrating lymphocytes, while its extent correlated significantly with grade, the degree of tumor infiltrating lymphocytes and stage. Tumor necrosis was a significant prognostic factor, which was confirmed even when limiting analysis to patients with intracapsular renal cell carcinoma. On multivariate analysis histological necrosis was not an independent predictor of cancer specific survival. The extent of tumor necrosis was not a significant prognostic factor. The presence and extent of histological necrosis was not associated with high Ki-67 expression and it did not correlate with pVHL expression or with nuclear and cytoplasmic HIF-1alpha expression. Based on our results we cannot support histological necrosis and its extent as prognostic factors for clear cell renal cell carcinoma. Efforts should be made to develop nomograms that use routinely available and objective predictor variables. The precise mechanism that causes tumor necrosis remains unknown but the host immune response might significantly contribute to its development.

  17. Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism

    Directory of Open Access Journals (Sweden)

    Yang M

    2014-08-01

    Full Text Available Ming Yang,1 Huizhong Su,1 Tomoyoshi Soga,2 Kamil R Kranc,3 Patrick J Pollard1 1Cancer Biology and Metabolism Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK; 2Institute for Advanced Biosciences, Keio University, Mizukami, Tsuruoka, Yamagata, Japan; 3MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK Abstract: The hypoxia-inducible factor (HIF prolyl hydroxylase domain enzymes (PHDs regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl residues in its α subunit in an oxygen-dependent manner. Trans-4-prolyl hydroxylation of HIFα under normal oxygen (O2 availability enables its association with the von Hippel-Lindau (VHL tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFα via the ubiquitin-proteasome pathway. Due to the obligatory requirement of molecular O2 as a co-substrate, the activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIFα, which dimerizes with HIFβ and, together with transcriptional co-activators CBP/p300, activates the transcription of its target genes. As a key molecular regulator of adaptive response to hypoxia, HIF plays important roles in multiple cellular processes and its overexpression has been detected in various cancers. The HIF1α isoform in particular has a strong impact on cellular metabolism, most notably by promoting anaerobic, whilst inhibiting O2-dependent, metabolism of glucose. The PHD enzymes also seem to have HIF-independent functions and are subject to regulation by factors other than O2, such as by metabolic status, oxidative stress, and abnormal levels of endogenous metabolites (oncometabolites that have been observed in some types of cancers. In this review, we aim to summarize current understandings of the function and regulation of PHDs in cancer with an emphasis on their roles in metabolism. Keywords: prolyl hydroxylase domain (PHD

  18. Cerebellar hemangioblastomas: A study of the immunoprofile of neoplastic stromal component

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    Tasić Desanka

    2004-01-01

    Full Text Available Background. Central nervous system hemangioblastomas (HBs are uncommon highly vascularized tumors that are predominantly found in the cerebellum. They occur sporadically or in association with von Hippel-Lindau (VHL disease. HBs are of unknown histogenesis, and the origin of stromal cells is still a subject of debate. The aim of this study was to investigate the immunoprofile of neoplastic stromal component, and to determine whether the profile of the expression of immunomarkers used can contribute to the elucidation of the histogenesis of HBs. Methods. A series of eight cerebellar HBs were histochemically examined for the detection of mast cells and immunohistochemically for the expression of factor VIII-related antigen (FVIII-RAg, CD34, vimentin, factor XIIIa (FXIIIa, S-100 protein, glial fibrillary acidic protein (GFAP, neuron-specific enolase (NSE neurofilaments (NF, synaptophysin, chromogranin, and somatostatin. Results. Mast cells were present in all hemangioblastomas, and were particularly abundant in one tumor. Immunohistochemically, intense reactivity for vimentin and NSE in the stromal cells was constantly seen. Immunoreactivity with S-100 protein and FXIIIa was variable, but generally many HBs stromal cells were negative for these markers. However, stromal cells were uniformly negative for FVIII-RAg in all HBs investigated. They were negative for CD34 GFAP, NF, synaptophysin, chromogranin, as well as somatostatin. GFAP-positivity of the occasional stromal type cells, located only peripherally, was interpreted as "pseudopositivity". Conclusion. The immunoprofile of neoplastic stromal component in this study suggested a possible origin from undifferentiated multipotential mesenchymal cells. High expression of NSE (glycolytic and hypoxia-inducible enzyme in the HBs stromal cells might be related to the loss of the VHL protein function.

  19. Degradation of HIF-1alpha under hypoxia combined with induction of Hsp90 polyubiquitination in cancer cells by hypericin: a unique cancer therapy.

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    Tilda Barliya

    Full Text Available The perihydroxylated perylene quinone hypericin has been reported to possess potent anti-metastatic and antiangiogenic activities, generated by targeting diverse crossroads of cancer-promoting processes via unique mechanisms. Hypericin is the only known exogenous reagent that can induce forced poly-ubiquitination and accelerated degradation of heat shock protein 90 (Hsp90 in cancer cells. Hsp90 client proteins are thereby destabilized and rapidly degraded. Hsp70 client proteins may potentially be also affected via preventing formation of hsp90-hsp70 intermediate complexes. We show here that hypericin also induces enhanced degradation of hypoxia-inducible factor 1α (HIF-1α in two human tumor cell lines, U87-MG glioblastoma and RCC-C2VHL-/- renal cell carcinoma and in the non-malignant ARPE19 retinal pigment epithelial cell line. The hypericin-accelerated turnover of HIF-1α, the regulatory precursor of the HIF-1 transcription factor which promotes hypoxic stress and angiogenic responses, overcomes the physiologic HIF-1α protein stabilization which occurs in hypoxic cells. The hypericin effect also eliminates the high HIF-1α levels expressed constitutively in the von-Hippel Lindau protein (pVHL-deficient RCC-C2VHL-/- renal cell carcinoma cell line. Unlike the normal ubiquitin-proteasome pathway-dependent turnover of HIF-α proteins which occurs in normoxia, the hypericin-induced HIF-1α catabolism can occur independently of cellular oxygen levels or pVHL-promoted ubiquitin ligation of HIF-1α. It is mediated by lysosomal cathepsin-B enzymes with cathepsin-B activity being optimized in the cells through hypericin-mediated reduction in intracellular pH. Our findings suggest that hypericin may potentially be useful in preventing growth of tumors in which HIF-1α plays pivotal roles, and in pVHL ablated tumor cells such as renal cell carcinoma through elimination of elevated HIF-1α contents in these cells, scaling down the excessive angiogenesis

  20. The phenotype of polycythemia due to Croatian homozygous VHL (571C>G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C>T:R200W).

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    Tomasic, Nikica Ljubas; Piterkova, Lucie; Huff, Chad; Bilic, Ernest; Yoon, Donghoon; Miasnikova, Galina Y; Sergueeva, Adelina I; Niu, Xiaomei; Nekhai, Sergei; Gordeuk, Victor; Prchal, Josef T

    2013-04-01

    Mutations of VHL (a negative regulator of hypoxia-inducible factors) have position-dependent distinct cancer phenotypes. Only two known inherited homozygous VHL mutations exist and they cause polycythemia: Chuvash R200W and Croatian H191D. We report a second polycythemic Croatian H191D homozygote distantly related to the first propositus. Three generations of both families were genotyped for analysis of shared ancestry. Biochemical and molecular tests were performed to better define their phenotypes, with an emphasis on a comparison with Chuvash polycythemia. The VHL H191D mutation did not segregate in the family defined by the known common ancestors of the two subjects, suggesting a high prevalence in Croatians, but haplotype analysis indicated an undocumented common ancestor ∼six generations ago as the founder of this mutation. We show that erythropoietin levels in homozygous VHL H191D individuals are higher than in VHL R200W patients of similar ages, and their native erythroid progenitors, unlike Chuvash R200W, are not hypersensitive to erythropoietin. This observation contrasts with a report suggesting that polycythemia in VHL R200W and H191D homozygotes is due to the loss of JAK2 regulation from VHL R200W and H191D binding to SOCS1. In conclusion, our studies further define the hematologic phenotype of VHL H191D and provide additional evidence for phenotypic heterogeneity associated with the positional effects of VHL mutations.

  1. Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF-1α synthesis, and decreases breast cancer metastasis.

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    Wei, Zhonghong; Shan, Yunlong; Tao, Li; Liu, Yuping; Zhu, Zhijie; Liu, Zhaoguo; Wu, Yuanyuan; Chen, Wenxing; Wang, Aiyun; Lu, Yin

    2017-10-01

    Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia-inducible factor-1α (HIF-1α) reflects the prognosis of a variety of cancers, especially breast cancer. Histone deacetylase (HDAC) inhibitors can target HIF-1α protein due to von Hippel-Lindau (VHL) protein-dependent degradation. Dietary organosulfur compounds, such as those in garlic, have been reported as HDAC inhibitors. The effects of diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) on the ratio of firefly/Renilla luciferase activity in hypoxic MDA-MB-231 cells were determined. The mRNA expressions of HIF-1α target genes ANGPTL4, LOXL4, and LOX in hypoxic MDA-MB-231 cells were significantly down-regulated by DATS. DATS attenuated the metastatic potential of MDA-MB-231 cells in hypoxia-induced embryonic zebrafish, xenograft, and orthotopic tumors. Endothelial cell-cancer cell adhesion, wound healing, transwell, and tube formation assays showed that DATS dose-dependently inhibited the migration and angiogenesis of MDA-MB-231 cells in vitro. The expressions of L1CAM, VEGF-A, and EMT-related proteins (Slug, Snail, MMP-2) were inhibited by DATS. DATS dose-dependently inhibited HIF-1α transcriptional activity and hypoxia-induced hematogenous metastasis of MDA-MB-231 cells. It reduced the protein expression of HIF-1α, which did not involve inhibition of HIF-1α mRNA expression or ubiquitin proteasome degradation. Efficient inhibition of HIF-1α expression was required for DATS to resist breast cancer. © 2017 Wiley Periodicals, Inc.

  2. Reduced cilia frequencies in human renal cell carcinomas versus neighboring parenchymal tissue

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    Basten Sander G

    2013-01-01

    Full Text Available Abstract Background Cilia are essential organelles in multiple organ systems, including the kidney where they serve as important regulators of renal homeostasis. Renal nephron cilia emanate from the apical membrane of epithelia, extending into the lumen where they function in flow-sensing and ligand-dependent signaling cascades. Ciliary dysfunction underlies renal cyst formation that is in part caused by deregulation of planar cell polarity and canonical Wnt signaling. Renal cancer pathologies occur sporadically or in heritable syndromes caused by germline mutations in tumor suppressor genes including VHL. Importantly, Von Hippel-Lindau (VHL patients frequently develop complex renal cysts that can be considered a premalignant stage. One of the well-characterized molecular functions of VHL is its requirement for the maintenance of cilia. In this study, tissue from 110 renal cancer patients who underwent nephrectomy was analyzed to determine if lower ciliary frequency is a common hallmark of renal tumorigenesis by comparing cilia frequencies in both tumor and adjacent parenchymal tissue biopsies from the same kidney. Methods We stained sections of human renal material using markers for cilia. Preliminary staining was performed using an immunofluorescent approach and a combination of acetylated-α-tubulin and pericentrin antibodies and DAPI. After validation of an alternative, higher throughput approach using acetylated-α-tubulin immunohistochemistry, we continued to manually quantify cilia in all tissues. Nuclei were separately counted in an automated fashion in order to determine ciliary frequencies. Similar staining and scoring for Ki67 positive cells was performed to exclude that proliferation obscures cilia formation potential. Results Samples from renal cell carcinoma patients deposited in our hospital tissue bank were previously used to compose a tissue microarray containing three cores of both tumor and parenchymal tissue per patient

  3. The role of inflammation in kidney cancer.

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    de Vivar Chevez, Antonio Roma; Finke, James; Bukowski, Ronald

    2014-01-01

    Renal cell carcinoma (RCC) constitutes more than 90 % of primary kidney tumors with the development of metastatic disease in the lung, bone, liver, and brain. Clear-cell RCC (CCRCC) is the most common histologic form of sporadic kidney cancer where the majority of tumors have inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene resulting in the accumulation of hypoxia-inducible factor (HIF) leading to dysregulation of cell growth and angiogenesis. Understanding of the genetic changes in RCC and the downstream events have led to the development of tyrosine kinase inhibitors (TKI) that target HIF-regulated proteins which currently represents front-line therapy for metastatic disease although resistance develops in most patients overtime. Despite the fact that RCC is an immunogenic tumor, there is mounting evidence that immune cells and inflammatory pathways can enhance tumor growth and immune escape. However, recent studies are beginning to uncover the mechanisms of immune escape in RCC, and the role inflammatory immune cells and cytokines play is this process. These new findings have led to renewed interest in the use of immunotherapy for the treatment of this disease that includes strategies to regulate inflammatory responses. Here, we will discuss the different inflammatory signaling pathways (e.g., VHL, hypoxia, TNF-α, STAT, and TGF-β) and the downstream transcription factors, cytokines, and chemokines involved in tumor development, and disease progression. This will include assessment of the role inflammatory molecules (e.g., pVHL, TGFb, IL6, select chemokines/chemokine receptors) play in promoting cell transformation, survival, proliferation of tumor cells, and metastasis derived from in vitro and in vivo studies. Included is a section on how select inflammatory cells (TAM, MDSC, and neutrophils) promote tumor evasion of immune cells. We also provide examples of molecules/cells that correlate negatively (CXCL12, CXCR4, and MMP, neutrophils, and

  4. KAI1 suppresses HIF-1α and VEGF expression by blocking CDCP1-enhanced Src activation in prostate cancer

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    Park Jung-Jin

    2012-03-01

    Full Text Available Abstract Background KAI1 was initially identified as a metastasis-suppressor gene in prostate cancer. It is a member of the tetraspan transmembrane superfamily (TM4SF of membrane glycoproteins. As part of a tetraspanin-enriched microdomain (TEM, KAI1 inhibits tumor metastasis by negative regulation of Src. However, the underlying regulatory mechanism has not yet been fully elucidated. CUB-domain-containing protein 1 (CDCP1, which was previously known as tetraspanin-interacting protein in TEM, promoted metastasis via enhancement of Src activity. To better understand how KAI1 is involved in the negative regulation of Src, we here examined the function of KAI1 in CDCP1-mediated Src kinase activation and the consequences of this process, focusing on HIF-1 α and VEGF expression. Methods We used the human prostate cancer cell line PC3 which was devoid of KAI1 expression. Vector-transfected cells (PC3-GFP clone #8 and KAI1-expressing PC3 clones (PC3-KAI1 clone #5 and #6 were picked after stable transfection with KAI1 cDNA and selection in 800 μg/ml G418. Protein levels were assessed by immunoblotting and VEGF reporter gene activity was measured by assaying luciferase activitiy. We followed tumor growth in vivo and immunohistochemistry was performed for detection of HIF-1, CDCP1, and VHL protein level. Results We demonstrated that Hypoxia-inducible factor 1α (HIF-1α and VEGF expression were significantly inhibited by restoration of KAI1 in PC3 cells. In response to KAI1 expression, CDCP1-enhanced Src activation was down-regulated and the level of von Hippel-Lindau (VHL protein was significantly increased. In an in vivo xenograft model, KAI1 inhibited the expression of CDCP1 and HIF-1α. Conclusions These novel observations may indicate that KAI1 exerts profound metastasis-suppressor activity in the tumor malignancy process via inhibition of CDCP1-mediated Src activation, followed by VHL-induced HIF-1α degradation and, ultimately, decreased VEGF

  5. Stabilization of HIF-2α through redox regulation of mTORC2 activation and initiation of mRNA translation.

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    Nayak, B K; Feliers, D; Sudarshan, S; Friedrichs, W E; Day, R T; New, D D; Fitzgerald, J P; Eid, A; Denapoli, T; Parekh, D J; Gorin, Y; Block, K

    2013-06-27

    Hypoxia inducible factor-2α (HIF-2α) has a critical role in renal tumorigenesis. HIF-2α is stabilized in von Hippel-Lindau (VHL)-deficient renal cell carcinoma through mechanisms that require ongoing mRNA translation. Mammalian target of rapamycin (mTOR) functions in two distinct complexes: Raptor-associated mTORC1 and Rictor-associated mTORC2. Rictor-associated mTORC2 complex has been linked to maintaining HIF-2α protein in the absence of VHL; however, the mechanisms remain to be elucidated. Although Raptor-associated mTORC1 is a known key upstream regulator of mRNA translation, initiation and elongation, the role of mTORC2 in regulating mRNA translation is not clear. Complex assembly of the mRNA cap protein, eukaryotic translation initiation factor 4 (eIF4)E, with activators (eIF4 gamma (eIF4G)) and inhibitors (eIF4E-binding protein 1 (4E-BP1)) are rate-limiting determinants of mRNA translation. Our laboratory has previously demonstrated that reactive oxygen species, mediated by p22(phox)-based Nox oxidases, are enhanced in VHL-deficient cells and have a role in the activation of Akt on S473, a site phosphorylated by the mTORC2 complex. In this study, we examined the role of Rictor-dependent regulation of HIF-2α through eIF4E-dependent mRNA translation and examined the effects of p22(phox)-based Nox oxidases on TORC2 regulation. We demonstrate for the first time that mTORC2 complex stability and activation is redox sensitive, and further defined a novel role for p22(phox)-based Nox oxidases in eIF4E-dependent mRNA translation through mTORC2. Furthermore, we provide the first evidence that silencing of p22(phox) reduces HIF-2α-dependent gene targeting in vitro and tumor formation in vivo. The clinical relevance of these studies is demonstrated.

  6. Functional Imaging of Paragangliomas with an Emphasis on Von Hippel–Lindau-Associated Disease: A Mini Review

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    Ioannis Ilias

    2017-09-01

    Full Text Available Few reports have presented data and results on functional (i.e., nuclear medicine imaging of paragangliomas and pheochromocytomas (PGLs/PHEOs for von Hippel–Lindau (VHL patients. Nuclear medicine localization modalities for chromaffin tumors can be specific or nonspecific. Specific methods make use of the expression of the human norepinephrine transporter (hNET and vesicular monoamine transporters (VMATs by these tumors. These permit the use of radiolabeled ligands that enter the synthesis and storage pathway of catecholamines. Nonspecific methods are not related to the synthesis, uptake, or storage of catecholamines but make use of the tumors’ high glucose metabolism or expression of somatostatin receptors. Consensuses and guidelines suggest that metastatic and sporadic PHEOs/PGLs in VHL patients (as in patients with chromaffin tumors of yet unknown genotype should be evaluated first with 18F-dihydroxyphenylalanine (18F-DOPA positron emission tomography/computed tomography (PET/CT. The functional imaging of second choice is 123I-metaiodobenzylguanidine (123I-MIBG for PHEOs in VHL patients. 123I-MIBG, 68Ga-DOTATATE/DOTATOC/DOTANOC PET/CT, or 18F-fluorodeoxyglucose (18F-FDG PET/CT can be a second choice of functional imaging for PGLs in VHL patients.

  7. Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution

    DEFF Research Database (Denmark)

    Fisher, Rosalie; Horswell, Stuart; Rowan, Andrew

    2014-01-01

    with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies......Background : Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution. Results : We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient...... are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient...

  8. VHL negatively regulates SARS coronavirus replication by modulating nsp16 ubiquitination and stability.

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    Yu, Xiao; Chen, Shuliang; Hou, Panpan; Wang, Min; Chen, Yu; Guo, Deyin

    2015-04-03

    Eukaryotic cellular and most viral RNAs carry a 5'-terminal cap structure, a 5'-5' triphosphate linkage between the 5' end of the RNA and a guanosine nucleotide (cap-0). SARS coronavirus (SARS-CoV) nonstructural protein nsp16 functions as a methyltransferase, to methylate mRNA cap-0 structure at the ribose 2'-O position of the first nucleotide to form cap-1 structures. However, whether there is interplay between nsp16 and host proteins was not yet clear. In this report, we identified several potential cellular nsp16-interacting proteins from a human thymus cDNA library by yeast two-hybrid screening. VHL, one of these proteins, was proven to interact with nsp16 both in vitro and in vivo. Further studies showed that VHL can inhibit SARS-CoV replication by regulating nsp16 ubiquitination and promoting its degradation. Our results have revealed the role of cellular VHL in the regulation of SARS-CoV replication. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex.

    Science.gov (United States)

    Cardote, Teresa A F; Gadd, Morgan S; Ciulli, Alessio

    2017-06-06

    Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2VHL complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL. The structure traps a closed state of full-length Cul2 and a new pose of Rbx1 in a trajectory from closed to open conformation. We characterize hotspots and binding thermodynamics at the interface between Cul2 and pVHL-EloBC and identify mutations that contribute toward a selectivity switch for Cul2 versus Cul5 recognition. Our findings provide structural and biophysical insights into the whole Cul2 complex that could aid future drug targeting. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  10. Diagnosis and Management of Hereditary Renal Cell Cancer.

    Science.gov (United States)

    Menko, Fred H; Maher, Eamonn R

    2016-01-01

    Renal cell cancer (RCC) is the common denominator for a heterogeneous group of diseases. The subclassification of these tumours is based on histological type and molecular pathogenesis. Insight into molecular pathogenesis has led to the development of targeted systemic therapies. Genetic susceptibility is the principal cause of RCC in about 2-4% of cases. Hereditary RCC is the umbrella term for about a dozen different conditions, the most frequent of which is von Hippel-Lindau disease . Here, we describe the main hereditary RCC syndromes, consider criteria for referral of RCC patients for clinical genetic assessment and discuss management options for patients with hereditary RCC and their at-risk relatives.

  11. Sporadic Endolymphatic Sac Tumor-A Very Rare Cause of Hearing Loss, Tinnitus, and Dizziness

    DEFF Research Database (Denmark)

    Schnack, Didde Trærup; Kiss, Katalin; Hansen, Søren

    2017-01-01

    Sporadic endolymphatic sac tumor is a very rare neoplasm. It is low malignant, locally destructive and expansive, but non-metastasizing. The tumor is very rare in the sporadic form, but more often associated with Von Hippel-Lindau disease. A 65-year old man with left sided tinnitus and hearing loss......-operative freeze-microscopy showed inflammation tissue, whereas subsequent microscopy showed papillary-cystic endolymphatic sac tumor. Endolymphatic sac tumor is a rare neoplasm. The tumor may present with asymmetrically sensory neural hearing loss with or without tinnitus, dizziness and facial nerve paresis...

  12. Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia)

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    Sable, Craig A.; Aliyu, Zakari Y.; Dham, Niti; Nouraie, Mehdi; Sachdev, Vandana; Sidenko, Stanislav; Miasnikova, Galina Y.; Polyakova, Lydia A.; Sergueeva, Adelina I.; Okhotin, Daniel J.; Bushuev, Vladimir; Remaley, Alan T.; Niu, Xiaomei; Castro, Oswaldo L.; Gladwin, Mark T.; Kato, Gregory J.; Prchal, Josef T.; Gordeuk, Victor R.

    2012-01-01

    Background Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. The objectives of this study were to provide a comprehensive echocardiographic assessment of cardiovascular physiology and to identify clinical, hematologic and cardiovascular risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia. Design and Methods This cross-sectional observational study of 120 adult and pediatric VHLR200W homozygotes and 31 controls at outpatient facilities in Chuvashia, Russian Federation included echocardiography assessment of pulmonary artery pressure (tricuspid regurgitation velocity), cardiac volume, and systolic and diastolic function, as well as hematologic and clinical parameters. We determined the prevalence and risk factors for elevation of tricuspid regurgitation velocity in this population and its relationship to phlebotomy. Results The age-adjusted mean ± SE tricuspid regurgitation velocity was higher in VHLR200W homozygotes than controls with normal VHL alleles (2.5±0.03 vs. 2.3±0.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.8±0.05 vs. 4.5±0.09 cm, P=0.005) and left atrial diameter (3.4±0.04 vs. 3.2±0.08 cm, P=0.011) were also greater in the VHLR200W homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHLR200W homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29; P=0.009). Conclusions Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic

  13. pVHL co-ordinately regulates CXCR4/CXCL12 and MMP2/MMP9 expression in human clear-cell renal cell carcinoma

    DEFF Research Database (Denmark)

    Struckmann, K; Mertz, Kd; Steu, S

    2008-01-01

    Loss of pVHL function, characteristic for clear-cell renal cell carcinoma (ccRCC), causes increased expression of CXCR4 chemokine receptor, which triggers expression of metastasis-associated MMP2/MMP9 in different human cancers. The impact of pVHL on MMP2/MMP9 expression and their relationship...

  14. Vhl deletion in renal epithelia causes HIF-1?-dependent, HIF-2?-independent angiogenesis and constitutive diuresis

    OpenAIRE

    Schönenberger, Désirée; Rajski, Michal; Harlander, Sabine; Frew, Ian J

    2016-01-01

    One of the earliest requirements for the formation of a solid tumor is the establishment of an adequate blood supply. Clear cell renal cell carcinomas (ccRCC) are highly vascularized tumors in which the earliest genetic event is most commonly the biallelic inactivation of the VHL tumor suppressor gene, leading to constitutive activation of the HIF-1α and HIF-2α transcription factors, which are known angiogenic factors. However it remains unclear whether either or both HIF-1α or HIF-2α stabili...

  15. Characteristics of scientific production in Special Education in Virtual Health Library (VHL: a bibliometric study

    Directory of Open Access Journals (Sweden)

    Luciana Pizzani

    2010-12-01

    Full Text Available Objective: To characterize, through bibliometric approach, the scientific literature in this Special Education in the databases of the Virtual Health Library (VHL. The VHL is coordinated by BIREME - Specialized Center of the Pan American Health Organization whose objective is to promote the dissemination and use of scientific information in health. Method: The research methodology was performed by observing the following steps: a literature review on education special and bibliometrics, data collection from the site of BIREME about the presence of special education in the databases, organization, processing and bibliometric analysis of data collected using the software MS Excel and Vantage Point. Results: indicators produced allow signal that the predominant language of scientific production was the Portuguese and the majority of records were written individually, the themes addressed were psychology and developmental psychology. Conclusion: These bibliometric indicators characterizing the state of the art of scientific literature in Special Education at the various bases Data Bireme and also showed a field of interconnections between Health Sciences and Special Education.

  16. Discovery of novel inhibitors disrupting HIF-1α/von Hippel–Lindau interaction through shape-based screening and cascade docking

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    Xin Xue

    2016-12-01

    Full Text Available Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein–protein interaction between HIF-1α and the von Hippel–Lindau protein (pVHL, which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucial drug target in cancer, chronic anemia, and ischemia. Currently there is only one class of compounds available to interdict the HIF-1α/pVHL interaction, urging the need to discover chemical inhibitors with more diversified structures. We report here a strategy combining shape-based virtual screening and cascade docking to identify new chemical scaffolds for the designing of novel inhibitors. Based on this strategy, nine active hits have been identified and the most active hit, 9 (ZINC13466751, showed comparable activity to pVHL with an IC50 of 2.0 ± 0.14 µM, showing the great potential of utilizing these compounds for further optimization and serving as drug candidates for the inhibition of HIF-1α/von Hippel–Lindau interaction.

  17. The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling*

    Science.gov (United States)

    Shanmugasundaram, Karthigayan; Nayak, Bijaya; Shim, Eun-Hee; Livi, Carolina B.; Block, Karen; Sudarshan, Sunil

    2014-01-01

    Inactivating mutations of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH) have been linked to an aggressive variant of hereditary kidney cancer (hereditary leiomyomatosis and renal cell cancer). These tumors accumulate markedly elevated levels of fumarate. Fumarate is among a growing list of oncometabolites identified in cancers with mutations of genes involved in intermediary metabolism. FH-deficient tumors are notable for their pronounced accumulation of the transcription factor hypoxia inducible factor-1α (HIF-1α) and aggressive behavior. To date, HIF-1α accumulation in hereditary leiomyomatosis and renal cell cancer tumors is thought to result from fumarate-dependent inhibition of prolyl hydroxylases and subsequent evasion from von Hippel-Lindau-dependent degradation. Here, we demonstrate a novel mechanism by which fumarate promotes HIF-1α mRNA and protein accumulation independent of the von Hippel-Lindau pathway. Here we demonstrate that fumarate promotes p65 phosphorylation and p65 accumulation at the HIF-1α promoter through non-canonical signaling via the upstream Tank binding kinase 1 (TBK1). Consistent with these data, inhibition of the TBK1/p65 axis blocks HIF-1α accumulation in cellular models of FH loss and markedly reduces cell invasion of FH-deficient RCC cancer cells. Collectively, our data demonstrate a novel mechanism by which pseudohypoxia is promoted in FH-deficient tumors and identifies TBK1 as a novel putative therapeutic target for the treatment of aggressive fumarate-driven tumors. PMID:25028521

  18. An Update on the Ophthalmologic Features in the Phakomatoses

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    Solmaz Abdolrahimzadeh

    2016-01-01

    Full Text Available Neurofibromatosis type 1, tuberous sclerosis complex, and Von Hippel-Lindau disease, historically classified as the phakomatoses, are hereditary multisystem disorders characterized by the presence of hamartoma, which carry the risk of malignant transformation. The alteration of tumor suppressor genes seems to be at the basis of their pathophysiogenetic mechanism. Lisch and choroidal nodules in neurofibromatosis type 1, retinal astrocytomas in tuberous sclerosis complex, and retinal capillary hemangioma in Von Hippel-Lindau disease are the principal ophthalmic hamartomatous manifestations. The advent of novel imaging techniques such as near infrared reflectance and optical coherence tomography has provided unprecedented insight on the choroidal and retinal features of these diseases. These methods have improved early diagnosis and the ongoing surveillance in these conditions. Among an array of treatment modalities, antivascular endothelial growth factor therapy has been used in the management of retinal hamartomas but results have been varied. This review is an update on the pathophysiogenetic mechanisms, ophthalmic manifestations, and novel treatment strategies in the phakomatoses with emphasis on the role of imaging techniques.

  19. von Willebrand Disease

    Science.gov (United States)

    ... for type 1 von Willebrand disease is called desmopressin. It causes a temporary increase in the von ... injection or by being sniffed into the nose. Desmopressin may also help some people with type 2 ...

  20. Interaktive Visualisierung von Strukturmechaniksimulationen

    OpenAIRE

    Sommer, Ove

    2003-01-01

    A) Motivation und Problemstellung Der Computer ist heute eines der wichtigsten Hilfsmittel beim Entwurf und der Entwicklung von Fahrzeugen. Zunächst wurde er von Konstrukteuren für das Computer Aided Design (CAD) von virtuellen Fahrzeugmodellen eingesetzt. Inzwischen ist er in vielen anderen Bereichen der Fahrzeugentwicklung unentbehrlich geworden: der Entwicklungszyklus von Automobilen ist durch die Computer-gestützte numerische Simulation substanziell verkürzt worden. An virtuellen Prot...

  1. Chondroitin sulfate proteoglycan CSPG4 as a novel hypoxia-sensitive marker in pancreatic tumors.

    Directory of Open Access Journals (Sweden)

    Shereen Keleg

    Full Text Available CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4 might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4 due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83 and validation (n = 221 cohorts comprising donors (n = 11+26 and patients with chronic pancreatitis (n = 11+20 or neoplasms: benign (serous cystadenoma SCA, n = 13+20, premalignant (intraductal dysplastic IPMNs, n = 9+55, and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86. Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139, western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissue(high/sera(low-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct

  2. Loss of the SxxSS motif in a human T-cell factor-4 isoform confers hypoxia resistance to liver cancer: an oncogenic switch in Wnt signaling.

    Directory of Open Access Journals (Sweden)

    Hironori Koga

    Full Text Available PURPOSE: Aberrantly activated Wnt/β-catenin signaling is important in hepatocellular carcinoma (HCC development. Downstream gene expressions involving the Wnt/β-catenin cascade occur through T-cell factor (TCF proteins. Here, we show the oncogenic potential of human TCF-4 isoforms based on the expression of a single conserved SxxSS motif. METHODS: We investigated the TCF-4J and K isoform pair characterized by the presence (K or absence (J of the SxxSS motif. The mRNA expression profiles were examined in 47 pairs of human HCCs and adjacent non-cancerous liver tissues by RT-PCR. Proliferation, sphere assays and immunoblot analysis were performed under normoxia and hypoxia conditions. The ability of HCC cells overexpressing TCF-4J (J cells and K (K cells to grow as solid tumors in nude mice was explored. RESULTS: TCF-4J expression was significantly upregulated in HCC tumors compared to corresponding peritumor and normal liver and was preferentially expressed in poorly differentiated HCCs. In contrast, TCF-4K was downregulated in those same HCC tumors. TCF-4J-overexpressing HCC cells (J cells revealed a survival advantage under hypoxic conditions, high proliferation rate and formation of aggregates/spheres compared to overexpression of TCF-4K (K cells. The hypoxic J cells had high expression levels of HIF-2α and EGFR as possible mechanisms to promote tumorigenesis. Increased stability of HIF-2α under hypoxia in J cells was associated with a decreased level of von Hippel-Lindau (VHL protein, a known E3 ligase for HIF-αs. In a xenograft model, the J cells rapidly developed tumors compared to K cells. Tumor tissues derived from J cells exhibited high expression levels of HIF-2α and EGFR compared to the slow developing and small K cell derived tumors. CONCLUSIONS: Our results suggest that the specific TCF-4J isoform, which lacks a regulatory SxxSS motif, has robust tumor-initiating potential under hypoxic conditions.

  3. klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes.

    Directory of Open Access Journals (Sweden)

    Peter Novodvorsky

    Full Text Available The zinc-finger transcription factor Krϋppel-like factor 2 (KLF2 transduces blood flow into molecular signals responsible for a wide range of responses within the vasculature. KLF2 maintains a healthy, quiescent endothelial phenotype. Previous studies report a range of phenotypes following morpholino antisense oligonucleotide-induced klf2a knockdown in zebrafish. Targeted genome editing is an increasingly applied method for functional assessment of candidate genes. We therefore generated a stable klf2a mutant zebrafish and characterised its cardiovascular and haematopoietic development.Using Transcription Activator-Like Effector Nucleases (TALEN we generated a klf2a mutant (klf2ash317 with a 14bp deletion leading to a premature stop codon in exon 2. Western blotting confirmed loss of wild type Klf2a protein and the presence of a truncated protein in klf2ash317 mutants. Homozygous klf2ash317 mutants exhibit no defects in vascular patterning, survive to adulthood and are fertile, without displaying previously described morphant phenotypes such as high-output cardiac failure, reduced haematopoetic stem cell (HSC development or impaired formation of the 5th accessory aortic arch. Homozygous klf2ash317 mutation did not reduce angiogenesis in zebrafish with homozygous mutations in von Hippel Lindau (vhl, a form of angiogenesis that is dependent on blood flow. We examined expression of three klf family members in wildtype and klf2ash317 zebrafish. We detected vascular expression of klf2b (but not klf4a or biklf/klf4b/klf17 in wildtypes but found no differences in expression that might account for the lack of phenotype in klf2ash317 mutants. klf2b morpholino knockdown did not affect heart rate or impair formation of the 5th accessory aortic arch in either wildtypes or klf2ash317 mutants.The klf2ash317 mutation produces a truncated Klf2a protein but, unlike morpholino induced klf2a knockdown, does not affect cardiovascular development.

  4. Lernen von und bei Max von Laue

    Science.gov (United States)

    Thiessen, P. A.

    Erinnerungen an die Entstehungsgeschichte und die Frühzeiten der Röntgenstrukturanalyse.Translated AbstractLearning at Max von LaueRemembrances of the historical rise and the early times of X-ray structure analysis.

  5. Bilateral papillopathy as a presenting sign of pheochromocytoma associated with von Hippel–Lindau disease

    Directory of Open Access Journals (Sweden)

    Shah V

    2014-03-01

    Full Text Available Veeral Shah, Leonid Zlotcavitch, Angela M Herro, Sander R Dubovy, Zohar Yehoshua, Byron L LamBascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, FL, USAAbstract: A 7-year-old girl presented with decreased vision in both eyes for 1 month. Examination showed visual acuity of 20/50 and 20/60, no afferent pupillary defect, cecocentral scotomas, and bilateral optic disc edema with extensive peripapillary and macular exudates. Magnetic resonance imaging showed multiple cortical and subcortical white matter lesions. Both the laboratory workup and the systemic examination were unrevealing. However, on follow-up, the patient showed episodic elevations of blood pressure as high as 240/160. Further workup revealed elevated urine catecholamines and a right supra-adrenal mass proven to be a pheochromocytoma by histopathologic analysis. The paroxysmal hypertension resolved, and the visual acuity, visual fields, fundus exam, and neuroimaging improved. The patient was lost to follow-up until age 18 when she developed shortness of breath and was found to have multiple pulmonary metastases identified as pheochromocytoma by biopsy. Genetic testing identified a 3p25-26 (c.482 G>A VHL gene chromosomal mutation consistent with von Hippel–Lindau disease genotype. Multiple peripheral retinal vascular dilations and small retinal capillary hemangioblastomas were also found. This case highlights the importance of recognizing the lability of blood pressure often seen with pheochromocytomas, which may mask the underlying cause of hypertensive papillopathy and retinopathy, a diagnosis of low clinical suspicion in the pediatric population. The case also underscores the importance of thorough systemic workup, including genotyping to detect conditions where pheochromocytoma may be the presenting sign of the disease, such as multiple endocrine neoplasia 2A and 2B, von Hippel–Lindau disease, von Recklinghausen disease, tuberous sclerosis, and

  6. Rare presentation of familial paraganglioma without evidence of mutation in the SDH, RET and VHL genes: towards further genetic heterogeneity.

    Science.gov (United States)

    Persu, Alexandre; Amyere, Mustapha; Gutierrez-Roelens, Ilse; Rustin, Pierre; Sempoux, Christine; Lecouvet, Frédéric E; Van Beers, Bernard E; Horsmans, Yves; De Plaen, Jean-François; MarcHamoir; Vikkula, Miikka

    2009-01-01

    Mutations in genes encoding succinate dehydrogenase and its anchoring subunits (SDH genes) are at the origin of hereditary head and neck paraganglioma (PGL) and a subset of apparently sporadic pheochromocytoma. We describe a family including three patients harbouring bilateral head and neck PGL diagnosed before 25 years of age. Multiple hypervascular hepatic lesions were subsequently discovered in two of them. In both, liver biopsy confirmed the diagnosis of PGL. In addition, in one patient, MRI disclosed multiple target-like lesions of the spine, highly suggestive of metastatic PGL. Family history was compatible with autosomal dominant inheritance with possible maternal imprinting. Combined single-strand conformation polymorphism and heteroduplex analysis followed by sequencing did not show any mutation of the coding parts of SDHB, SDHC, SDHD, RET or VHL genes. Screening of copy number alterations and loss of heterozygosity in the three affected family members showed no deletion or amplification of the SDH, RET and VHL genes. Furthermore, succinate dehydrogenase activity measured in a liver PGL sample was not significantly decreased in the affected patient as compared with controls, underscoring the exclusion of the SDH genes. To our knowledge, this is the first reported family of hereditary head and neck PGL with metastatic dissemination in the liver and the spine. A large body of evidence supports the absence of mutations in SDH, RET and VHL genes, which suggests the existence of a yet unknown gene at the origin of this particular form of familial PGL.

  7. von Willebrand Disease

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  8. Carl von Clausewitz

    DEFF Research Database (Denmark)

    Højrup, Thomas

    2009-01-01

    Forskningsbaseret præsentation af Carl von Clausewitz' krigsteori og dens betydning for statsbegrebet og udviklingen af teori om statsdannelse og statssystem. Krigsbegrebets betydning for politikbegrebet ekspliciteres, og de indre relationer imellem de to begreber demonstreres med konkrete eksemp...

  9. 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.

  10. Von Braun Fountain

    Science.gov (United States)

    1999-01-01

    A fountain representing a rocket launch was dedicated in the Von Braun courtyard outside of Building 4200 at Marshall Space Flight Center during the weekend celebrating the 30th arniversary of the Apollo 11 lunar landing. On hand for the festivities were many of the Saturn and Apollo astronauts.

  11. 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

  12. Karman, Prof. Theodore von

    Indian Academy of Sciences (India)

    Home; Fellowship. Fellow Profile. Elected: 1961 Honorary. Karman, Prof. Theodore von. Date of birth: 11 May 1881. Date of death: 6 May 1963. YouTube; Twitter; Facebook; Blog. Academy News. IAS Logo. Theory Of Evolution. Posted on 23 January 2018. Joint Statement by the Three Science Academies of India on the ...

  13. 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

  14. Myelopathy and sciatica induced by an extradural S1 root haemangioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Hermier, M.; Cotton, F.; Froment, J.C. [Department of Radiology, Hopital Neurologique et Neurochirurgical, Lyon (France); Saint-Pierre, G.; Jouvet, A. [Department of Neuropathology, Hopital Neurologique et Neurochirurgical, Lyon (France); Ongolo-Zogo, P. [Department of Radiology, Hopital Neurologique et Neurochirurgical, Lyon (France); Department of Radiology, Hopital Central, Yaounde (Cameroon); Fischer, G. [Department of Neurosurgery, Hopital Neurologique et Neurochirurgical, Lyon (France)

    2002-06-01

    Haemangioblastomas are vascular tumours which mainly involve the central nervous system and retina, often in the setting of von Hippel-Lindau disease. Haemangioblastomas occurring outside the central nervous system are uncommon. Wherever it is, recognising this tumour prior to surgery is desirable, as preoperative embolisation may be considered. We report the clinical, imaging and pathological features of a sporadic sacral root haemangioblastoma in a 58-year-old man with chronic sciatica and myelopathy. The diagnosis was questioned preoperatively because an enlarged sacral foramen, seen to be filled by a highly vascular, enhancing mass and dilated vessels. Myelopathy was attributed to the presumed high venous pressure resulting from increased flow in veins draining the vascular tumour. Microneurosurgical excision was performed after endovascular embolisation and led to persistent clinical improvement. (orig.)

  15. Pediatric genetic ocular tumors.

    Science.gov (United States)

    Rouhani, Behnaz; Ramasubramanian, Aparna

    2014-12-01

    Pediatric genetic ocular tumors include malignancies like retinoblastoma and phakomatosis like neurofibromatosis, tuberous sclerosis, von Hippel-Lindau syndrome, and nevoid basal cell carcinoma syndrome. It is important to screen for ocular tumors both for visual prognosis and also for systemic implications. The phakomatosis comprise of multitude of benign tumors that are aysmptomatic but their detection can aid in the diagnosis of the syndrome. Retinoblastoma is the most common malignant intraocular tumor in childhood and with current treatment modalities, the survival is more than 95%. It is transmitted as an autosomal dominant fashion and hence the offsprings of all patients with the germline retinoblastoma need to be screened from birth. This review discusses the various pediatric genetic ocular tumors discussing the clinical manifestation, diagnosis and treatment.

  16. Bilateral Adrenal Incidentalomas: A Case Report and Review of Diagnostic Challenges

    Directory of Open Access Journals (Sweden)

    Anders L. Carlson

    2013-01-01

    Full Text Available Incidentally discovered adrenal masses (incidentalomas are common and present challenges both in diagnosis and management. When incidentally discovered adrenal masses are bilateral, a refined diagnostic approach is warranted since bilateral disease is more likely to be pathologic. We review a case of a 34-year-old man with incidentally discovered bilateral adrenal nodules. A comprehensive diagnostic strategy led to the diagnosis of bilateral pheochromocytoma caused by von Hippel-Lindau syndrome. He was successfully treated with bilateral laparoscopic adrenalectomy and has recovered well. While the initial diagnostic approach is similar to the unilateral incidentaloma, additional testing and/or genetic testing should be considered in the case of the bilateral adrenal mass.

  17. Familial Investigations of Childhood Cancer Predisposition

    Science.gov (United States)

    2018-01-03

    Acute Leukemia; Adenomatous Polyposis; Adrenocortical Carcinoma; AML; BAP1 Tumor Predisposition Syndrome; Carney Complex; Choroid Plexus Carcinoma; Constitutional Mismatch Repair Deficiency Syndrome; Diamond-Blackfan Anemia; DICER1 Syndrome; Dyskeratosis Congenita; Emberger Syndrome; Familial Acute Myeloid Leukemia; Familial Adenomatous Polyposis; Fanconi Anemia; Familial Cancer; Familial Wilms Tumor; Familial Neuroblastoma; GIST; Hereditary Breast and Ovarian Cancer; Hereditary Paraganglioma-Pheochromocytoma Syndrome; Hodgkin Lymphoma; Juvenile Polyposis; Li-Fraumeni Syndrome; Lynch Syndrome; MDS; Melanoma Syndrome; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2; Neuroblastoma; Neurofibromatosis Type 1; Neurofibromatosis Type II; Nevoid Basal Cell Carcinoma Syndrome; Non Hodgkin Lymphoma; Noonan Syndrome and Other Rasopathy; Overgrowth Syndromes; Pancreatic Cancer; Peutz-Jeghers Syndrome; Pheochromocytoma/Paraganglioma; PTEN Hamartoma Tumor Syndrome; Retinoblastoma; Rhabdoid Tumor Predisposition Syndrome; Rhabdomyosarcoma; Rothmund-Thomson Syndrome; Tuberous Sclerosis; Von Hippel-Lindau Disease

  18. Renal oncocytosis in a pediatric patient: Case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Stacey Speer

    2015-11-01

    Full Text Available Renal oncocytosis is a rare condition in which the kidney develops numerous oncocytomas. We present a case of a 12-year-old female who presented with right-sided flank pain of one-year duration. Imaging revealed several masses in the right kidney. Tissue biopsy confirmed multiple benign oncocytomas. Due to the presence of multiple oncocytomas throughout the kidney, a radical nephrectomy was performed. Given the rarity of this condition, as well as its known association with von Hippel-Lindau disease and Birt-Hogg-Dube syndrome, genetic investigations were pursued but failed to identify any abnormalities. This patient remains well and disease free six years after surgery. A review of the literature of this rare condition was performed.

  19. CASE REPORT: Papillary Adenoma of Kidney- An Incidental Autopsy Finding: Report of Two Cases

    Directory of Open Access Journals (Sweden)

    Bhakti D. Deshmukh

    2012-01-01

    Full Text Available Background: Renal papillary adenoma is usually an incidental finding at autopsy with an incidence of 7% to 23%. The frequency of small papillary tumours of kidney increases with age to approximately 40% of the population over the age of 65. These tumours occur morefrequently in scarred kidneys, acquired renal cystic disease and in children with von Hippel-Lindau syndrome. Case history: In this report we describe renal papillary adenoma incidentally detected during autopsies of two elderly males. Gross examination of kidneyshowed two tiny subcapsular yellowish nodules in one case and single nodule with similar morphology in the other. Microscopic examination in both the cases showed a well circumscribed tumour composed of densely packed tubules and papillae lined by small cuboidal to columnar cells with rounded uniform nuclei. However there was no nuclear atypia, mitosis or necrosis.

  20. Renal cystic diseases and renal neoplasms: a mini-review.

    Science.gov (United States)

    Bonsib, Stephen M

    2009-12-01

    The past two decades have witnessed recognition of several new types of renal cell carcinoma, each with distinct cytogenetic abnormalities. Included are several genetic and acquired cystic kidney diseases associated with development of renal cell carcinoma, the topic of this review. The risk in patients with autosomal dominant polycystic kidney disease is not accurately known but may be slightly increased. The risk for patients with von Hippel-Lindau disease is substantial, and death from renal cancer is common. For patients with tuberous sclerosis complex, the challenge is recognition of the occasional malignancy arising in a field of many benign tumors. Patients with end-stage kidney disease and acquired cystic kidney disease may develop a variety of renal cell carcinoma types. Progress in understanding the molecular basis of renal cyst formation and neoplastic disease has fostered development of targeted therapies that now hold promise for a group of neoplasms whose cure was traditionally dependent on surgical approaches.

  1. Complete remission with sunitinib in a poor-risk patient with metastatic renal cell carcinoma: the fine balance between toxicity and efficacy.

    Science.gov (United States)

    Massari, Francesco; Ciccarese, Chiara; Bimbatti, Davide; Fantinel, Emanuela; Modena, Alessandra; Simbolo, Michele; Brunelli, Matteo; Artibani, Walter; Martignoni, Guido; Scarpa, Aldo; Tortora, Giampaolo

    2015-04-01

    Sunitinib represents a reasonable therapeutic option for first-line treatment of poor-risk metastatic renal cell carcinoma and the treatment should aim at the delicate balance between managing side effects to improve the toxicity profile and patient compliance to treatment while maintaining anticancer efficacy. Achievement of a complete response, although rare, is possible, even in poor-risk patients. Treatment discontinuation represents a viable alternative for both tumour biology and patients' quality of life. To date, no molecular markers have been identified with prognostic and/or predictive value for guiding therapeutic decisions. Further research should aim at gaining in-depth knowledge of renal cell carcinoma biology for a tailored personalized therapy. We report a case of poor-risk metastatic renal cell carcinoma, with Von Hippel-Lindau loss of function, which achieved and maintained a complete remission after first-line therapy with sunitinib by using a reduced dosage and a modified schedule of treatment.

  2. The oncometabolite fumarate promotes pseudohypoxia through noncanonical activation of NF-κB signaling.

    Science.gov (United States)

    Shanmugasundaram, Karthigayan; Nayak, Bijaya; Shim, Eun-Hee; Livi, Carolina B; Block, Karen; Sudarshan, Sunil

    2014-08-29

    Inactivating mutations of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH) have been linked to an aggressive variant of hereditary kidney cancer (hereditary leiomyomatosis and renal cell cancer). These tumors accumulate markedly elevated levels of fumarate. Fumarate is among a growing list of oncometabolites identified in cancers with mutations of genes involved in intermediary metabolism. FH-deficient tumors are notable for their pronounced accumulation of the transcription factor hypoxia inducible factor-1α (HIF-1α) and aggressive behavior. To date, HIF-1α accumulation in hereditary leiomyomatosis and renal cell cancer tumors is thought to result from fumarate-dependent inhibition of prolyl hydroxylases and subsequent evasion from von Hippel-Lindau-dependent degradation. Here, we demonstrate a novel mechanism by which fumarate promotes HIF-1α mRNA and protein accumulation independent of the von Hippel-Lindau pathway. Here we demonstrate that fumarate promotes p65 phosphorylation and p65 accumulation at the HIF-1α promoter through non-canonical signaling via the upstream Tank binding kinase 1 (TBK1). Consistent with these data, inhibition of the TBK1/p65 axis blocks HIF-1α accumulation in cellular models of FH loss and markedly reduces cell invasion of FH-deficient RCC cancer cells. Collectively, our data demonstrate a novel mechanism by which pseudohypoxia is promoted in FH-deficient tumors and identifies TBK1 as a novel putative therapeutic target for the treatment of aggressive fumarate-driven tumors. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Kommunikative Konstitution von Organisationen

    DEFF Research Database (Denmark)

    Schoeneborn, Dennis; Wehmeier, Stefan

    2014-01-01

    Beiträge zur Unternehmenskommunikation behandeln in der Regel (strategisch) geplante interne oder externe Kommunikation. Der vorliegende Beitrag stellt einen alternativen Theorieansatz vor, der aktuell im nordamerikanischen Forschungsgebiet „Organizational Communication“ vorherrschend ist....... zunehmende Aufmerksamkeit erhält Der sogenannten „CCO-Perspektive“ („Communicative Constitution of Organizations“) zufolge bestehen Unternehmen aus einer Vielzahl von internen und externen Kommunikationspraktiken, die nur in bedingtem Maße strategisch steuerbar sind. Zugleich sind es eben diese...

  4. Kulturelle Aspekte von Textsorten

    Directory of Open Access Journals (Sweden)

    Siegfried Heusinger

    1998-12-01

    Full Text Available Ich fasse meine Überlegungen zu kulturellen Aspekten von Textsorten zusammen: 1. Mit unseren Kulturverständnis ist die terminologisierte Wortgruppe "interkulturelle Kommunikation" nicht zu begreifen als Kommunikation zwischen Menschen verschiedener kultureller Bindungen, sondern sie ist nicht zu begreifen als Kommunikation zwischen Menschen verschiedener kultureller Bindungen, sondern sie ist ethnisch wie auch ethisch angepasstes sprachlichkommunikatives Verhalten an kulturelle Traditionen der jeweils für den Kommunkations- akt vereinbarten Sprache. 2. Das Adjektiv "interkulturell" referiert auf idiomatisierte Wendungen im zwischenmenschlichen Kontakt wie auch auf kulturell gebundene Unterschiede in der Benennungsmotivation (z.B. anloben/österr./, vereidigen /dt./ 3. Das Adjektiv "interkulturell" ist ebenfalls zu beziehen auf den Austausch von Erfahrungen und Ideen, auf den Dialog von Kulturen. 4. Textsorten existieren in ihrer kulturellen in ihrer kulturellen Tradition, wobei das Kulturspezifische vornehmlich in traditionellen (aber entwicklungsoffenen Formulierungs- und Gestaltungsmustern zu suchen iost. Andere Textsortencharakteristika wie die situative Einbettung, die kommunikative Zwecksetzung, die thematische Bindung und die Komposition haben offenbar kaum eine kulturspezifische Prägung. 5. Im Trend zur Internationalisierung der Textsorten erweisen sich die kulturell geprägten Textmustervor allem zwischen angrenzenden Nationen häufig als affin.

  5. 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.

  6. John von Neumann Birthday Centennial

    Energy Technology Data Exchange (ETDEWEB)

    Grcar, Joseph F.

    2004-11-12

    In celebration of John von Neumann's 100th birthday, a series of four lectures were presented on the evening of February 10, 2003 during the SIAM Conference on Computational Science and Engineering in San Diego. The venue was appropriate because von Neumann spent much of the later part of his life, in the 1950's, as an unofficial ambassador for computational science. He was then the only senior American scientist who had experience with the new computers (digital, electronic, and programmable) and a vision of their future importance. No doubt he would have relished the chance to attend a meeting such as this. The first speaker, William Aspray, described the ''interesting times'' during which computers were invented. His remarks were based on his history [1] of this period in von Neumann's life. We were honored to have John von Neumann's daughter, Marina von Neumann-Whitman, as our second speaker. Other accounts of von Neumann's life can be found in books by two of his colleagues [2] and [3]. Our third speaker, Peter Lax, provided both mathematical and international perspectives on John von Neumann's career. Finally, Pete Stewart spoke about von Neumann's numerical error analysis [4] in the context of later work; this talk did not lend itself to transcription, but readers may consult the historical notes in [5]. Our thanks to all the speakers for a remarkable evening. We are grateful to the DOE Applied Mathematical Sciences (AMS) program for partially supporting these lectures. Thanks are also due to SIAM and William Kolata, to our emcee, Gene Golub, to Paul Saylor for recording and editing, and to Barbara Lytle for the transcriptions. More about von Neumann's work can be learned from the recent American Mathematical Society proceedings [6].

  7. Alejandro Von Humboldt

    Directory of Open Access Journals (Sweden)

    Gerardo Paz Otero

    1965-09-01

    Full Text Available Diverso fue y sigue siéndolo, el destino de los dos hermanos Humboldt, Guillermo y Alejandro. Sino que se inicia con el nacimiento: Guillermo, el mayor, nace el 22 de junio de 1767 en Potsdam, residencia de los emperadores prusianos, la ciudad de los palacios imperiales, el imperio del militarismo germano; su cuna se meció cerca al palacete de Sans-Soussi, donde Federico el Grande forja ba el poderío de Prusia, cultivaba las ciencias y las artes, anfitrionaba a los intelectuales de Europa, y era "vasallo espiritual de Volta ire", según la aguda frase de Goethe. Alejandro viene al mundo dos años después (14 de septiembre de 1769 en Berlín, en la casa burguesa de la Jagerstrasse (calle del cazador que su madre Elizabeth von Humboldt heredara de su primer esposo.

  8. Der Einfluss von Phlorizin auf den programmierten Zelltod von Erythrozyten

    OpenAIRE

    Meier, Anja Doris

    2013-01-01

    Erythrozyten sind in der Lage, suizidalen Zelltod zu betreiben. Von einigen Substanzen ist bereits bekannt, dass sie die sogenannte Eryptose beeinflussen. Beispiele dafür sind Quecksilber, Monensin, Benzethonium und Oridonin, welche zu den Stimulatoren der Eryptose gehören. Blebbistatin, Koffein und Endothelin, gehören zu den Inhibitoren. In dieser Studie sollte untersucht werden, welchen Einfluss Phlorizin auf den Ablauf des suizidalen Zelltodes von Erythrozyten hat. Es wurde belegt, dass si...

  9. Einsatz von Nickel-Katalysatoren zum Cracken von Teerprodukten aus der Niederdruckaufkohlung von Stahl mit Ethin

    OpenAIRE

    Mbadinga Mouanda, Gelase

    2009-01-01

    Die Niederdruckaufkohlung von Stahl ist ein modernes Verfahren, das zur Einsatzhärtung von Stahlbauteilen dient. Bei Temperaturen zwischen 900 und 1050 °C und Drücken unter 50 mbar werden Bauteile durch heterogene Pyrolyse von Ethin in einem Ofen einsatzgehärtet. Das während der Pyrolyse erzeugte Abgas enthält aromatische Kohlenwasserstoffe und kann katalytisch behandelt werden. Der Katalysator wird durch Rußablagerung desaktiviert und muss zyklisch durch Verbrennung mit Luft regeneriert werd...

  10. Living with von Willebrand Disease

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  11. Ueber einige Coelenterata von Australien

    NARCIS (Netherlands)

    Stiasny, G.

    1931-01-01

    I. Hydromedusen. *Olindias singularis Browne. II. Scyphomedusen. *Atolla wyvillei Haeckel. *Linuche unguiculata O. Swartz. Pelagia noctiluca Péron u. Lesueur. Cyanea capillata var. annaskala von Lendenfeld. Netrostoma coerulescens Maas. *Versura anadyomene (Maas) Mayer. Catostylus mosaicus L.

  12. 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.

  13. Fluorido-Komplexe von Technetium

    OpenAIRE

    Mariappan Balasekaran, Samundeeswari

    2013-01-01

    Zusammenfassung Diese Dissertationsschrift befasst sich mit der Synthese und Charakterisierung neuer Technetiumfluoride mit dem Metall in den Oxidationsstufen “+1”, “+2”, “+4” und “+6”. Im ersten Kapitel wird über die Isolierung von unterschiedlichen Salzen von Fluoridonitridotechnetaten(VI) entweder aus Nitridotechnetium(VI)-säure oder aus Pertechnetat durch den Einsatz geeigneter Reduktionsmittel berichtet. Das Cäsiumsalz dieser Verbindung bildet einen oxido-verbrückten, dimeren Kompl...

  14. Effiziente chemoenzymatische Synthese von dhydroartemisinaldehyd

    OpenAIRE

    Demiray, Melodi; Tang, Xiaoping; Wirth, Thomas; Faraldos, Juan A.; Allemann, Rudolf K.

    2017-01-01

    Artemisinin aus der Pflanze Artemisia annua ist das wirkungsvollste Arzneimittel zur Behandlung von Malaria. Die Sesquiterpen-Cyclase Amorphadien-Synthase, ein Cytochrom-abhängiges CYP450 und eine Aldehyd-Reduktase wandeln in der Pflanze Farnesyl-Diphosphat (FDP) in Dihydroartemisinaldehyd (DHAAl) um, welches ein Schlüsselzwischenprodukt in der Biosynthese von Artemisinin und eine halbsynthetische Vorstufe in der chemischen Synthese des Arzneimittels ist. Hier berichten wir über einen chemoen...

  15. Die Wertigkeit von Bildinformationskategorien und ihre Rolle bei der Beurteilung von Bildern als Medien

    OpenAIRE

    Wieczorek, Ulrich

    1997-01-01

    Die Wertigkeit von Bildinformationskategorien und ihre Rolle bei der Beurteilung von Bildern als Medien. - In: Die Geographiedidaktik ist tot, es lebe die Geographiedidaktik : Festschr. zur Emeritierung von Josef Birkenhauer / hrsg. von Friedhelm Frank ... - München, 1997. - S. 253-271. - (Münchner Studien zur Didaktik der Geographie ; 8)

  16. Ethnographische Filme und die Darstellung von Frauen

    Directory of Open Access Journals (Sweden)

    Judith Keilbach

    2002-03-01

    Full Text Available In dieser Filmographie werden ethnographische und koloniale Filme aus dem Bestand des Nederlands Filmmuseum kommentiert, die für die Frage nach der Darstellung von Frauen und Geschlechterverhältnissen von Interesse sind.

  17. Stage-dependent prognostic impact of molecular signatures in clear cell renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    Weber T

    2014-05-01

    Full Text Available Thomas Weber,1,2 Matthias Meinhardt,3 Stefan Zastrow,1 Andreas Wienke,4 Kati Erdmann,1 Jörg Hofmann,1 Susanne Fuessel,1 Manfred P Wirth11Department of Urology, Technische Universität Dresden, Dresden, Germany; 2Department of Oncology and Hematology, Martin-Luther-University Halle-Wittenberg, Halle (Saale, Germany; 3Institute of Pathology, Technische Universität Dresden, Dresden, Germany; 4Institute of Medical Epidemiology, Biostatistics, and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale, GermanyPurpose: To enhance prognostic information of protein biomarkers for clear cell renal cell carcinomas (ccRCCs, we analyzed them within prognostic groups of ccRCC harboring different tumor characteristics of this clinically and molecularly heterogeneous tumor entity.Methods: Tissue microarrays from 145 patients with primary ccRCC were immunohistochemically analyzed for VHL (von Hippel-Lindau tumor suppressor, Ki67 (marker of proliferation 1, p53 (tumor protein p53, p21 (cyclin-dependent kinase inhibitor 1A, survivin (baculoviral IAP repeat containing 5, and UEA-1 (ulex europaeus agglutinin I to assess microvessel-density.Results: When analyzing all patients, nuclear staining of Ki67 (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.04–1.12 and nuclear survivin (nS; HR 1.04, 95% CI 1.01–1.08 were significantly associated with disease-specific survival (DSS. In the cohort of patients with advanced localized or metastasized ccRCC, high staining of Ki67, p53 and nS predicted shorter DSS (Ki67: HR 1.07, 95% CI 1.02–1.11; p53: HR 1.05, 95% CI 1.01–1.09; nS: HR 1.08, 95% CI 1.02–1.14. In organ-confined ccRCC, patients with high p21-staining had a longer DSS (HR 0.96, 95% CI 0.92–0.99. In a multivariate model with stepwise backward elimination, tumor size and p21-staining showed a significant association with DSS in patients with "organ-confined" ccRCCs. The p21-staining increased the concordance index of tumor size from

  18. 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.

  19. An Invitation from Lars von Trier

    DEFF Research Database (Denmark)

    Skadhauge, Troels; Tønder, Lars

    2015-01-01

    Translation of Martin Krasnik interview with Lars von Trier broadcast on DR2, January 12, 2015. The following is an interview of Lars von Trier (LvT) by the Danish journalist Martin Krasnik (MK). The interview took place in Lars von Trier’s home in Brede, a small town just outside Copenhagen...

  20. Management von Anforderungsdokumenten mittels semantischer Wikis

    OpenAIRE

    Decker, B.

    2005-01-01

    Im Projekt RISE wird untersucht, wie durch den Einsatz von Wikis das Anforderungsmanagement von Software Projekten agil unterstützt werden kann. Um das oftmals chaotische Wachstum von Inhalten in den Griff zu bekommen, werden maschinelle Lernverfahren genutzt, um Inhalte zu strukturieren und dem Benutzer zugänglich zum machen.

  1. Multivariat-statistische Auswertung von energiedispersiven Röntgenfluoreszenzspektren zur Identifizierung von Substanzen

    OpenAIRE

    Kessler, Thorsten

    2001-01-01

    Es wurde der Einsatz von multivariater Auswertung von energiedispersiven Röntgenfluoreszenzanalyse (EDRFA) -Spektren für die Zuordnung von Substanzen getestet. Hierbei erfolgten u. a. Untersuchungen zur Zuordnungsanalytik von Chemikalien ohne und mit Verpackungen. Zur Untersuchung von Chemikalien mit Verpackung wurden ausschließlich anorganische, feste Chemikalien in z.T. unterschiedlicher Verpackung herangezogen. Zusätzlich sollte ein Vergleich zwischen Messungen durch gleiche Verpackungen u...

  2. 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

  3. Replikation von µ-Peptidarrays

    OpenAIRE

    Striffler, Jakob

    2014-01-01

    In der vorliegen Arbeit wurde ein Verfahren erarbeitet und mit Photometrie, XPS und ToF-SIMS charakterisiert, mit dem durch mikropartikelbasierte Verfahren hergestellte µ-Peptidarrays von Syntheseoberflächen abgespalten und auf beliebige Zieloberflächen transferiert werden können.

  4. Von Krahl ON! / Terje Metsavas

    Index Scriptorium Estoniae

    Metsavas, Terje

    2008-01-01

    Madli Pesti ja Terje Metsavas kohtusid Von Krahli teatri tehnilise meeskonnaga teatri black-box-saalis. Teatri tehniline meeskond on tehnikadirektor Enar Tarmo, video- ja multimeediaga tegelev Lauri Sepp, tehnikud Janno "John" Jaanus, Oliver Kulpsoo ja Allan Räim. Selles, kuidas sünnivad "tehnikaimed" ja kuidas lahendatakse lavastuslikke projekte

  5. Integration von Produktion und Instandhaltung

    OpenAIRE

    Hans-Böckler-Stiftung

    2003-01-01

    Die Faktoren Produktqualität und Kosten-Nutzen-Verhältnis sind entscheidend im Wettbewerb. Um diese Faktoren zu optimieren, suchen die Unternehmen nach innovativen Modellen der Integration von Produktion und Instandhaltung. Über Konzeption und Erprobung solcher Modelle berichtet eine Arbeitsgruppe der Engeren Mitarbeiter der Arbeitsdirektoren Stahl Fachausschuss 1/00.

  6. [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

  7. Von den Veranschaulichungsmethoden in den Rundfunkpredigten von der Heiligkreuz- Kirche

    Directory of Open Access Journals (Sweden)

    Witold Ostafiński

    2004-12-01

    Full Text Available In der gegenwärtigen Verkündigung des Wortes Gottes spielt die Veranschaulichung der Überlieferung eine nicht zu überschätzende Rolle. Vor diesem Hintergrund wird es sehr wichtig, dass man den Predigern nicht nur auf die Funktion des Bildes in der Verkündigung, sondern auch auf die Art und Weise seines Entstehens auf der narrativen Ebene aufmerksam macht. Während die Kenner der Homiletik die Notwendigkeit des Auftretens der Bildeigenschaften in den Predigten betonen, erinnern sie gleichzeitig daran, dass der moderne, von der „Bild-Zivilisation“ gestaltete Mensch, „immer mehr sehen als hören“ möchte. Der vorliegende, die Rundfunkpredigten von der Heiligkreuz-Kirche analysierende Aufsatz, nimmt auf und bringt zugleich nahe die Problematik der Notwendigkeit des Bildes in der Wort-Gottes-Verkündigung. Der Artikel stellt die Erzählungsform als eine wichtige Möglichkeit der Glaubensüberlieferung dar, behandelt das Problem der Aktualisierung evangelischen Werte, bringt das von den Predigten gestaltete synästhetische Weltbild nahe und analysiert die Rolle des Zitats und Beispiels (exemplum bei der Gestaltung der Bildhaftigkeit einer Predigt. Darüber hinaus überprüft der Aufsatz in seinem letzten Teil die in den gegenwärtigen Rundfunkpredigten meist verwendeten Redefiguren

  8. Analyse von Schnittstellenkompatibilität von Steuergeräten auf Basis von MSC-Beschreibungen

    OpenAIRE

    Ma, Zheng

    2008-01-01

    In modernen Fahrzeugen befindet sich eine Vielzahl von Steuergeräten, die verschiedenste Funktionen, wie z.B. das Antiblockiersystem (ABS) realisieren. Die Funktionalitäten von Steuergeräten werden heute mit unterschiedlichen Methoden beschrieben. Eine dieser Methoden sind Message Sequence Charts (MSCs). Aufgrund der Freiheitsgrade von MSCs gibt es verschiedene Möglichkeiten gleiche Funktionalität unterschiedlich zu beschreiben. In dieser Arbeit wird eine Methode definiert, wie...

  9. Männlichkeiten von rechts

    Directory of Open Access Journals (Sweden)

    Marc Gärtner

    2004-11-01

    Full Text Available Oliver Geden, Doktorand am Institut für europäische Ethnologie der Humboldt Universität Berlin untersucht Männlichkeitskonzepte im zeitgenössischen Rechtspopulismus – ein Thema, zu dem überraschend lange keine einschlägigen Studien vorlagen. Anhand von Parteimedien und Interviews rekonstruiert er strategische Positionen zu Männlichkeit und Geschlechterverhältnissen auf unterschiedlichen Organisationsebenen der Österreichischen „Haider-Partei“ FPÖ. Statt eines monolithischen „Neo-Macho-Projektes“ findet er im Kern zwar ähnliche Traditionalisierungsbemühungen auf allen Ebenen, je nach Kontext aber differenzierbare pragmatische, verunsicherte und neo-naturalistische Perspektiven auf die Geschlechterthematik. Durch die Einbeziehung von Gruppeninterviews im Nachwuchsverband der Partei erhält die Publikation eine besondere Brisanz. Geden analysiert die methodischen und forschungsethischen Implikationen ebenso hervorragend wie das Kernthema selbst.

  10. Von Willebrand factor and aging.

    Science.gov (United States)

    Konkle, Barbara A

    2014-09-01

    von Willebrand factor (VWF) plays critical roles in initiating primary hemostasis and extending the half-life of coagulation factor VIII in circulation. VWF levels increase with age and elevated levels are associated with an increased risk of venous thromboembolism and cardiovascular disease (CVD). Patients with von Willebrand disease (VWD) due to a deficiency or dysfunction of VWF may have symptoms that ameliorate with aging or may have exacerbation of their disease. Bleeding sites of particular challenge in the aging patient include gastrointestinal bleeding and hematuria. Some medications used to treat VWD should be used with special precaution in older patients, including desmopressin and VWF-containing factor concentrates. Patients with VWD may have some protection from CVD, but in those patients who develop CVD, management is very challenging, given the role of antiplatelet therapy as the mainstay of treatment. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  11. Methode zur Entwicklung von Prozessportalen

    OpenAIRE

    Alt, Rainer; Caesar, Marc; Leser, Florian; Österle, Hubert; Puschmann, Thomas; Reichmayr, Christian; Zurmuehlen, Rudolf

    2004-01-01

    Die in Kapitel 2 dargestellte Architektur zeigt Gestaltungselemente auf den drei Ebenen Strategie, Prozess und System. Zahlreiche Beispiele in den darauf folgenden Kapiteln haben die Anwendung dieser Architektur gezeigt. Um ein intuitives Vorgehen bei Entwurf und der Umsetzung von Echtzeit-Portalen zu vermeiden, sollen die bei den Fallbeispielen erzielten Erkenntnisse und Erfahrungen in ein systematisches Vorgehen einfliessen. Obgleich sich der Entwurf einer Architektur für das Echtzeit-Unter...

  12. Einfluss von Hypoxie auf das Transkriptom und das mitochondriale Proteom von Arabidopsis thaliana

    OpenAIRE

    Willeke, Claudia

    2011-01-01

    Hypoxie beeinflusst Wachstum und Entwicklung von Pflanzen. Da Sauerstoff als finaler Elektronenakzeptor der Atmungskette dient, sind Mitochondrien möglicherweise an der Wahrnehmung von Hypoxie und der Weiterleitung des Signals durch retrograde Regulierung beteiligt. In dieser Arbeit wurden daher die Auswirkungen von Hypoxie auf das Transkriptom und das mitochondriale Proteom von Arabidopsis thaliana untersucht. Zu diesem Zweck wurden Inkubationssysteme für Zellkulturen, Keimlinge und Pflanzen...

  13. 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.

  14. Offenes Baukastensystem zur effizienten Dimensionierung von Materialflusssystemen

    OpenAIRE

    Meinhardt, Ingolf; Marquardt, Hans-Georg

    2007-01-01

    Die optimale Gestaltung logistischer Systeme und Prozesse bekommt eine immer größere Bedeutung für die Wirtschaftlichkeit und Wettbewerbsfähigkeit von Unternehmen. Für Einzelkomponenten von Materi-alflusssystemen sind neben exakten analytischen Verfahren auch Näherungslösungen und Ersatzmodelle in Form von Polynomen, neuronalen Netzen oder zeitdiskreten Verfahren vorhanden, mit denen eine gute Nachbildung des Verhaltens dieser Komponenten möglich ist. Ziel des Baukastensystems ist es, für...

  15. von Willebrand disease phenotype and von Willebrand factor marker genotype in Doberman Pinschers.

    Science.gov (United States)

    Brooks, M B; Erb, H N; Foureman, P A; Ray, K

    2001-03-01

    To define the relationship between clinical expression of a type-1 von Willebrand disease phenotype and genotype at 2 von Willebrand factor marker loci in Doberman Pinschers. 102 client-owned Doberman Pinschers. Dogs were recruited on the basis of plasma von Willebrand factor concentration, clinical history, and pedigree. Blood samples and response to a history questionnaire were obtained for each dog. Plasma von Willebrand factor concentration was measured by use of an ELISA, and genotyping was performed via polymerase chain reaction for 1 intragenic and 1 extragenic von Willebrand factor marker. Amplification product size was determined by use of polyacrylamide gel electrophoresis (intragenic marker) or automated sequence analysis (extragenic marker). Western blots were prepared from a subset of dogs with low plasma von Willebrand factor concentration to evaluate multimer distribution. Strong associations were detected between plasma von Willebrand factor concentration and von Willebrand factor marker genotype. Twenty-five dogs had substantial reduction in plasma von Willebrand factor concentration and multiple hemorrhagic events. All were homozygous for a 157-base-pair intragenic marker allele and homozygous or compound heterozygous for 1 of 4 extragenic marker alleles. These marker genotypes were exclusively detected in dogs with low plasma von Willebrand factor concentration, although some dogs with these genotypes did not have abnormal bleeding. Type-1 von Willebrand disease in Doberman Pinschers is associated with the von Willebrand factor gene locus; however, the expression pattern in this breed appears more complex than that of a simple recessive trait.

  16. Modellierung von Anwenderverhalten im Social Semantic Web

    Science.gov (United States)

    Ulbrich, Armin; Höfler, Patrick; Lindstaedt, Stefanie

    Ziel dieses Kapitels ist es, gemeinsame Verwendungsszenarien des Semantic Web und des Social Web zu identifizieren und zu benennen. Dabei wird ein Teilaspekt des Themengebiets im Detail betrachtet: die Nutzung von Services, die Beobachtungen des Verhaltens von Anwendern analysieren, um daraus maschinell interpretierbare Informationen zu erhalten und diese als Modelle zu organisieren. Es werden zunächst einige Eigenschaften und Unterscheidungsmerkmale von Anwenderverhalten und organisierten Modellen dargestellt. Anschließend wird der mögliche wechselseitige Nutzen von Anwenderverhalten und Modellen diskutiert. Den Abschluss bildet eine Betrachtung einiger exemplarischer Software-Services, die heute schon verwendet werden, um Anwenderverhalten in Modelle überzuführen.

  17. The Social Science of Carl von Clausewitz

    Science.gov (United States)

    2006-01-01

    The Social Science of Carl von Clausewitz JANEEN KLINGER C arl von Clausewitz’s great, unfinished book On War is well-known as be- ing prone to...COVERED 00-00-2006 to 00-00-2006 4. TITLE AND SUBTITLE The Social Science of Carl von Clausewitz 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c...Raymond Aron, Clausewitz: Philos- opher of War (New York: Simon and Schuster, 1983), p. 206. 88 Parameters 2. Carl Von Clausewitz , On War, ed. and trans

  18. Die naturräumliche Gliederung von Schwaben

    OpenAIRE

    Fischer, Klaus

    1985-01-01

    Die naturräumliche Gliederung von Schwaben. - In: Historischer Atlas von Bayerisch-Schwaben / hrsg. von Hans Frei ... - 2., neu bearb. u. erg. Aufl. - Augsburg : Schwäb. Forschungsgem. - Lifg. 2. (1985). - Kt. II, 7.

  19. Planung von CLIL-Unterricht

    Directory of Open Access Journals (Sweden)

    Josef Leisen

    2015-10-01

    Full Text Available Der Beitrag formuliert die Sprachlernbedingungen und die Leitlinien des Sprachlernens im Fach und nennt Merkmale des guten integrierten Fach- und Sprachlehrens. Ausgehend von den Sprachproblemen, die sich im CLIL-Unterricht auftun, wird der sprachsensible CLIL-Unterricht definiert, und es werden Anregungen zur Gestaltung gegeben. Sprachliche Standardsituationen umfassen die kommunikativen Situationen im CLIL-Unterricht, die beim fachlichen Lernen auftreten und von der CLIL-Lehrkraft professionell bewältigt werden müssen. Im Beitrag wird ein Lehr-Lern-Modell ausführlich beschrieben und erläutert. Die Steuerungen von Sprachlernprozessen im CLIL durch Aufgabenstellungen, Methoden-Werkzeuge, Moderation und Diagnose/Rückmeldung werden ausführlich beschrieben. Die Planung einer Lernlinie in sechs Schritten wird dargestellt und erläutert. Planungsraster für CLIL-Lernlinien schließen den Beitrag ab. The article sets out the conditions for language learning in general as well as guiding principles of language learning in the subject and puts forward criteria for successfully integrated content and language learning. Based on typical language problems arising in CLIL-classrooms, the language-sensitive CLIL-classroom is defined and organisational suggestions are given. Linguistic standard situations comprise the communicative situations in the CLIL-classroom which are encountered in subject-related learning and have to be professionally mastered by the CLIL-teacher. The article extensively describes and explains a model of teaching and learning that can be used for the CLIL-classroom. It gives detailed information on managing language learning processes in CLIL by means of tasks, resources and methods as well as discourse facilitation, evaluation and feedback. In addition, a six-step lesson unit is outlined and explained. The article concludes by giving a planning matrix for CLIL lesson units.

  20. Homoepitaxie von ZnO

    OpenAIRE

    Neumann, Christian

    2006-01-01

    Die Arbeit beschäftigt sich mit der homoepitaktischen Darstellung von ZnO-Dünnschichten. Die Arbeit beginnt mit einer theoretischen Betrachtung des Materialsystems und den daraus für eine erfolgreiche Epitaxie zu ziehenden Schlüssen. Es wurde eine Temperbehandlung zur Oberflächenmodifikation kommerziell erhältlicher ZnO-Einkristallsubstrate erarbeitet, die für eine erfolgreiche Epitaxie erforderlich ist. Im Anschluß daran wird die Entwicklung eines CVD-Prozesses mit metallischer Zin...

  1. Riidaja mõis / Elma von Stryk

    Index Scriptorium Estoniae

    Stryk, Elma von

    2006-01-01

    renoveerimise ootel barokne puithäärber (1762), kompleksi ümbritsev kivimüür, maakividest hobusetall, pargivaade, punastest tellistest neogooti stiilis kabel (1864), mis taastati von Strykkide perekonna toel. 11 ill.; fotod: Raivo Tasso; kabelis on Elma von Stryki loodud Kristust kujutav altarimaal

  2. Sorten- und Nachbaueignung von Hafer und Weizen

    OpenAIRE

    Spieß, Hartmut

    2000-01-01

    Der Beitrag gibt anhand alter und neuer Sortenvergleiche von Hafer und Weizen Einblick in die Problematik ökologischer Züchtung und Sortenwahl. Dabei geht es neben spezifischen Sorteneigenschaften um die Ausgewogenheit von Ertrags- und Qualitätsbildung im Verhältnis zur Pflanzengesundheit.

  3. 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

  4. 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

  5. Indikatorenbasierte Bewertung von Entwurfsentscheidungen auf Systemebene

    Science.gov (United States)

    Freier, M.; Wenzler, A.; Mayer, T.; Gerlach, J.; Rosenstiel, W.

    2013-07-01

    Bei dem Entwurf von anwendungsspezifischen integrierten Schaltungen muss ein Entwickler zusätzliche Funktionen integrieren und die zunehmende Komplexität bewältigen. Für die Reduzierung der Kosten bleibt weiterhin die Verkürzung der benötigten Entwicklungszeit ein Ziel. Ein entscheidender Faktor dabei ist die zuverlässige Absicherung von Entwurfsentscheidungen in einer frühen Entwurfsphase. In der vorliegenden Arbeit wird eine Methode vorgestellt, die eine Bewertung von Entwurfsentscheidungen bei Systemmodellen mittels automatisch ermittelter Indikatoren ermöglichen soll. Die Systemmodelle können mit der Entwurfsumgebung MATLAB/Simulink oder in SystemC beschrieben sein.

  6. The Digital Von Fahrenheid Pyramid

    Science.gov (United States)

    Bura, M.; Janowski, J.; Wężyk, P.; Zięba, K.

    2017-08-01

    3D Scanners Lab from Digital Humanities Laboratory at the University of Warsaw initiated the scientific project, the purpose of which was to call attention to systematically penetrated and devastated pyramid-shaped tomb from the XVIII/XIX century, of family von Fahrenheid in Rapa in Banie Mazurskie commune (NE Poland). By conducting a series of non-invasive studies, such as 3D inventory using terrestrial laser scanning (TLS), thermal imaging, georadar measurements (around and inside the tomb) and anthropological research of mummified remains as well - the complete dataset was collected. Through the integration of terrestrial (TLS) and airborne laser scanning (ALS) authors managed to analyse the surroundings of Fahrenheid pyriamid and influence of some objects (like trees) on the condition and visibility of the Pyramids in the landscape.

  7. Khazanah: Friedrich Karl von Savigny

    Directory of Open Access Journals (Sweden)

    Atip Latipulhayat

    2015-04-01

    Full Text Available Friedrich Karl von Savigny (1779-1861 adalah ahli hukum Jerman yang juga dianggap sebagai salah satu Bapak hukum Jerman. Savigny adalah tokoh mazhab sejarah (historical school jurisprudence yang dikembangkannya pada paruh pertama abad ke 19. Dia juga dianggap sebagai pelopor kajian mengenai relasi antara perkembangan hukum dan sosial. Sebagai seorang pemikir hukum yang senantiasa kreatif dalam membuat terobosan-terobosan (trail-blazing legal scientist, Savigny memberikan kontribusi penting dalam perkembangan ilmu hukum dan bahkan terhadap ilmu sosial. Dari sekian banyak kontribusinya antara lain teorinya mengenai kontinuitas antara institusi hukum saat ini dengan institusi hukum masa lalu, meletakkan fondasi bagi kajian sosiologi hukum, dan menegaskan mengenai urgensi metode historis dalam kajian hukum.

  8. Evaluierung und Entwicklung von Methoden zur automatisierten Erfassung von Waldstrukturen aus Daten flugzeuggetragener Fernerkundungssensoren

    OpenAIRE

    Heurich, Marco

    2006-01-01

    Auf Grund der rasanten technologischen Entwicklung im Bereich der Sensorik sowie der Computerhard- und -software haben sich in den letzten Jahren neue Perspektiven zur Erforschung von Wäldern ergeben. Im Rahmen dieser durch die High-Tech-Offensive Bayern geförderten Arbeit wurde deshalb untersucht, inwieweit sich der Einsatz neuer Technologien zur automatisierten Erfassung von Waldstrukturen eignet. Als Voraussetzung dafür wurde zunächst ein Referenzgebiet zum Testen von Fernerkundungssensore...

  9. Spezifische Bindung von Aluminium und Eisen an den kationenselektiven Kanal MppA von Microthrix parvicella

    OpenAIRE

    Knaf, Tobias

    2013-01-01

    Schwermetallsalze wie beispielsweise Aluminium- oder Eisensalze werden in der Abwasserbehandlung zur Prävention und Bekämpfung von Blähschlamm, Schwimmschlamm und Schaumbildung verwendet. Dadurch kann eine Verbesserung der Schlammabsetzeigenschaften im Nachklärbecken erreicht werden. Übermäßiges Wachstum des grampositiven Bakteriums Microthrix parvicella gilt dabei als Hauptursache von Schlammabsetzproblemen und kann ebenfalls durch die Dosierung von schwermetallhaltigen Flockungs- und Fällun...

  10. Das Tumorsuppressorprotein p53 - Rolle bei der Induktion von Apoptose und bei der Replikation von Adenoviren

    OpenAIRE

    Koch, Philipp

    2003-01-01

    Das Tumorsuppressorgen p53 gehört zu den zentralen Steuereinheiten von Proliferation und Wachstum in der Zelle. Mutationen und funktioneller Verlust bei diesem Protein ist eng mit der Entstehung maligner Tumoren assoziiert. So kann man in über 50% aller soliden Tumoren Mutationen von p53 nachweisen. Es vermittelt seine Funktion hauptsächlich durch transkriptionelle Aktivierung p53-responsiver Gene. Folge der Aktivierung von p53 is...

  11. How Is von Willebrand Disease Treated?

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  12. How Is von Willebrand Disease Diagnosed?

    Science.gov (United States)

    ... the condition. For example, the school nurse, teacher, daycare provider, coach, or any leader of afterschool activities ... MedlinePlus) Von Willebrand Disease (MedlinePlus) Building 31 31 Center Drive Bethesda, MD 20892 Learn more about getting ...

  13. 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 ...

  14. Genetics Home Reference: von Willebrand disease

    Science.gov (United States)

    ... Jun;5(6):1165-9. Citation on PubMed Kessler CM. Diagnosis and treatment of von Willebrand disease: ... consult with a qualified healthcare professional . About Selection Criteria for Links Data Files & API Site Map Customer ...

  15. 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.

  16. Ist Pop die Volksmusik von heute?

    OpenAIRE

    Arbeitskreis Studium Populärer Musik

    1986-01-01

    Zugegeben, die Frage, ob Pop die Volksmusik von heute sei, ist provokant. Genau das war beabsichtigt. Sehr schnell erhielten wir auf unser Vorhaben, ein Seminar zu diesem Thema zu veranstalten, eine Vielzahl von Rückmeldungen. Pop-, Rock- und Jazzspezialisten, Musikwissenschaftler und Musikotiunologen fühlten sich animiert, Stellung zu beziehen und ein Referat zu halten. Intensive Diskussionen schlossen sich an, beflügelt auch durch die ansprechende Atmosphdre in der stil...

  17. Begehrte Körper jenseits von Geschlecht?

    Directory of Open Access Journals (Sweden)

    Corinna Tomberger

    2001-03-01

    Full Text Available Obwohl die visuelle Konstruktion des männlichen Körpers im Mittelpunkt von Daniel Wildmanns Studie steht, gelingt es ihm paradoxerweise, die Kategorie Geschlecht weitgehend zu ignorieren. In seiner Analyse des Films Olympia von Leni Riefenstahl zeigt der Autor auf, wie der ‚arische‘ Körper als Objekt des Begehrens für das Publikum entworfen wird.

  18. Dr. von Braun With German Rocket Experimenters

    Science.gov (United States)

    1930-01-01

    Dr. von Braun was among a famous group of rocket experimenters in Germany in the 1930s. This photograph is believed to be made on the occasion of Herman Oberth's Kegelduese liquid rocket engine being certified as to performance during firing. From left to right are R. Nebel, Dr. Ritter, Mr. Baermueller, Kurt Heinish, Herman Oberth, Klaus Riedel, Wernher von Braun, and an unidentified person.

  19. 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!

  20. Dr. von Braun With Management Team

    Science.gov (United States)

    1961-01-01

    Dr. von Braun is shown in this photograph, which was probably taken in the early 1960s, with members of his management team. Pictured from left to right are, Werner Kuers, Director of the Manufacturing Engineering Division; Dr. Walter Haeussermarn, Director of the Astrionics Division; Dr. William Mrazek, Propulsion and Vehicle Engineering Division; Dr. von Braun; Dieter Grau, Director of the Quality Assurance Division; Dr. Oswald Lange, Director of the Saturn Systems Office; and Erich Neubert , Associate Deputy Director for Research and Development.

  1. 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

  2. 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.

  3. 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.

  4. An MRI Von Economo - Koskinas atlas.

    Science.gov (United States)

    Scholtens, Lianne H; de Reus, Marcel A; de Lange, Siemon C; Schmidt, Ruben; van den Heuvel, Martijn P

    2016-12-28

    The cerebral cortex displays substantial variation in cellular architecture, a regional patterning that has been of great interest to anatomists for centuries. In 1925, Constantin von Economo and George Koskinas published a detailed atlas of the human cerebral cortex, describing a cytoarchitectonic division of the cortical mantle into over 40 distinct areas. Von Economo and Koskinas accompanied their seminal work with large photomicrographic plates of their histological slides, together with tables containing for each described region detailed morphological layer-specific information on neuronal count, neuron size and thickness of the cortical mantle. Here, we aimed to make this legacy data accessible and relatable to in vivo neuroimaging data by constructing a digital Von Economo - Koskinas atlas compatible with the widely used FreeSurfer software suite. In this technical note we describe the procedures used for manual segmentation of the Von Economo - Koskinas atlas onto individual T1 scans and the subsequent construction of the digital atlas. We provide the files needed to run the atlas on new FreeSurfer data, together with some simple code of how to apply the atlas to T1 scans within the FreeSurfer software suite. The digital Von Economo - Koskinas atlas is easily applicable to modern day anatomical MRI data and is made publicly available online. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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

  6. Von der Universitätsbibliothek Regensburg zum Bayerischen Bibliotheksverbund

    OpenAIRE

    Frankenberger, Rudolf

    1989-01-01

    Von der Universitätsbibliothek Regensburg zum Bayerischen Bibliotheksverbund : d. Entwicklung d. Bayer. Bibliotheksverbundes. - In: Bibliothekslandschaft Bayern : Festschr. für Max Pauer zum 65. Geburtstag / hrsg. von Paul Niewalda. - Wiesbaden : Harrassowitz, 1989. - S. 84-96

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Polylaktidbeschichtung zur antithrombogenen Ausrüstung von Biomaterialien

    OpenAIRE

    Mebus, Siegrun

    2007-01-01

    In der Klinik etablierte Biomaterialien wurden mit einer Polylaktidbeschichtung und eingearbeiteten Antikoagulanzien ausgerüstet. Die mit einem in-vitro-Modell erarbeiteten Daten zeigen, daß der Arzneistoffträger innerhalb von 90 Tagen nicht abgebaut wurde. Die Freisetzung der Arzneistoffe erfolgte abhängig von deren Konzentration und dem Mischungsverhältnis von Iloprost und Hirudin. Iloprost beeinflußt die Freisetzungsrate von PEG-Hirudin bzw. r-Hirudin. Es konnte mit mikrobiologischen Metho...

  10. Nutzung der Eisenkorrosion zur Entfernung von Arsen aus Trinkwasser

    OpenAIRE

    Karschunke, Karsten

    2005-01-01

    In dieser Arbeit werden experimentelle Untersuchungen zur Nutzung von Eisenkorrosionsprozessen zur Entfernung von Arsen aus Trinkwasser vorgestellt. Auch in geringen Konzentrationen stellt diese Verunreinigung auf Grund der krebserregenden Wirkung von Arsen langfristig eine Gefahr für die menschliche Gesundheit dar. Verschiedene Entfernungsmethoden sind bekannt und in der Praxis der Trinkwasseraufbereitung bewährt, beispielsweise Flockungsverfahren unter Einsatz von Eisensalzen oder die Adsor...

  11. Liouville-von Neumann molecular dynamics.

    Science.gov (United States)

    Jakowski, Jacek; Morokuma, Keiji

    2009-06-14

    We present a novel first principles molecular dynamics scheme, called Liouville-von Neumann molecular dynamics, based on Liouville-von Neumann equation for density matrices propagation and Magnus expansion of the time-evolution operator. The scheme combines formally accurate quantum propagation of electrons represented via density matrices and a classical propagation of nuclei. The method requires a few iterations per each time step where the Fock operator is formed and von Neumann equation is integrated. The algorithm (a) is free of constraint and fictitious parameters, (b) avoids diagonalization of the Fock operator, and (c) can be used in the case of fractional occupation as in metallic systems. The algorithm is very stable, and has a very good conservation of energy even in cases when a good quality conventional Born-Oppenheimer molecular dynamics trajectories is difficult to obtain. Test simulations include initial phase of fullerene formation from gaseous C(2) and retinal system.

  12. 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)

  13. [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)

  14. Wachstum und Aufbau von Spongomorpha aeruginosa (Chlorophyta, Acrosiphoniales)

    NARCIS (Netherlands)

    Kornmann, Peter

    1967-01-01

    In zahlreichen Arbeiten dienten Algen als Objekte für das Studium von Regenerationsvorgängen und Erscheinungen der Polarität. Dagegen ist — von Chara abgesehen — über das normale Wachstum, den zeitlichen Ablauf von Teilung und Streckung der Zellen und die Entstehungsgeschichte des typischen Thallus

  15. Modellierung von Dienstleistungen mittels Business Service Blueprinting Modeling

    OpenAIRE

    Meis, Jochen; Menschner, Philipp; Leimeister, Jan Marco

    2010-01-01

    Der Beitrag stellt mit Business Service Blueprint Modeling (BSBM) einen konzeptionellen Ansatz zur Modellierung von Dienstleistungen vor, der ein systematisches und standardisiertes Vorgehen zur Modellierung von Dienstleistungen mit Kundeninteraktion anstrebt. BSBM verwendet hierzu die Business Process Modeling Notation (BPMN) in einem Service Blueprint (SB). Somit wird ein Modellierungskonzept geschaffen, das sowohl Kundeninteraktionspunkte berücksichtigt als auch von aktuellen Werkzeugen un...

  16. 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 ...

  17. Market Timing und Finanzierungsentscheidungen: Unterscheidet sich Europa von den USA?

    NARCIS (Netherlands)

    Sautner, Z.; Spranger, J..

    2009-01-01

    Seit der Arbeit von Baker/Wurgler (2002) hat sich die Market-Timing-Theorie als alternative Kapitalstrukturtheorie etabliert. Sie impliziert, dass die Kapitalstruktur von Unternehmen das kumulierte Ergebnis von Versuchen des Equity Market Timing ist. Im Rahmen dieser Studie wird untersucht,

  18. 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).

  19. [Von Recklinghausen disease and hepatic neurofibromatosis].

    Science.gov (United States)

    Guzman Toro, F; Hinestroza, D; Colmenares, D

    1995-01-01

    Von Recklinghausen's neurofibromatosis is one of the most common autosomal dominant disease with an estimated frecuency of 1:3000 live births. Characteristic lesions include cafe-au-lait spots and neurofibromas following the path of peripheral nerves. Liver involvement by neurofibromatosis is rare and very few cases have been reported. We present a case of a young man with Von Recklinhausen's disease and hepatic neurofibromatosis with multiple caf-au-lait spots, cutaneous neurofibromas, short stature and osseous lesions and compare the clinical, radiological, surgical and anatomopathological findings with others describe previously in the literature.

  20. Zur Aktivierung des Verbundtragverhaltens von Glaslaminaten

    OpenAIRE

    Sastré-Terrasa, Johannes (Hanno)

    2007-01-01

    Für jedes konstruktiv planerische Handeln ist ein fundiertes Wissen über die Baustoffe primäre Voraussetzung. Das trifft für Glas, auf Grund der Komplexität des Materialverhaltens, im besonderen Maße zu. Diese Arbeit beschäftigt sich deshalb zunächst mit dem Werkstoff Glas, den Grundlagen zum schadensfreien Fügen von Glas sowie dem Verhalten seiner Fügepartner. Die wichtigste Methode, das Kleben von Glas, wird im Wesentlichen durch die viskoelastischen und temperaturabhängig...

  1. [Migration of the distal catheter of ventriculo-peritoneal shunt into the thoracic cavity].

    Science.gov (United States)

    Miyamoto, Junichi; Niijima, Kyo

    2012-03-01

    A 69-year-old woman suffered from ataxia of her right upper and lower limbs and infection in a distal tube of a ventriculo-peritoneal shunt (VPS). She had a thirty-year history of treatment for intracranial hemangioblastoma due to von Hippel-Lindau disease and hydrocephalus. Head magnetic resonance imaging demonstrated recurrent multiple hemangioblastoma in the cerebellum without hydrocephalus. Chest computed tomography showed a migrated distal tube of a VPS into the thoracic cavity. The VPS had been revised several times because of repeated infection before the present admission. The hydrocephalus was considered to be independent on the VPS because the VPS had become obstructed. A pleural effusion, which was probably caused by hypoalbuminemia during the postoperative course of the hemangioblastoma, increased and disappeared in association with her postoperative nutritional status. Therefore, revision of the migrated distal catheter was not needed. The distal tube most likely migrated through the intercostal space because the patient was very skinny. Migration of the distal catheter of VPS into the thoracic cavity may occur when the course of the distal tube is close to the thoracic cavity, especially in thin patients. Care should be taken when routing the distal catheter after VPS in skinny patients.

  2. Chemical approaches to targeted protein degradation through modulation of the ubiquitin-proteasome pathway.

    Science.gov (United States)

    Collins, Ian; Wang, Hannah; Caldwell, John J; Chopra, Raj

    2017-03-15

    Manipulation of the ubiquitin-proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer and other diseases. An increased understanding of the molecular mechanism of thalidomide and its analogues following their clinical use has unlocked small-molecule modulation of the substrate specificity of the E3 ligase cereblon (CRBN), which in turn has resulted in the advancement of new immunomodulatory drugs (IMiDs) into the clinic. The degradation of multiple context-specific proteins by these pleiotropic small molecules provides a means to uncover new cell biology and to generate future drug molecules against currently undruggable targets. In parallel, the development of larger bifunctional molecules that bring together highly specific protein targets in complexes with CRBN, von Hippel-Lindau, or other E3 ligases to promote ubiquitin-dependent degradation has progressed to generate selective chemical compounds with potent effects in cells and in vivo models, providing valuable tools for biological target validation and with future potential for therapeutic use. In this review, we survey recent breakthroughs achieved in these two complementary methods and the discovery of new modes of direct and indirect engagement of target proteins with the proteasome. We discuss the experimental characterisation that validates the use of molecules that promote protein degradation as chemical tools, the preclinical and clinical examples disclosed to date, and the future prospects for this exciting area of chemical biology. © 2017 The Author(s).

  3. Gramicidin A induces metabolic dysfunction and energy depletion leading to cell death in renal cell carcinoma cells.

    Science.gov (United States)

    David, Justin M; Owens, Tori A; Barwe, Sonali P; Rajasekaran, Ayyappan K

    2013-11-01

    Ionophores are lipid-soluble organic molecules that disrupt cellular transmembrane potential by rendering biologic membranes permeable to specific ions. They include mobile-carriers that complex with metal cations and channel-formers that insert into the membrane to form hydrophilic pores. Although mobile-carriers possess anticancer properties, investigations on channel-formers are limited. Here, we used the channel-forming ionophore gramicidin A to study its effects on the growth and survival of renal cell carcinoma (RCC) cells. RCC is a histologically heterogeneous malignancy that is highly resistant to conventional treatments. We found that gramicidin A reduced the in vitro viability of several RCC cell lines at submicromolar concentrations (all IC50 cells regardless of histologic subtype or the expression of either the von Hippel-Lindau tumor suppressor gene or its downstream target, hypoxia-inducible factor-1α. Gramicidin A decreased cell viability equal to or greater than the mobile-carrier monensin depending on the cell line. Mechanistic examination revealed that gramicidin A blocks ATP generation by inhibiting oxidative phosphorylation and glycolysis, leading to cellular energy depletion and nonapoptotic cell death. Finally, gramicidin A effectively reduced the growth of RCC tumor xenografts in vivo. These results show a novel application of gramicidin A as a potential therapeutic agent for RCC therapy. ©2013 AACR.

  4. Stereotactic radiosurgery in hemangioblastoma: Experience over 14 years

    Directory of Open Access Journals (Sweden)

    Nishant Goyal

    2016-01-01

    Full Text Available Background: Although gamma knife has been advocated for hemangioblastomas, it is not used widely by neurosurgeons. Objective: We review our experience over 14 years in an attempt to define the role of stereotactic radiosurgery (SRS in the management of hemangioblastomas. Patients and Methods: A retrospective study was conducted on all patients of hemangioblastoma who underwent SRS at our institute over a period of 14 years (1998–2011. Gamma knife plans, clinical history, and radiology were reviewed for all patients. Results: A total of 2767 patients underwent gamma knife during the study period. Of these, 10 (0.36% patients were treated for 24 hemangioblastomas. Eight patients (80% had von Hippel-Lindau disease while two had sporadic hemangioblastomas. The median peripheral dose (50% isodose delivered to the tumors was 29.9 Gy. Clinical and radiological follow-up data were available for eight patients. Of these, two were re-operated for persisting cerebellar symptoms. The remaining six patients were recurrence-free at a mean follow-up of 48 months (range 19–108 months. One patient had an increase in cyst volume along with a decrease in the size of the mural nodule. Conclusions: SRS should be the first option for asymptomatic hemangioblastomas. Despite the obvious advantages, gamma knife is not widely used as an option for hemangioblastomas.

  5. A Serous Cystic Neoplasm of the Pancreas Coexisting with High-Grade Pancreatic Intraepithelial Neoplasia Mimicking an Intraepithelial Papillary Mucinous Neoplasm: A Case Report.

    Science.gov (United States)

    Kawanishi, Aya; Hirabayashi, Kenichi; Kono, Hirotaka; Takanashi, Yumi; Hadano, Atsuko; Kawashima, Yohei; Ogawa, Masami; Kawaguchi, Yoshiaki; Yamada, Misuzu; Nakagohri, Toshio; Nakamura, Naoya; Mine, Tetsuya

    2017-01-01

    Serous cystic neoplasms of the pancreas are rare exocrine pancreatic neoplasms, most of which are benign and do not communicate with the pancreatic duct. Pancreatic intraepithelial neoplasm (PanIN) is considered a precursor of ductal adenocarcinoma that is microscopically recognized in pancreatic ducts. A 67-year-old Japanese woman presented with a 10-mm multilocular cystic lesion at the pancreatic body. Magnetic resonance pancreatography showed stenosis of the main pancreatic duct at the pancreatic body and dilatation of the distal side of the main pancreatic duct. Furthermore, communication between the cystic lesion and the main pancreatic duct was suspected based on magnetic resonance pancreatography findings. Distal pancreatectomy was performed under the preoperative diagnosis of intraductal papillary mucinous neoplasm. Histologically, the cystic lesion was lined with a non-atypical cuboidal or flat epithelium with clear cytoplasm and was thus diagnosed as a serous cystic neoplasm. High-grade PanIN lesions with stromal fibrosis were observed at the main and branch pancreatic ducts. Histological examination revealed no communication between the serous cystic neoplasm and the pancreatic ducts. Immunohistochemically, the epithelium of the serous cystic neoplasm showed positive anti-von Hippel-Lindau antibody staining, whereas the epithelium of the PanIN showed negative staining. A serous cystic neoplasm coexisting with another pancreatic neoplasm is rare. When dilatation of the main or branch pancreatic ducts coexists with a serous cystic neoplasm, as in this case, the lesion clinically mimics an intraductal papillary mucinous neoplasm.

  6. MicroRNAs in the pathogenesis of cystic kidney disease.

    Science.gov (United States)

    Phua, Yu Leng; Ho, Jacqueline

    2015-04-01

    Cystic kidney diseases are common renal disorders characterized by the formation of fluid-filled epithelial cysts in the kidneys. The progressive growth and expansion of the renal cysts replace existing renal tissue within the renal parenchyma, leading to reduced renal function. While several genes have been identified in association with inherited causes of cystic kidney disease, the molecular mechanisms that regulate these genes in the context of post-transcriptional regulation are still poorly understood. There is increasing evidence that microRNA (miRNA) dysregulation is associated with the pathogenesis of cystic kidney disease. In this review, recent studies that implicate dysregulation of miRNA expression in cystogenesis will be discussed. The relationship of specific miRNAs, such as the miR-17∼92 cluster and cystic kidney disease, miR-92a and von Hippel-Lindau syndrome, and alterations in LIN28-LET7 expression in Wilms tumor will be explored. At present, there are no specific treatments available for patients with cystic kidney disease. Understanding and identifying specific miRNAs involved in the pathogenesis of these disorders may have the potential to lead to the development of novel therapies and biomarkers.

  7. Caenorhabditis elegans, a model organism for kidney research: from cilia to mechanosensation and longevity.

    Science.gov (United States)

    Müller, Roman-Ulrich; Zank, Sibylle; Fabretti, Francesca; Benzing, Thomas

    2011-07-01

    The introduction of Caenorhabditis elegans by Sydney Brenner to study 'how genes might specify the complex structures found in higher organisms' revolutionized molecular and developmental biology and pioneered a new research area to study organ development and cellular differentiation with this model organism. Here, we review the role of the nematode in renal research and discuss future perspectives for its use in molecular nephrology. Although C. elegans does not possess an excretory system comparable with the mammalian kidney, various studies have demonstrated the conserved functional role of kidney disease genes in C. elegans. The finding that cystic kidney diseases can be considered ciliopathies is based to a great extent on research studying their homologues in the nematode's ciliated neurons. Moreover, proteins of the kidney filtration barrier play important roles in both correct synapse formation, mechanosensation and signal transduction in the nematode. Intriguingly, the renal cell carcinoma disease gene product von-Hippel-Lindau protein was shown to regulate lifespan in the nematode. Last but not least, the worm's excretory system itself expresses genes involved in electrolyte and osmotic homeostasis and may serve as a valuable tool to study these processes on a molecular level. C. elegans has proven to be an incredibly powerful tool in studying various aspects of renal function, development and disease and will certainly continue to do so in the future.

  8. Genetic kidney diseases: Caenorhabditis elegans as model system.

    Science.gov (United States)

    Ganner, Athina; Neumann-Haefelin, Elke

    2017-07-01

    Despite its apparent simplicity, the nematode Caenorhabditis elegans has a high rating as a model in molecular and developmental biology and biomedical research. C. elegans has no excretory system comparable with the mammalian kidney but many of the genes and molecular pathways involved in human kidney diseases are conserved in C. elegans. The plethora of genetic, molecular and imaging tools available in C. elegans has enabled major discoveries in renal research and advanced our understanding of the pathogenesis of genetic kidney diseases. In particular, studies in C. elegans have pioneered the fundamental role of cilia for cystic kidney diseases. In addition, proteins of the glomerular filtration barrier and podocytes are critical for cell recognition, assembly of functional neuronal circuits, mechanosensation and signal transduction in C. elegans. C. elegans has also proved tremendously valuable for aging research and the Von Hippel-Lindau tumor suppressor gene has been shown to modulate lifespan in the nematode. Further, studies of the excretory canal, membrane transport and ion channel function in C. elegans have provided insights into mechanisms of tubulogenesis and cellular homeostasis. This review recounts the way that C. elegans can be used to investigate various aspects of genetic and molecular nephrology. This model system opens up an exciting and new area of study of renal development and diseases.

  9. Heterogeneous Effects of Direct Hypoxia Pathway Activation in Kidney Cancer.

    Directory of Open Access Journals (Sweden)

    Rafik Salama

    Full Text Available General activation of hypoxia-inducible factor (HIF pathways is classically associated with adverse prognosis in cancer and has been proposed to contribute to oncogenic drive. In clear cell renal carcinoma (CCRC HIF pathways are upregulated by inactivation of the von-Hippel-Lindau tumor suppressor. However HIF-1α and HIF-2α have contrasting effects on experimental tumor progression. To better understand this paradox we examined pan-genomic patterns of HIF DNA binding and associated gene expression in response to manipulation of HIF-1α and HIF-2α and related the findings to CCRC prognosis. Our findings reveal distinct pan-genomic organization of canonical and non-canonical HIF isoform-specific DNA binding at thousands of sites. Overall associations were observed between HIF-1α-specific binding, and genes associated with favorable prognosis and between HIF-2α-specific binding and adverse prognosis. However within each isoform-specific set, individual gene associations were heterogeneous in sign and magnitude, suggesting that activation of each HIF-α isoform contributes a highly complex mix of pro- and anti-tumorigenic effects.

  10. Pheochromocytomas and secreting paragangliomas

    Directory of Open Access Journals (Sweden)

    Gimenez-Roqueplo Anne-Paule

    2006-12-01

    Full Text Available Abstract Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas or in extraadrenal chromaffin cells (secreting paragangliomas. Their prevalence is about 0.1% in patients with hypertension and 4% in patients with a fortuitously discovered adrenal mass. An increase in the production of catecholamines causes symptoms (mainly headaches, palpitations and excess sweating and signs (mainly hypertension, weight loss and diabetes reflecting the effects of epinephrine and norepinephrine on α- and β-adrenergic receptors. Catecholamine-producing tumors mimic paroxysmal conditions with hypertension and/or cardiac rhythm disorders, including panic attacks, in which sympathetic activation linked to anxiety reproduces the same signs and symptoms. These tumors may be sporadic or part of any of several genetic diseases: familial pheochromocytoma-paraganglioma syndromes, multiple endocrine neoplasia type 2, neurofibromatosis 1 and von Hippel-Lindau disease. Familial cases are diagnosed earlier and are more frequently bilateral and recurring than sporadic cases. The most specific and sensitive diagnostic test for the tumor is the determination of plasma or urinary metanephrines. The tumor can be located by computed tomography, magnetic resonance imaging and metaiodobenzylguanidine scintigraphy. Treatment requires resection of the tumor, generally by laparoscopic surgery. About 10% of tumors are malignant either at first operation or during follow-up, malignancy being diagnosed by the presence of lymph node, visceral or bone metastases. Recurrences and malignancy are more frequent in cases with large or extraadrenal tumors. Patients, especially those with familial or extraadrenal tumors, should be followed-up indefinitely.

  11. SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes.

    Science.gov (United States)

    Pasini, B; Stratakis, C A

    2009-07-01

    A genetic predisposition for paragangliomas and adrenal or extra-adrenal phaeochromocytomas was recognized years ago. Beside the well-known syndromes associated with an increased risk of adrenal phaeochromocytoma, Von Hippel Lindau disease, multiple endocrine neoplasia type 2 and neurofibromatosis type 1, the study of inherited predisposition to head and neck paragangliomas led to the discovery of the novel 'paraganglioma-phaeochromocytoma syndrome' caused by germline mutations in three genes encoding subunits of the succinate dehydrogenase (SDH) enzyme (SDHB, SDHC and SDHD) thus opening an unexpected connection between mitochondrial tumour suppressor genes and neural crest-derived cancers. Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma. The disease is characterized by autosomal dominant inheritance with a peculiar parent-of-origin effect for SDHD mutations. Life-time tumour risk seems higher than 70% with variable clinical manifestantions depending on the mutated gene. In this review we summarize the most recent knowledge about the role of SDH deficiency in tumorigenesis, the spectrum and prevalence of SDH mutations derived from several series of cases, the related clinical manifestantions including rare phenotypes, such as the association of paragangliomas with gastrointestinal stromal tumours and kidney cancers, and the biological hypotheses attempting to explain genotype to phenotype correlation.

  12. Metabolome profiling by HRMAS NMR spectroscopy of pheochromocytomas and paragangliomas detects SDH deficiency: clinical and pathophysiological implications.

    Science.gov (United States)

    Imperiale, Alessio; Moussallieh, François-Marie; Roche, Philippe; Battini, Stéphanie; Cicek, A Ercument; Sebag, Frédéric; Brunaud, Laurent; Barlier, Anne; Elbayed, Karim; Loundou, Anderson; Bachellier, Philippe; Goichot, Bernard; Stratakis, Constantine A; Pacak, Karel; Namer, Izzie-Jacques; Taïeb, David

    2015-01-01

    Succinate dehydrogenase gene (SDHx) mutations increase susceptibility to develop pheochromocytomas/paragangliomas (PHEOs/PGLs). In the present study, we evaluate the performance and clinical applications of (1)H high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy-based global metabolomic profiling in a large series of PHEOs/PGLs of different genetic backgrounds. Eighty-seven PHEOs/PGLs (48 sporadic/23 SDHx/7 von Hippel-Lindau/5 REarranged during Transfection/3 neurofibromatosis type 1/1 hypoxia-inducible factor 2α), one SDHD variant of unknown significance, and two Carney triad (CTr)-related tumors were analyzed by HRMAS-NMR spectroscopy. Compared to sporadic, SDHx-related PHEOs/PGLs exhibit a specific metabolic signature characterized by increased levels of succinate (P SDH-like pattern in the two CTr-related PGLs. The present study demonstrates that HRMAS-NMR provides important information for SDHx-related PHEO/PGL characterization. Besides the high succinate-low glutamate hallmark, SDHx tumors also exhibit high values of methionine, a finding consistent with the hypermethylation pattern of these tumors. We also found important levels of glutamine, suggesting that glutamine metabolism might be involved in the pathogenesis of SDHx-related PHEOs/PGLs. Copyright © 2014 Neoplasia Press, Inc. All rights reserved.

  13. Hereditary Renal Cancer Syndromes

    Science.gov (United States)

    Haas, Naomi B.

    2013-01-01

    Inherited susceptibility to kidney cancer is a fascinating and complex topic. Our knowledge about types of genetic syndromes associated with an increased risk of disease is continually expanding. Currently, there are 10 syndromes associated with an increased risk of all types of renal cancer, which are reviewed herein. Clear cell renal cancer is associated with von Hippel Lindau disease, chromosome 3 translocations, PTEN hamartomatous syndrome and mutations in BAP1, as well as several of the genes encoding the proteins comprising the succinate dehydrogenase complex (SDHB/C/D). Type 1 papillary renal cancers arise in conjunction with germline mutations in MET and type 2 as part of Hereditary Leiomyomatosis and Renal Cell Cancer (FH mutations). Chromophone and oncocytic renal cancers are predominantly associated with Birt Hogg Dubé syndrome. Angiomyolipomas are commonly and their malignant counterpart epitheliod angiomyolipomas rarely are found in patients with Tuberous Sclerosis Complex. The targeted therapeutic options for the renal cancer associated with these diseases are just starting to expand, and are an area of active clinical research. PMID:24359990

  14. Malignant pheochromocytomas and paragangliomas - the importance of a multidisciplinary approach

    DEFF Research Database (Denmark)

    Andersen, Kim Francis; Altaf, Rahim; Krarup-Hansen, Anders

    2011-01-01

    Approximately 10% of the pheochromocytomas and 20% of the paragangliomas are malignant with poor survival. As the biological behaviour of these tumours cannot be predicted with certainty from pathology the diagnosis of malignancy is difficult. Genetic testing is gaining impact as mutations in the...... in the tumour suppressor gene Von Hippel-Lindau and the mitochondrial succinate dehydrogenase enzyme complex subunit B (SDHB) are associated with malignancy. Excess release of catecholamines is characteristic for pheochromocytomas. High levels of chromogranin A, that is co-stored and co......-secreted with catecholamines, may indicate tumour mass and malignancy and can be used to monitor response and relapse. The secretory and non-secretory tumours can be visualised with functional (specific and non-specific) imaging as SPECT and PET using ¹²³I-MIBG, somatostatin analogues, ¹8F-DOPA, and ¹8F-FDG. These modalities...... are recommended in patients with extra-adrenal and suspected metastatic/malignant disease, in case of distorted post-operative anatomy, and when suspected recurrence. The sensitivities of ¹²³I-MIBG scintigraphy or ¹8F-DOPA PET are relatively low in SDHB mutated tumours, but high using ¹8F-FDG. Specific PET...

  15. Genetic predisposition to kidney cancer.

    Science.gov (United States)

    Schmidt, Laura S; Linehan, W Marston

    2016-10-01

    Kidney cancer is not a single disease but is made up of a number of different types of cancer classified by histology that are disparate in presentation, clinical course, and genetic basis. Studies of families with inherited renal cell carcinoma (RCC) have provided the basis for our understanding of the causative genes and altered metabolic pathways in renal cancer with different histologies. Von Hippel-Lindau disease was the first renal cancer disorder with a defined genetic basis. Over the next two decades, the genes responsible for a number of other inherited renal cancer syndromes including hereditary papillary renal carcinoma, Birt-Hogg-Dube´syndrome, hereditary leiomyomatosis and renal cell carcinoma, and succinate dehydrogenase-associated renal cancer were identified. Recently, renal cell carcinoma has been confirmed as part of the clinical phenotype in individuals from families with BAP1-associated tumor predisposition syndrome and MiTF-associated cancer syndrome. Here we summarize the clinical characteristics of and causative genes for these and other inherited RCC syndromes, the pathways that are dysregulated when the inherited genes are mutated, and recommended clinical management of patients with these inherited renal cancer syndromes. Published by Elsevier Inc.

  16. Endolymphatic sac tumor (aggressive papillary tumor of middle ear and temporal bone): sine qua non radiology-pathology and the University of Texas MD Anderson Cancer Center experience.

    Science.gov (United States)

    Bell, Diana; Gidley, Paul; Levine, Nicholas; Fuller, Gregory N

    2011-04-01

    Endolymphatic sac tumor (ELST) is a rare lesion of the skull base for which the origin has recently been ascertained. The endolymphatic sac is derived from neuroectoderm and is located subjacent to the posteromedial surface of the temporal bone. Patients characteristically present with hearing loss, tinnitus, and vertigo; facial nerve paralysis occurs less commonly. An indolent clinical course and long-standing symptom history is typical. Endolymphatic sac tumors are known to occur more frequently in patients with von Hippel-Lindau disease, but this is not a prerequisite for diagnosis because sporadic occurrence is common. Morphologically, all of the ELSTs showed a papillary and glandular architecture. The papillary and glandular structures were lined by a single layer of flattened cuboidal-to-columnar cells that were variably ciliated. Surgery is the treatment of choice for small ELST. Remission may last for years, but local recurrence after surgery, likely secondary to incomplete resection, can occur. Radiotherapy has a 50% cure rate with large or residual tumors. Endolymphatic sac tumor is a rare tumor that can easily be confused with other papillary lesions on histopathologic grounds, with significant treatment implications. Precise preoperative anatomic localization and computed tomography and magnetic resonance imaging feature interpretation play a paramount role in achieving an accurate final diagnosis. Published by Elsevier Inc.

  17. Premalignant Lesions in the Kidney

    Directory of Open Access Journals (Sweden)

    Ziva Kirkali

    2001-01-01

    Full Text Available Renal cell carcinoma (RCC is the most malignant urologic disease. Different lesions, such as dysplasia in the tubules adjacent to RCC, atypical hyperplasia in the cyst epithelium of von Hippel-Lindau syndrome, and adenoma have been described for a number of years as possible premalignant changes or precursor lesions of RCC. In two recent papers, kidneys adjacent to RCC or removed from other causes were analyzed, and dysplastic lesions were identified and defined in detail. Currently renal intraepithelial neoplasia (RIN is the proposed term for classification. The criteria for a lesion to be defined as premalignant are (1 morphological similarity; (2 spatial association; (3 development of microinvasive carcinoma; (4 higher frequency, severity, and extent then invasive carcinoma; (5 progression to invasive cancer; and (6 similar genetic alterations. RIN resembles the neoplastic cells of RCC. There is spatial association. Progression to invasive carcinoma is described in experimental cancer models, and in some human renal tumors. Similar molecular alterations are found in some putative premalignant changes. The treatment for RCC is radical or partial nephrectomy. Preneoplastic lesions may remain in the renal remnant in patients treated by partial nephrectomy and may be the source of local recurrences. RIN seems to be a biologic precursor of some RCCs and warrants further investigation. Interpretation and reporting of these lesions would reveal important resources for the biological nature and clinical significance. The management of RIN diagnosed in a renal biopsy and partial nephrectomy needs to be answered.

  18. Reproductive disturbances in multiple neuroendocrine tumor syndromes.

    Science.gov (United States)

    Lytras, Aristides; Tolis, George

    2009-12-01

    In the context of multiple neuroendocrine tumor syndromes, reproductive abnormalities may occur via a number of different mechanisms, such as hyperprolactinemia, increased GH/IGF-1 levels, hypogonadotropic hypogonadism, hypercortisolism, hyperandrogenism, hyperthyroidism, gonadotropin hypersecretion, as well as, tumorigenesis or functional disturbances in gonads or other reproductive organs. Precocious puberty and/or male feminization is a feature of McCune-Albright syndrome (MAS), neurofibromatosis type 1 (NF1), Carney complex (CNC), and Peutz-Jeghers syndrome (PJS), while sperm maturation and ovulation defects have been described in MAS and CNC. Although tumorigenesis of reproductive organs due to a multiple neuroendocrine tumor syndrome is very rare, certain lesions are characteristic and very unusual in the general population. Awareness leading to their recognition is important especially when other endocrine abnormalities coexist, as occasionally they may even be the first manifestation of a syndrome. Lesions such as certain types of ovarian cysts (MAS, CNC), pseudogynecomastia due to neurofibromas of the nipple-areola area (NF1), breast disease (CNC and Cowden disease (CD)), cysts and 'hypernephroid' tumors of the epididymis or bilateral papillary cystadenomas (mesosalpinx cysts) and endometrioid cystadenomas of the broad ligament (von Hippel-Lindau disease), testicular Sertoli calcifying tumors (CNC, PJS) monolateral or bilateral macroochidism and microlithiasis (MAS) may offer diagnostic clues. In addition, multiple neuroendocrine tumor syndromes may be complicated by reproductive malignancies including ovarian cancer in CNC, breast and endometrial cancer in CD, breast malignancies in NF1, and malignant sex-cord stromal tumors in PJS.

  19. Mitochondrial Sirt3 supports cell proliferation by regulating glutamine-dependent oxidation in renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jieun; Koh, Eunjin; Lee, Yu Shin; Lee, Hyun-Woo; Kang, Hyeok Gu [Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Yoon, Young Eun; Han, Woong Kyu [Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Choi, Kyung Hwa [Department of Urology, CHA Bundang Medical Center, CHA University, Seongnam 463-712 (Korea, Republic of); Kim, Kyung-Sup, E-mail: KYUNGSUP59@yuhs.ac [Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Institute of Genetic Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)

    2016-06-03

    Clear cell renal carcinoma (RCC), the most common malignancy arising in the adult kidney, exhibits increased aerobic glycolysis and low mitochondrial respiration due to von Hippel-Lindau gene defects and constitutive hypoxia-inducible factor-α expression. Sirt3 is a major mitochondrial deacetylase that mediates various types of energy metabolism. However, the role of Sirt3 as a tumor suppressor or oncogene in cancer depends on cell types. We show increased Sirt3 expression in the mitochondrial fraction of human RCC tissues. Sirt3 depletion by lentiviral short-hairpin RNA, as well as the stable expression of the inactive mutant of Sirt3, inhibited cell proliferation and tumor growth in xenograft nude mice, respectively. Furthermore, mitochondrial pyruvate, which was used for oxidation in RCC, might be derived from glutamine, but not from glucose and cytosolic pyruvate, due to depletion of mitochondrial pyruvate carrier and the relatively high expression of malic enzyme 2. Depletion of Sirt3 suppressed glutamate dehydrogenase activity, leading to impaired mitochondrial oxygen consumption. Our findings suggest that Sirt3 plays a tumor-progressive role in human RCC by regulating glutamine-derived mitochondrial respiration, particularly in cells where mitochondrial usage of cytosolic pyruvate is severely compromised. -- Highlights: •Sirt3 is required for the maintenance of RCC cell proliferation. •Mitochondrial usage of cytosolic pyruvate is severely compromised in RCC. •Sirt3 supports glutamine-dependent oxidation in RCC.

  20. Small Intestinal Tumours: An Overview on Classification, Diagnosis, and Treatment

    Directory of Open Access Journals (Sweden)

    Chiara Notaristefano

    2014-12-01

    Full Text Available The small intestinal neoplasia group includes different types of lesions and are a relatively rare event, accounting for only 3-6% of all gastrointestinal (GI neoplasms and 1-3% of all GI malignancies. These lesions can be classified as epithelial and mesenchymal, either benign or malignant. Mesenchymal tumours include stromal tumours (GIST and other neoplasms that might arise from soft tissue throughout the rest of the body (lipomas, leiomyomas and leiomyosarcomas, fibromas, desmoid tumours, and schwannomas. Other lesions occurring in the small bowel are carcinoids, lymphomas, and melanomas. To date, carcinoids and GIST are reported as the most frequent malignant lesions occurring in the small bowel. Factors that predispose to the development of malignant lesions are different, and they may be hereditary (Peutz-Jeghers syndrome, familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, neuroendocrine neoplasia Type 1, von Hippel-Lindau disease, and neurofibromatosis Type 1, acquired (sporadic colorectal cancer and small intestine adenomas, coeliac disease, Crohn’s disease, or environmental (diet, tobacco, and obesity. Small bowel tumours present with different and sometimes nonspecific symptoms, and a prompt diagnosis is not always so easily performed. Diagnostic tools, that may be both radiological and endoscopic, possess specificity and sensitivity, as well as different roles depending on the type of lesion. Treatment of these lesions may be different and, in recent years, new therapies have enabled an improvement in life expectancy.

  1. {sup 68}Ga-labelled peptides in the management of neuroectodermal tumours

    Energy Technology Data Exchange (ETDEWEB)

    Naji, Meeran [Maidstone and Tunbridge Wells NHS Trust, Departments of Nuclear Medicine and Radiology, Maidstone (United Kingdom); Al-Nahhas, Adil [Hammersmith Hospital, Imperial College NHS Trust, Department of Nuclear Medicine, London (United Kingdom)

    2012-02-15

    Neuroectodermal tumours arise from chromaffin cells and possess the ability to secrete catecholamines. They are generally rare and may occur in association with a variety of hereditary syndromes such as MEN-2A and 2B, neurofibromatosis type 1 and von Hippel-Lindau disease. The most common types are phaeochromocytoma arising from the adrenal medulla and paraganglioma of extra-adrenal origin. Phaeochromocytomas tend to be benign and are often associated with a gene mutation if the disease is bilateral, while paragangliomas are often malignant, have a more aggressive nature and tend to metastasize. There are no specific histological or immunohistochemical features that indicate the malignant potential and the diagnosis of malignancy can only be established by the presence of distant metastases. Therefore, imaging can play a vital role in the diagnosis, localization, staging and assessment of spread. Traditionally, this is achieved with a combination of cross-sectional (CT and MRI) and functional ({sup 123}I-MIBG or {sup 111}In-octreotide) imaging. However, these modalities are not adequate and achieve moderate sensitivity. The introduction of {sup 68}Ga-DOTA peptide in PET/CT imaging has led to improved receptor targeting and superb PET resolution, as well as accurate localization of lesions. The use of this technique in neuroectodermal tumours has been shown to be superior to all available modalities, but the available data are limited and larger studies are awaited to establish its role in the management of these tumours. (orig.)

  2. Li-Fraumeni Syndrome and p53 in 2015: Celebrating their Silver Anniversary.

    Science.gov (United States)

    Malkin, David

    2016-02-01

    In a typical morning in the Cancer Genetics Clinic at The Hospital for Sick Children in Toronto, the following array of patients and families might be seen: a family of three children, all harbouring a mutation of the succinyl dehydrogenase C gene inherited from their father who had had extensive surgery several years ago for a secreting paraganglioma; three families with Li-Fraumeni syndrome, each with at least one child harbouring a TP53 gene mutation conferring a lifetime risk of cancer approaching 100% and currently undergoing surveillance for early tumour detection; two children with Li-Fraumeni syndrome undergoing treatment for cancer - one having had three cancer diagnoses before 19 months of age and the other just completing therapy for metastatic adrenocortical carcinoma at age 3; two children with von Hippel-Lindau disease being monitored for persistent pancreatic neuroendocrine tumors and cerebellar hemangioblastomas, respectively; and one child with Beckwith-Wiedeman syndrome and Wilms tumor and another child completing therapy for a pleuropulmonary blastoma (PPB).

  3. All along the watchtower: is the cilium a tumor suppressor organelle?

    Science.gov (United States)

    Mans, Dorus A; Voest, Emile E; Giles, Rachel H

    2008-12-01

    Cilia or flagella have been around since almost the beginning of life, and have now developed specialized cell-type specific functions from locomotion to acting as environmental sensors participating in cell signalling. Genetic defects affecting cilia result in a myriad of pathological instances, including infertility, obesity, blindness, deafness, skeletal malformations, and lung problems. However, the consistency in which the common kidney cyst is coupled with cilia dysfunction has raised interest in the possibility that ciliary dysfunction might contribute to other neoplasms as well. A suite of recent papers convincingly linking cilia to hedgehog signalling, platelet-derived growth factor signalling, Wnt signalling and the von Hippel-Lindau tumor suppressor protein has rapidly expanded the knowledge base connecting cilia to cancer. We propose that these data support the notion of the cilium as a cellular Watchtower, whose absence can be an initiating event in neoplastic growth. Furthermore, we predict that we are just now seeing the tip of the iceberg, and that the list of cancers associated with altered ciliary signalling will grow exponentially in the next few years.

  4. Erwachsenenbildung im Spannungsfeld von Wissenschaft, Politik und Praxis: Heide von Felden, Christiane Hof und Sabine Schmidt-Lauff (Hrsg.). [Rezension

    OpenAIRE

    Filla, Wilhelm

    2016-01-01

    Rezension von: Felden, Heide von/Hof, Christiane/Schmidt-Lauff, Sabine (Hrsg.) (2013): Erwachsenenbildung im Spannungsfeld von Wissenschaft, Politik und Praxis. Dokumentation der Jahrestagung der Sektion Erwachsenenbildung der Deutschen Gesellschaft für Erziehungswissenschaften vom 27. bis 29. September 2012. Baltmannsweiler: Schneider Verlag Hohengehren.

  5. 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...

  6. 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.

  7. Deletion of von Hippel–Lindau Protein Converts Renin-Producing Cells into Erythropoietin-Producing Cells

    Science.gov (United States)

    Paliege, Alexander; Willam, Carsten; Schwarzensteiner, Ilona; Schucht, Kathrin; Neymeyer, Hanna; Sequeira-Lopez, Maria Luisa S.; Bachmann, Sebastian; Gomez, R. Ariel; Eckardt, Kai-Uwe; Kurtz, Armin

    2013-01-01

    States of low perfusion pressure of the kidney associate with hyperplasia or expansion of renin-producing cells, but it is unknown whether hypoxia-triggered genes contribute to these changes. Here, we stabilized hypoxia-inducible transcription factors (HIFs) in mice by conditionally deleting their negative regulator, Vhl, using the Cre/loxP system with renin-1d promoter-driven Cre expression. Vhl −/−REN mice were viable and had normal BP. Deletion of Vhl resulted in constitutive accumulation of HIF-2α in afferent arterioles and glomerular cells and HIF-1α in collecting duct cells of the adult kidney. The preglomerular vascular tree developed normally, but far fewer renin-expressing cells were present, with more than 70% of glomeruli not containing renin cells at the typical juxtaglomerular position. Moreover, these mice had an attenuated expansion of renin-producing cells in response to a low-salt diet combined with an ACE inhibitor. However, renin-producing cells of Vhl −/−REN mice expressed the erythropoietin gene, and they were markedly polycythemic. Taken together, these results suggest that hypoxia-inducible genes, regulated by VHL, are essential for normal development and physiologic adaptation of renin-producing cells. In addition, deletion of Vhl shifts the phenotype of juxtaglomerular cells from a renin- to erythropoietin-secreting cell type, presumably in response to HIF-2 accumulation. PMID:23393316

  8. Interpenetration bei Parsons und Luhmann : Von der Integration zur Produktion von Unordnung

    OpenAIRE

    Künzler, Jan

    2010-01-01

    Talcott Parsons hatte den Interpenetrationsbegriff eingeführt, um strukturelle Beziehungen zwischen verschiedenen System arten erfassen zu können. Niklas Luhmann übernimmt den Begriff von Parsons und benutzt ihn nach weitreichenden Revisionen v. a. dazu, das Verhältnis von psychischen und sozialen Systemen auf den Begriff zu bringen. In dieser Intersystembeziehung spielt Sprache eine entscheidende Rolle. Ein systemtheoretisches Sprachkonzept, das dieser Vermittlungsleistung Rechnung trägt, st...

  9. Dentinhaftung von Zementen. Der Haftverbund von Zementen mit Dentin in Kombination mit verschiedenen indirekten Restaurationsmaterialien

    OpenAIRE

    Peutzfeldt, Anne; Sahafi, Alireza; Flury, Simon

    2011-01-01

    Einleitung: Die Anzahl zahnärztlicher Zemente sowie Restaurationsmaterialien steigt stetig. Die richtige Zementwahl für einen zuverlässigen Haftverbund zwischen Restaurationsmaterial und Zahnsubstanz ist von Interesse für den Kliniker. Ziel der vorliegenden in vitro-Studie war es daher, den Dentinhaftverbund von verschiedenen Zementen in Kombination mit verschiedenen indirekten Restaurationsmaterialien zu untersuchen. Material und Methoden: Zylindrische Probekörper aus sechs Restaurations...

  10. Identifizierung von Mikrodomän-Proteinen und funktionelle Charakterisierung von Cholesterin im Golgi-Apparat

    OpenAIRE

    Stüven, Ernstpeter

    2002-01-01

    Mittels Detergenzextraktion von Golgimembranen bei 0°C mit anschließender Dichtegradientenzentrifugation wurden sphingolipid- und cholesterinreiche Mikrodomänen isoliert, die zehn Proteine entsprechend der Coomassiefärbung in der SDS-PAGE enthalten. Im Rahmen dieser Arbeit wurden die zwei bisher nicht charakterisierten Proteine mit Molekulargewichten von 72 und 56 kDa als Untereinheiten A und B der vakuolären ATPase identifiziert. Daneben konnte mit NAP-22 eine elfte Komponente identifiziert ...

  11. Der "Bindungsfragebogen" von Grau und der "Bielefelder Fragebogen zu Partnerschaftserwartungen" von Hoger und Buschkamper im Vergleich

    National Research Council Canada - National Science Library

    Ina Grau; Ulrich Clashausen; Diether Hoger

    2003-01-01

    ...". Das Bindungsmuster ergibt sich aus der speziellen anhand von Clusteranalysen ermittelten Konfiguration der Skalen. In Clusteranalysen mit dem BinFB wurden vier Cluster aufgefunden, mit dem BFPE funf Cluster. Wahrend vier der BFPE-Cluster recht gut mit den vier BinFB-Clustern ubereinstimmen, wird eine funfte Personengruppe vom BFPE als "vermeidend-offnungsbereit" und von BinFB als "sicher" klassifiziert. Beide Interprctationsmoglichkeiten werden unter besonderer Berucksichtigung der Skala "Zuwendungsbedurfn...

  12. Authentizität von Milch und Fisch – Erkennung von Bioprodukten im Labor

    OpenAIRE

    Molkentin, Joachim

    2008-01-01

    Die Nachfrage nach Bio-Lebensmitteln ist in Deutschland in den letzten Jahren stetig gestiegen. So erhöhte sich der Absatz von Bio-Trinkmilch in 2007 im Vergleich zum Vorjahr erneut um 34 %. Aufgrund sporadisch resultierender Lieferengpässe bei Bio-Milch aber auch der erheblichen Handelspreisdifferenz – wie z. B. insbesondere bei Bio-Lachs – besteht ein potenzielles Risiko der Falschdeklaration konventioneller Produkte als Bio-Ware. Zum Schutz von Verbrauchern wie auch Erzeugern werden dah...

  13. Die Rezeptionsgeschichte von Ulrich Schmidels Wahrhaftige Beschreibung von 1567 bis heute

    OpenAIRE

    Obermeier, Franz

    2001-01-01

    Schmidels Werk hat bisher nur in Ansätzen die ihm zustehende Würdigung als eines der wichtigsten Quellenwerke der frühen Kolonialzeit Südamerikas erfahren. Es stand lange Zeit im Schatten des bekannteren und auch literarisch ansprechenderen Reisebuchs von Hans Staden (Wahrhaftige Historia, Marburg 1557), dessen persönliche Schilderung seiner Gefangenschaft dem modernen Leser durch den geschickten Einsatz von narrativen Elementen entsprechend der heutigen Genretradition des persönlich gefasste...

  14. Analyse von Arbeitsplätzen auf halbautomatischen Pflanzmaschinen mit Hilfe von MTM (Methods Time Measurement)

    OpenAIRE

    Remmele, Edgar

    2017-01-01

    Mit Hilfe von MTM (Methods Time Measurement), einem System vorbestimmter Zeiten, werden Bewegungsstudien an drei verschiedenen halbautomatischen Pflanzmaschinen durchgeführt. Hauptunterscheidungsmerkmal der untersuchten Pflanzmaschinen ist die Methode der Übergabe der Pflanze von der Pflanzperson an die Pflanzmaschine. Analysiert wird der Arbeitsplatz der Pflanzmaschine ACCORD-Standard mit der Methode Klemmscheibe, PES-Beetpflanzer 1500/1900 mit der Methode Pflanzfinger und Lännen RT-2 mit de...

  15. Zur Entwicklung von Containerschiffsflotten : eine Paneldatenanalyse

    OpenAIRE

    Prinz, Alexander; Schulze, Peter M.

    2004-01-01

    Diese Arbeit untersucht die regional aggregierten Containerschiffsflotten der wichtigsten Wirtschaftsräume entlang der Hauptverkehrsrouten der Seeschifffahrt. Anhand einer Paneldatenanalyse mit festen Effekten werden die positive Abhängigkeit der Containerschifffahrt von Weltwirtschaft und Welthandel quantifiziert und erklärende Variablen für die Entwicklung der Containerschifffahrt identifiziert.

  16. 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)

  17. Euler-Chelpin, Prof. Hans von

    Indian Academy of Sciences (India)

    Euler-Chelpin, Prof. Hans von. Nobel Laureate (Chemistry) - 1929. Date of birth: 15 February 1873. Date of death: 6 November 1964 ... Posted on 21 December 2017. ASTROPHYSICS: An Observational View of the Universe. Math Art and Design: MAD about Math, Math Education and Outreach. Math and Finance ...

  18. Ueberreste vorweltlicher Proboscidier von Java und Banka

    NARCIS (Netherlands)

    Martin, K.

    1884-01-01

    Junghuhn führte in seinem Werke über Java nur einen einzigen Wirbelthierrest, Carcharias megalodon, an (7, IV, pag. 97); es war ihm nicht gelungen bei seinem ersten Aufenthalte auf der Insel Reste von Säugethieren zu finden, so eifrig er auch darnach in den Höhlen des Tertiaergebirges suchte (7, IV,

  19. Alte und neue Scyphomedusen von Australien

    NARCIS (Netherlands)

    Stiasny, G.

    1926-01-01

    In einer Collection Coelenterata, von verschiedenen australischen Fundorten herrührend, die mir vom Direktor des Australian Museum in Sydney, Dr. Ch. Anderson, zur Untersuchung übersendet wurden, fanden sich auch einige Scyphomedusen, die in den australischen Gewässern bisher noch nicht nachgewiesen

  20. Eigenschaften von Gott. Eine quantitative Analyse

    Directory of Open Access Journals (Sweden)

    Thomas Benesch

    2016-12-01

    Full Text Available ENGLISH: A quantitative research on 32 pupils of an elementary school (third and fourth class was performed. The questions regarded to socio-demographic issues as well as so called opposition pairs for God. These opposition pairs include the semantic differential of the loving God combined with the selection of 27 opposition pairs which were derived from literature. The image of God has been developed due to a factor analysis with respect to human and divine properties. These characteristics are depending on the religious education of children as well as their habits of reading in the Holy Bible. DEUTSCH: Eine quantitative Erhebung von 32 Volksschulkindern einer 3. und 4. Klasse wurde einerseits mit erweiterten sozio-demographischen Fragen und gleichzeitig mit Gegensatzpaaren für Gott beschrieben. Die Gegensatzpaare beinhalteten das semantische Differential des liebenden Gottes zusammen mit einer Auswahl von 27 Gegensatzpaaren, die deduktiv aus der Literatur abgeleitet wurden. Das Gottesbild hat sich anhand einer Faktorenanalyse darin entwickelt, dass Gott einerseits mit menschlichen Attributen versehen wird und andererseits mit Eigenschaften von Gott. Diese Eigenschaften von Gott sind abhängig davon, ob die Kinder religiös erzogen werden und ob sie gerne die Heilige Schrift lesen.

  1. Active Von Willebrand Factor, thrombocytopenia and thrombosis

    NARCIS (Netherlands)

    Hulstein, J.J.J.

    2006-01-01

    Platelets and von Willebrand factor (VWF) are unable to interact in circulation. To induce an interaction, a conversion of VWF to a platelet-binding conformation is required. At higher shear stresses, the first step in thrombus formation is binding of VWF to the subendothelium. This results in

  2. Molecular mechanisms of von Willebrand Factor mechanoregulation

    NARCIS (Netherlands)

    Jakobi, A.J.|info:eu-repo/dai/nl/311489621

    2012-01-01

    Von Willebrand factor (VWF) multimers mediate primary adhesion and aggregation of platelets. The potency to recruit platelets critically depends on the size of VWF multimers, which is regulated by a feedback mechanism involving shear-induced unfolding of the A2 domain in VWF and cleavage by the

  3. Measurements and von Neumann projection/collapse

    Indian Academy of Sciences (India)

    unwanted superpositions of (system + apparatus)-states can be shown to be suppressed, leading eventually to the projection/collapse rule postulated in von Neumann's treatment of measurements [3]. In the next section, the measurement problem in quantum mechanics (QM) is recalled. In §3, some proposed improvements ...

  4. Guido von Pirquet: Austrian pioneer of astronautics

    Science.gov (United States)

    Sykora, F.

    1977-01-01

    The works of Guido von Pirquet, Austrian pioneer of rocketry, were assessed. Major emphasis was given to Pirquet's calculation of the route to Venus which in fact was followed by the first Russian rocket to Venus. Of interest also is Pirquet's valuable construction of a space station and his analysis of interstellar space flight.

  5. Soolopartiid Von Krahli katuse all / Kristi Eberhart

    Index Scriptorium Estoniae

    Eberhart, Kristi

    2007-01-01

    Von Krahli Teatri kolmest lavastusest: "Erki ja Tiina" (lavastaja Mart Kangro, tantsivad Erki Laur ja Tiina Tauraite), "Faust" (J. W. Goethe ainetel tekst ja lavastus Taavi Eelmaa, muusika ja laulud Chalice, osades Jarek Kasar ja Rein Pakk), "Hamletid" (William Shakespeare'i ainetel kontseptsiooni, lavastuse, koreograafia, kujunduse, valguse autor Sasha Pepeljajev, video- ja helikunstnik Taavet Jansen. Esitaja Juhan Ulfsak)

  6. 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

  7. Laue, Prof. Max Theodor Felix von

    Indian Academy of Sciences (India)

    Home; Fellowship. Fellow Profile. Elected: 1954 Honorary. Laue, Prof. Max Theodor Felix von. Nobel Laureate (Physics) - 1914. Date of birth: 9 October 1897. Date of death: 24 April 1960. YouTube; Twitter; Facebook; Blog. Academy News. IAS Logo. Theory Of Evolution. Posted on 23 January 2018. Joint Statement by the ...

  8. Ueber zwei neue Vogelarten von Java

    NARCIS (Netherlands)

    Finsch, O.

    1902-01-01

    Die beiden nachstehend beschriebenen Vögel wurden mir von Herrn Max Bartels als muthmasslich neu zugesandt. Die genaue Untersuchung hat dies bestätigt. Ich freue mich daher eine der Arten zu Ehren des Entdeckers benennen zu können. Seit einigen Jahren als Leiter der Plantage Pangerango bei Pasir

  9. Classical diagnostic radiological features of Von Recklinghausen's ...

    African Journals Online (AJOL)

    Neurofibromatosis type 1(NF-1, Von Recklinghausen disease or peripheral NF) is a rare autosomal dominant disorder with varied clinical manifestations involving the skin, nerves and bones. It is the most common of the neurocutaneous syndromes, with variable pathological and clinical expression. Approximately half of all ...

  10. Joint bleeding in von Willebrand disease

    NARCIS (Netherlands)

    Galen, K.P.M. van

    2017-01-01

    Von Willebrand disease (VWD) is the most common inherited bleeding disorder occurring in approximately 1/100 people. Until now, joint bleeds did not get much attention in clinical research on VWD, since mucocutaneous bleeding is predominant. However, recurrent joint bleeds lead to arthropathy, the

  11. Das Druckprofil von Sportkompressionsstrümpfen.

    Science.gov (United States)

    Reich-Schupke, Stefanie; Surhoff, Stefan; Stücker, Markus

    2016-05-01

    Zunehmend werden Sportkompressionsstrümpfe (SKS) eingesetzt, doch fehlt eine Norm in Analogie zu medizinischen Kompressionsstrümpfen (MKS). Ziel dieser Pilotstudie war der Vergleich der Druckprofile von fünf SKS ex vivo und in vivo miteinander sowie mit MKS-Normen. CEP Running-Progressive-Socks, Falke Running--Energizing, Sigvaris Performance, X-Socks Speed-Metal-Energizer und 2XU Compression--Race-Socks wurden an zehn Leistungssportlern (standardisiert in vivo, Kikuhime--Sensor) sowie im Hohenstein Institut (ex vivo) hinsichtlich ihres Druckprofils getestet. Die Ex-vivo-Messungen im Fesselbereich von CEP (25,6 mmHg) und 2XU (23,2 mmHg) entsprachen der deutschen MKS-Klasse 2, von Sigvaris-SKS (20,8 mmHg) der deutschen MKS-Klasse 1. Die übrigen SKS lagen darunter. Die ermittelten Druckprofile differierten stark und entsprachen nicht der MKS-Norm. Die In-vivo-Messungen zeigten für drei SKS (2XU, CEP, Sigvaris) durchschnittlich einen höheren Anpressdruck als die SKS von Falke und X-Socks. Alle SKS lagen in vivo jedoch unter der deutschen MKS-Klasse 1. Kein SKS bot den für MKS geforderten Druckabfall vom Messpunkt B nach D. Die in vivo und ex vivo ermittelten SKS-Druckprofile zeigten heterogene Ergebnisse und folgten kaum den MKS-Anforderungen. Entsprechend sind auch die klinisch-praktischen Effekte von SKS nicht vergleichbar. Wünschenswert wäre eine SKS-Klassifikation, die erlaubt, Produkte einzuordnen, zu vergleichen und nach konkreten Vorlieben und Bedürfnissen (hoher vs. geringer Druck, progressiver vs. degressiver Gradient) auszuwählen. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  12. Integrales Lernen in und von Organisationen

    Directory of Open Access Journals (Sweden)

    Wendelin Kupers

    2006-06-01

    Full Text Available Bezogen auf das integrale Models von Ken Wilber untersucht der Beitrag die Bedeutung des Lernens in und von Organisationen. Nach einer Darstellung der Relevanz und des Grundverständnisses des Lernens im Organisationskontext, werden integrale Dimensionen des Lernens dargestellt. Im Einzelnen werden die verschiedenen Sphären eines inneren-subjektiven und äusseren-„objektiven“ Lernens des Einzelnen als auch ein gemeinschaftliches Lernen und Lernen im System auf der kollektiven Ebene dargestellt sowie deren interrelationaler Zusammenhang diskutiert. Schließlich beschreibt der Beitrag noch integrale Lernprozesse sowie integrale Gestaltungsfelder zur Förderung des Lernens in den verschiedenen Bereichen. Abschließend spricht der Artikel noch Schwierigkeiten und Probleme an sowie nimmt im Fazit ein perspektivischen Ausblick vor.

  13. Laboratory Testing for Von Willebrand Factor Multimers.

    Science.gov (United States)

    Oliver, Susan; Lau, Kun Kan Edwin; Chapman, Kent; Favaloro, Emmanuel J

    2017-01-01

    Von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders develop due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for the VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. As an additional step, an evaluation of VWF structural features by multimer analysis is useful in selective investigations. The current paper therefore describes a protocol for assessment of VWF multimers by gel electrophoresis, thus enabling identification of protein bands that represent differently sized multimers. The sample protocol described in this chapter is the methodology developed by Sebia.

  14. 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.

  15. Virchow's triad: Kussmaul, Quincke and von Recklinghausen.

    Science.gov (United States)

    Stanifer, John W

    2016-02-01

    For most of the 19th century, Germany was the centre of the medical world. From there the most innovating research came and many of the physicians of that era are known to nearly every medical student and physician of today. Virchow, Kussmaul, Quincke, von Recklinghausen, Müller and Schönlein are familiar names in today's medicine but insofar as they are merely eponyms associated with signs, symptoms, disease and anatomy. The story of their lives, their research and their influence on each other has been little examined. This is an essay about Virchow's relationship with his mentors Müller and Schönlein and how these relationships shaped the development of Kussmaul, Quincke and von Recklinghausen as students of Virchow and their work in medicine and clinical observation after leaving Virchow's laboratory. © The Author(s) 2014.

  16. Evolution equations of von Karman type

    CERN Document Server

    Cherrier, Pascal

    2015-01-01

    In these notes we consider two kinds of nonlinear evolution problems of von Karman type on Euclidean spaces of arbitrary even dimension. Each of these problems consists of a system that results from the coupling of two highly nonlinear partial differential equations, one hyperbolic or parabolic and the other elliptic. These systems take their name from a formal analogy with the von Karman equations in the theory of elasticity in two dimensional space. We establish local (respectively global) results for strong (resp., weak) solutions of these problems and corresponding well-posedness results in the Hadamard sense. Results are found by obtaining regularity estimates on solutions which are limits of a suitable Galerkin approximation scheme. The book is intended as a pedagogical introduction to a number of meaningful application of classical methods in nonlinear Partial Differential Equations of Evolution. The material is self-contained and most proofs are given in full detail. The interested reader will gain a ...

  17. 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.

  18. Von Medien, Übertragungen und Automaten

    Directory of Open Access Journals (Sweden)

    Alessandro Barberi

    2013-12-01

    Full Text Available Im Zuge der Debatten zum Medialen Habitus wurde vielfach betont, dass die >Theorie der Praxispraxeologischen Medientheorie< des Medialen Habitus avant la lettre gesprochen werden kann. Dieser Artikel untersucht – ausgehend von den Debatten zur "Medienkompetenz" – wie Bourdieu Sprache, Sprechen und Diskurs, sowie Akteure, Felder und Habitus als Medien begreift und betont dabei die Nützlichkeit der Bourdieuschen Bildungssoziologie im Rahmen einer sozialwissenschaftlichen Grundlegung der Medienpädagogik.

  19. Untersuchungen von Nanostrukturen magnetischer Kolloide mit Kleinwinkelstreuung

    OpenAIRE

    Kammel, Martin

    2005-01-01

    Mit Hilfe der Neutronenkleinwinkelstreuung mit polarisieren Neutronen wird eine Analyse so genannter Ferrofluide durchgeführt. Ferrofluide sind Dispersionen magnetisierbarer Teilchen, welche durch in den meisten Fällen organische Hüllen gegen irreversibler Aggregation geschützt sind. Anhand von verdünnten Magnetit-Kolloidlösungen wurden als Stabilisierung Dextran, Tenside (Laurinsäure/Marlipal) und elektrostatisch stabilisierte Magnetitteilchen untersucht. Dabei fanden sich in jedem dieser Fl...

  20. Maschinelle Erkennung von Verkehrsteilnehmern mittels heterogener Sensorik

    OpenAIRE

    Walchshäusl, Leonhard

    2009-01-01

    In modernen Fahrzeugen halten verstärkt Fahrerassistenzsysteme zum Insassenschutz und zum Schutz anderer Verkehrsteilnehmer Einzug. Typische, bereits seit längerem verfügbare Systeme, wie Airbag und Antiblockiersystem, erreichen schon heute eine hohe Marktdurchdringung. Künftige aktive Sicherheitssysteme, die von der Kollisionswarnung bis hin zur autonomen Gefahrenbremsung reichen, sind Gegenstand aktueller Forschung. Insbesondere Systeme, die aktiv in das Fahrgeschehen eingreifen, erfordern ...

  1. Mikrobieller Befall von Elektrotauchlack in der Automobilindustrie

    OpenAIRE

    Gühring, Ina Katrin

    2000-01-01

    Nach Umstellung auf umweltverträglichere Lackmaterialien (Reduzierung biozid wirkender Lösemittel, Schwermetalle) traten in Elektrotauchanlagen verschieder Werke der DaimlerChrysler AG vermehrt Beschichtungsstörungen bei Karossen auf. Dabei war ein pH-Anstieg des Lackmaterials, Schichtdickenanstieg, Abblättern des Lacks („Striptease“ Effekt), Oberflächenstörungen (Pusteln, Blasen, Krater), schlechter Umgriff, eine Bildung von Lackschlamm und geringerer Schichtwiderstand zu beobachten. Gleichz...

  2. Die Usability von Rich Internet Applications

    Science.gov (United States)

    Linder, Jörg

    Interaktiven Services, die dem Themenkreis Web 2.0 zugeordnet werden, haftet unter anderem das Attribut an, besonders leicht bedienbar zu sein. Flickr, Youtube und Wikipedia gelten als Erfolgsprojekte dieser neuen Art von interaktiven Websites. Wodurch zeichnet sich nun eine Usability 2.0 (so es sie überhaupt geben sollte) aus? Was ist zu beachten, wenn so genannte Rich Internet Applications gestaltet werden?

  3. Therapie von Vorhofflimmern: Rolle der Katheterablation

    OpenAIRE

    Hindricks G; Kircher S; Gaspar T.; Arya A

    2009-01-01

    Vorhofflimmern ist die häufigste Herzrhythmusstörung in der Gesamtbevölkerung und geht einher mit erhöhter Morbidität und Mortalität. Als prinzipielle Behandlungskonzepte stehen die "Frequenzkontrolle" und die "Rhythmuskontrolle" zur Verfügung. Während sich die medikamentöse Rhythmuskontrolle als insgesamt unzureichend erwiesen hat, stellt die Katheterablation von Vorhofflimmern einen etablierten, potenziell kurativen Therapieansatz mit beachtlichen Erfolgsraten dar. Obwohl hinsichtlich d...

  4. Modellierung von Preiserwartungen durch neuronale Netze

    OpenAIRE

    Heinemann, Maik; Lange, Carsten

    1997-01-01

    Das Papier untersucht, wie Erwartungsbildung mit Hilfe neuronaler Netze modelliert werden kann. Die Grundlage bildet ein Cobweb-Modell, in dem Firmen Preiserwartungen auf Basis eines Feedforward-Netzes bilden.Zunächst wird anhand von Simulationen gezeigt, daß Firmen durch neuronale Erwartungsbildung approximativ rationale Erwartungen bilden können. Im Gegensatz zur Hypothese rationaler Erwartungen ist dafür die Kenntnis des relevanten Modells nicht mehr erforderlich, lediglich Beobachtungen d...

  5. Expression von Blutgruppenantigenen durch humane mesenchymale Stammzellen

    OpenAIRE

    Schüle, Michael Christian

    2013-01-01

    Die vorliegende experimentelle Arbeit befasst sich mit der Untersuchung der Expression von Blutgruppenantigenen durch humane mesenchymale Stammzellen (MSC) aus dem Knochenmark. Der Fokus lag hierbei auf den klinisch bedeutsamen Antigenen A, B, H, Rhesus-D, -C, -c, -E, -e, RhAG, K, k, Jka, Jkb und DARC. Die Expression wurde systematisch auf Genom-, Transkriptom- und Proteinebene evaluiert. Alle untersuchten MSC Populationen exprimierten FUT1, RHCE, KEL und Kidd (HUT11) mRNA. mRNA der AB0-Gl...

  6. Weitere Vorkommen von Impatiens capensis in Hessen

    OpenAIRE

    Nawrath, Stefan

    1996-01-01

    Neue hessische Fundorte von Impatiens capensis aus dem Taunus und dessen Vorland sowie aus der Rheinebene werden berichtet. Die insbesondere im Schwarzbach-System zahlreichen Fundorte werden beschrieben und in einer Verbreitungskarte dargestellt. New Hessian stations of Impatiens capensis in the Taunus mountains as well as their foothills and in the Rhine valley are reported on. The stations which are particularly numerous in the Schwarzbach system, are described and demonstrated on a dist...

  7. [Orthopaedic manifestations of Von Recklinghausen's neurofibromatosis].

    Science.gov (United States)

    Trigui, Moez; Ayadi, Kamel; Sakka, Mourad; Zribi, Wassim; Frikha, Faten; Gdoura, Fakher; Sallemi, Sami; Zribi, Mohamed; Keskes, Hassib

    2011-03-01

    Von Recklinghausen's neurofibromatosis is a dominant autosomic genetic disease characterized by different clinical manifestations. The goal of this work was to study its orthopaedic manifestations and to show the characteristics of their management. A retrospective study was carried out on 15 patients having a Von Recklinghausen's neurofibromatosis. For each patient, different orthopaedic manifestations and their evolution after treatment were analyzed. These manifestations were classified in spinal deformities, pseudarthrosis of long bones and tumours of the peripheral nerves. The spinal deformities were observed in 9 cases. A dystrophic scoliosis was observed in 6 patients with an average angle of 50° and was associated to a kyphosis in 5 patients. The treatment was surgical by posterior arthrodesis in 2 cases and circumferential arthrodesis in 2 cases. The congenital curves and pseudarthroses of leg were observed in 5 cases, localized at the lower third of the leg in all cases. An Ilizarov external fixator with segmental osseous transport was carried out in 2 patients. The duration of the external fixator was 23 months ½ with 5 interventions in each case. Four plexiform neurofibromas and 3 nodular neurofibromas were observed. A transformation into neurofibrosarcoma was found in 2 patients. In one case, a resection without functional sacrifice was carried out and in the other case the patient was dead before the resection. The orthopaedic manifestations of Von Recklinghausen's neurofibromatosis are frequent, varied and have a difficult management. The functional and sometimes vital prognoses are challenging. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

  8. Treatment of patients with von Willebrand disease

    Directory of Open Access Journals (Sweden)

    Tuohy E

    2011-04-01

    Full Text Available Emma Tuohy1, Emma Litt1, Raza Alikhan1,21Department of Haematology, University Hospital of Wales, Cardiff, UK; 2Haemophilia and Thrombosis Centre, University Hospital of Wales, Cardiff, UKAbstract: Von Willebrand disease (vWD is the most common hereditary bleeding disorder. The aim of therapy is to correct the dual hemostatic defect, due to defective platelet adhesion-aggregation and abnormal coagulation due to Factor VIII (FVIII deficiency. The choice of treatment depends on a number of factors, including the severity of the bleed, the procedure planned, the subtype and severity of the disease and the age and morbidity of the patient. Desmopressin (DDAVP is the treatment of choice for type 1 vWD as it increases endogenous release of FVIII and von Willebrand factor (vWF and is also used in some subtypes of type 2 vWD. In those patients in whom DDAVP is ineffective or contraindicated, levels can be restored by infusing vWF:FVIII concentrates. The role of antifibrinolytic treatment is an important adjunct to replacement therapy during minor or major surgery involving mucosal surfaces. The dosing and timing of vWF:FVIII concentrates is important depending on the nature of the surgical procedure. The role of secondary prophylaxis needs to be further defined.Keywords: von Willebrand disease, treatment, DDAVP 

  9. Gestalt und Funktion von Animal Design : Versuch einer semiotischen Analyse

    OpenAIRE

    Schlüter, Wolfgang

    2009-01-01

    Dissertation zur Gestalt und Funktion von Animal Design (tieranaloges Design). Untersucht wird eine Auswahl an Produkten, die in ihrem Äußeren an Tiere erinnern. Hierbei stehen Aspekte wie die Emotionalisierung von Produkten, demonstrativer Konsum und die soziale Funktion im Fokus der Analyse. Anhand von Abbildungen und Zeichnungen wird u.a. dargestellt, welche Bedeutung die Tiergestalt für das jeweilige Produktdesign hat. Die Objekte werden jeweils unter phänomenologischen, hermeneutischen u...

  10. Bioethik in der Ukraine: Von Medizinischer zur Integrativen Bioethik

    OpenAIRE

    Gubenko, Anna

    2014-01-01

    Im Artikel wird die Chronologie der Entstehung und Entwicklung der Bioethik in der Ukraine analysiert. Dabei werden drei Hauptetappen der Herausbildung von Bioethik als a) einer gesellschaftlichen Organisation, b) einer Lerndisziplin und c) einer integrativen Wissenschaft unterschieden. Der Autor hat den Vektor von medizinischer zur integrativen Bioethik durch Ausbildung und soziale sowie pädagogische Praktiken bezeichnet. In diesem Sinne wird der Begriff von “pädagogischer Bioethik“ einge...

  11. 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.

  12. Risiko und Akzeptanz von Industrieansiedlungen: Eine empirische Studie

    OpenAIRE

    Burgemeister, Jörg; Weber, Martin

    1992-01-01

    In der Bundesrepublik Deutschland stoßen Industrieansiedlungen oft auf den Widerstand der Bevölkerung. Bei der Akzeptanz einer Ansiedlung sind von den Bürgern subjektiv wahrgenommene Risiken und Nutzen der Ansiedlung von erheblicher Bedeutung. In einer Fragebogenstudie haben wir untersucht, wie Personen die Nutzen und Risiken von Industrieansiedlungen einschätzen, inwieweit sie Absiedlungen akzeptieren, welche Bestimmungsfaktoren ihren Risiko- und Akzeptanzurteilen zugrundeliegen, und wie sic...

  13. Erfolgsfaktoren von Internet-Auktionen: Eine empirische Analyse in PLS

    OpenAIRE

    Fritz, Wolfgang; Möllenberg, Antje; Dees, Heiko

    2004-01-01

    Internet-Auktionen haben sich zu einem der erfolgreichsten Geschäftsmodelle im E-Commerce entwickelt. Die stetig steigende Anzahl von Auktionen beim Marktführer eBay zeugen von einer zunehmenden Beliebtheit solcher Auktionen. Doch welche Determinanten beeinflussen den Erfolg einer Internet-Auktion? Im vorliegenden Beitrag wird dieses Thema aus dem Blickwinkel des Verkäufers am Beispiel von Ticket-Auktionen empirisch untersucht. Im Mittelpunkt steht dabei eine Kausalanalyse, die den Einfluss v...

  14. 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

  15. Abbaukinetiken - und mechanismen von Lignin und Vanillin unter hydrothermalen Bedingungen

    OpenAIRE

    Curtze, Jan Henning

    2017-01-01

    Eine Methode zur energetischen Aufkonzentrierung von feuchten Abfallbiomassen ist die Hydrothermale Carbonisierung (HTC). Um technische HTC-Reaktoren rational auslegen zu können, sollte die Formalkinetik der vier Hauptkomponenten von Biomasse - Kohlenhydrate, Lignin, Fette/Öle und Proteine – bekannt sein. Des Weiteren spielt die Änderungskinetik des Feststoffes während der HTC eine wichtige Rolle. Der Fokus dieser Arbeit liegt auf der Untersuchung der HTC von Lignin, was ein hochkomplexes, ch...

  16. Studien zur Kinetik der Fehlfaltung un Aggregation von Proteinen

    OpenAIRE

    Modler, Andreas Johannes

    2003-01-01

    Diese Arbeit befasst sich mit der Kinetik der Fehlfaltung und Aggregation von Proteinen. Anhand dreier Beispiele, der Phosphoglyceratkinase (PGK) aus Hefe, einer Variante von Barstar und des Prion-Proteins des Syrischen Hamsters (SHaPrP(90-232)) wurde insbesondere die Kinetik der Bildung von Amyloidfibrillen und deren kinetischer Vorläuferstrukturen mittels dynamischer und statischer Lichtstreuung, Circulardichroismus, Infrarotspektroskopie, Elektronenmikroskopie und teilweise analytischer Ch...

  17. Dr. von Braun and Army Ballistics Missile Agency (ABMA) Group

    Science.gov (United States)

    1959-01-01

    This photograph of Dr. von Braun, shown here to the left of General Bruce Medaris, was taken in the fall of 1959, immediately prior to Medaris' retirement from the Army. At the time, von Braun and his associates worked for the Army Ballistics Missile Agency in Huntsville, Alabama. Those in the photograph have been identified as Ernst Stuhlinger, Frederick von Saurma, Fritz Mueller, Hermarn Weidner, E.W. Neubert (partially hidden), W.A. Mrazek, Karl Heimburg, Arthur Rudolph, Otto Hoberg, von Braun, Oswald Lange, Medaris, Helmut Hoelzer, Hans Maus, E.D. Geissler, Hans Heuter, and George Constan.

  18. Einfluss von rekombinantem Adiponektin auf die monozytäre Expression von Annexin A6

    OpenAIRE

    Stögbauer, Fabian

    2009-01-01

    In der vorliegenden Arbeit wurden zunächst die CD14 Micro Beads titriert und so die Menge an CD14 Micro Beads bestimmt, die nötig ist, um eine große Anzahl Monozyten mit einem hohen Reinheitsgrad, verbunden mit geringen Kosten, aus Vollblut isolieren zu können. In den folgenden in vitro Untersuchungen wurden dann periphere Monozyten von humanen Spendern isoliert, um die dosis- und zeitabhängige Veränderung der Annexin A6-Proteinexpression unter dem Einfluss von Adiponektin feststellen zu k...

  19. Einfluss von Eugenol und Silikonöl auf die Dentinhaftung von adhäsiven Befestigungsmaterialien

    OpenAIRE

    Bigdali, Puria

    2015-01-01

    Zielsetzung Eugenolhaltige Zemente und Silikone stehen in Verdacht den Verbund von Kompositzementen zu beeinflussen. Ziel dieser Arbeit war es den Einfluss eugenolhaltiger und eugenolfreier Zemente und von Additions- und Kondensationssilikonen auf konventionell adhäsive und selbstadhäsive Kompositzemente zu untersuchen. Material und Methode Aus 200 extrahierten Rinderzähnen wurden 200 Dentinscheiben mit einer Dicke von 1 mm hergestellt, in welche eine definierte Kavität mit einem ...

  20. Automatisierte Generierung von Postleitzahlgebieten aus OpenStreetMap-Daten unter Verwendung von Open Source GIS Software

    OpenAIRE

    Hauck, Christian

    2011-01-01

    Das Projekt OpenStreetMap als freie Wiki-Weltkarte gewinnt als Quelle von Geodaten für unter-schiedlichste Bedürfnisse innerhalb der Geowissenschaften, des Geomarketings und auch im Alltag immer mehr an Bedeutung. Die kostenlosen, von Freiwilligen einer Community gesammelten geo-graphischen Daten, sogenannte nutzergenerierte Daten, dienen heute vielen Anwendern als Daten-grundlage und stehen in der Konkurrenz zu proprietären Geodaten von kommerziellen Anbietern. Neben Straßendaten sind zahlre...

  1. 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

  2. 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

  3. 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

  4. Rezension: Träume von Räumen von Georges Perec

    Directory of Open Access Journals (Sweden)

    Thomas Ballhausen

    2015-12-01

    Full Text Available Mit "Träume von Räumen" liegt ein zentraler Text aus dem umfangreichen Œuvre Geroges Perecs vor, der zuletzt 1990 als Übersetzung greifbar war. Der ursprünglich 1974 erschienene Band ist in mehrfacher Hinsicht wesentlich für das Verständnis Perecs und seiner literarisch-philosophische Wunderwelt ...

  5. Wege des Exports von Glutathion aus Astrocyten

    OpenAIRE

    Minich, Tobias Florian

    2008-01-01

    Vorliegender Arbeit lag die Aufgabe zugrunde herauszufinden, welche(s) Transportsystem(e) außer dem Multidrug-Transporter 1 (multidrug resistance protein 1, MRP1) zum Austritt des Tripeptides Glutathion aus Primärkulturen von Astrogliazellen in das extrazelluläre Milieu beitragen. Als Grundlage für die Untersuchungen wurde zunächst an zwei Wildtyp Mausstämmen (NMRI und FVB/N) sichergestellt, dass astrogliareiche Primärkulturen aus Mäusen sowohl reduziertes als auch oxidiertes Glutathion expor...

  6. Die Behandlung von Intersexuellen in der Diskussion

    Directory of Open Access Journals (Sweden)

    Heinz-Jürgen Voß

    2008-11-01

    Full Text Available Wissenschaftler/-innen aus unterschiedlichen Fachdisziplinen und mit unterschiedlichen Ansichten zum Umgang mit intersexuellen Menschen kommen zu Wort – in diesem Sinne ist der Sammelband sehr heterogen. Es werden Erfahrungen mit Geschlechtsanpassung dargestellt, Begrifflichkeiten analysiert und Probleme bei der Therapie und in der Forschung erörtert. Vorangestellt, aber erfreulicherweise nicht abgetrennt, äußern sich Betroffene. Bereits wegen der sich im Abschluss des Bandes befindlichen Handlungsempfehlungen zur Behandlung von Säuglingen und Kindern mit ‚abweichenden‘ bzw. ‚uneindeutigen‘ Geschlechtsmerkmalen, die sich insbesondere an Eltern, Mediziner/-innen und Sozialpädagog/-innen wenden, ist das Buch unbedingt empfehlenswert.

  7. Electronic Resource Management System. Vernetzung von Lizenzinformationen

    OpenAIRE

    Michaela Selbach; Daniel Armin Rupp

    2014-01-01

    In den letzten zehn Jahren spielen elektronische Ressourcen im Bereich der Erwerbung eine zunehmend wichtige Rolle: Eindeutig lässt sich hier ein Wandel in den Bibliotheken (fort) vom reinen Printbestand zu immer größeren E-Only-Beständen feststellen. Die stetig wachsende Menge an E-Ressourcen und deren Heterogenität stellt Bibliotheken vor die Herausforderung, die E-Ressourcen effizient zu verwalten. Nicht nur Bibliotheken, sondern auch verhandlungsführende Institutionen von Konsortial- und ...

  8. Authentifizierung von Bio-Milch im Labor

    OpenAIRE

    Molkentin, Joachim

    2008-01-01

    In Deutschland ist die Nachfrage nach Bio-Lebensmitteln in den letzten Jahren stetig gestiegen. So erhöhte sich der Absatz von Bio-Trinkmilch in 2007 im Vergleich zum Vorjahr erneut kräftig um 34 Prozent (ZMP, Bonn) und der Bio-Anteil beträgt inzwischen bei Frischmilch knapp elf Prozent. Aufgrund sporadisch resultierender Lieferengpässe bei Bio-Milch sowie der vorhandenen Handelspreisdifferenz besteht zunehmend ein potenzielles Risiko der Falschdeklaration konventionell erzeugter Milch als Bi...

  9. Der Denkmalwert von Illegalität

    OpenAIRE

    Beyer, Dennis

    2012-01-01

    Kunst oder Schmiererei - Graffiti spalten die Gesellschaft. Für die einen sind sie illegale Schmierereien und Ausdruck von Vandalismus, für die anderen gelten sie als Kunst am Bau einer verkannten Avantgarde. Das Spektrum an Motivationen und Produkten innerhalb der Sprayer-Gemeinschaft ist tatsächlich derart vielfältig, dass eine sachliche Debatte ohne Polarisation kaum möglich scheint. Dennoch stellt sich die Frage, welche Bedeutung diese flüchtigen und illegalen Zeugnisse einer Minderheit i...

  10. Comparison of automated von Willebrand factor activity assays

    DEFF Research Database (Denmark)

    Timm, Annette; Hillarp, Andreas; Philips, Malou

    2015-01-01

    INTRODUCTION: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. Measurement of von Willebrand factor (VWF) activity in plasma is often based on platelet agglutination stimulated by the ristocetin cofactor activity. Novel assays, based on latex beads with recombinant...

  11. Illustrierte Bestimmungshilfe zur Unterscheidung von Candelaria concolor und Candelaria pacifica

    OpenAIRE

    Stapper, Norbert J.

    2012-01-01

    Unterscheidungsmerkmale von Candelaria concolor und C. pacifica werden anhand von Makro- und Mikrofotos dargestellt. Im Gelände kann C. pacifica anhand der fehlenden Unterrinde erkannt werden. Characteristic features separating Candelaria concolor from C. pacifica are presented on macro and micro photographs. The lack of a lower cortex can be used to identify C. pacifica in the field.

  12. On two matrix derivatives by Kollo and von Rosen

    OpenAIRE

    Neudecker, Heinz

    2003-01-01

    The article establishes relationships between the matrix derivatives of Fwith respect to Xas introduced by von Rosen (1988), Kollo and von Rosen (2000) and the Magnus-Neudecker (1999) matrix derivative. The usual transformations apply and the Moore-Penrose inverse of the duplication matrix is used. Both Xand F have the same dimension. Peer Reviewed

  13. A New Generalization of von Neumann Relative Entropy

    Science.gov (United States)

    Li, Jing; Cao, Huaixin

    2017-11-01

    In quantum information, von Neumann relative entropy has a great applications and operational interpretations in diverse fields, and von Neumann entropy is an important tool for describing the uncertainty of a quantum state. In this paper, we generalize the classical von Neumann relative entropy S( ρ|| σ) and von Neumann entropy S( ρ) to f-von Neumann relative entropy \\widetilde {S}f(ρ ||σ ) and f-von Neumann entropy \\widetilde {S}f(ρ ) induced by a logarithm-like function f, respectively, and explore their properties. We prove that \\widetilde {S}f(ρ ||σ ) is nonnegative and then prove that \\widetilde {S}f(ρ ) has nonnegativity, boundedness, concavity, subadditivity and so on. Later, we show the stability and continuity of the \\widetilde {S}f(ρ ) with respect to the trace distance. In the case that f( x) = -log x, the resulted entropies reduce the classical von Neumann relative entropy and von Neumann entropy, respectively. This means that our results extend the usual results to a more general setting and then have some potential applications in quantum information.

  14. 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

  15. Minimum Moduli in Von Neumann Algebras | Gopalraj | Quaestiones ...

    African Journals Online (AJOL)

    Minimum Moduli in Von Neumann Algebras. Perumal Gopalraj, Anton Ströh. Abstract. In this paper we answer a question raised in [12] in the affirmative, namely that the essential minimum modulus of an element in a von. Neumann algebra, relative to any norm closed two-sided ideal, is equal to the minimum modulus of the ...

  16. Spin–momenta entanglement in moving frames: Properties of von ...

    Indian Academy of Sciences (India)

    well as locality, of information [9–11]. Expressed differently, the von Neumann entropy measures the stored qubits of information per states of the combined system while the reduced one quantifies the qubits per states that may be stored in one of the subsystems. [1]. It is then obvious that a deeper understanding of von ...

  17. Victor or Villain? Wernher von Braun and the Space Race

    Science.gov (United States)

    O'Brien, Jason L.; Sears, Christine E.

    2011-01-01

    Set during the Cold War and space race, this historical role-play focuses on Wernher von Braun's involvement in and culpability for the use of slave laborers to produce V-2 rockets for Nazi Germany. Students will grapple with two central questions. Should von Braun have been allowed to emigrate to the United States given his affiliation with the…

  18. Von Krahli teatris etenduvad Tõnu Kõrvitsa kammerooperid / Esme Kassak

    Index Scriptorium Estoniae

    Kassak, Esme

    2006-01-01

    20. apr. esietenduvad Von Krahli Teatris Peeter Jalaka lavastuses Tõnu Kõrvitsa uued kammerooperid "Tuleaed" ja "Mu luiged, mu mõtted", mille aluseks on luuletaja Marie Heibergi saatus. Libretode 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

  19. von Willebrand disease and aging : an evolving phenotype

    NARCIS (Netherlands)

    Sanders, Y. V.; Giezenaar, M. A.; Laros-van Gorkom, B. A. P.; Meijer, K.; van der Bom, J. G.; Cnossen, M. H.; Nijziel, M. R.; Ypma, P. F.; Fijnvandraat, K.; Eikenboom, J.; Mauser-Bunschoten, E. P.; Leebeek, F. W. G.

    Background: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. Objectives: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related

  20. [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

  1. Kontextualisierung von Queer Theory Contextualizing Queer Theory

    Directory of Open Access Journals (Sweden)

    Anna Voigt

    2008-03-01

    Full Text Available Christine M. Klapeer legt in diesem Einführungsband dar, aus welchen politischen und theoretischen Kontexten heraus sich ‚queer‘ zu einem Begriff mit besonderem politischem und theoretischem Gehalt entwickelt hat. Wesentlich zielt sie dabei auf eine kritische Kontextualisierung von „queer theory”. Die Autorin geht zunächst auf das Gay Liberation Movement ein, grenzt die Queer Theory vom Poststrukturalismus, von feministischen Theorien und den Lesbian and Gay Studies ab, beleuchtet Eckpunkte queeren Denkens und zeichnet schließlich die Entwicklungen in Österreich sowohl politisch-rechtlich als auch bewegungsgeschichtlich und in der Wissenschaftslandschaft nach.Christine M. Klapeer’s introductory volume demonstrates the manner in which ‘queer’ grew out of various political and theoretical contexts to become a term with special political and theoretical content. She focuses primarily on a critical contextualization of “queer theory.” The author begins by approaching the Gay Liberation Movement and then distinguishes Queer Theory from poststructuralism, from feminist theories, and from Lesbian and Gay Studies. She continues on to illuminate the key aspects of queer thought and concludes by sketching the development in Austria in terms of politics and the law, the history of movements, and within the landscape of knowledge.

  2. 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...

  3. Suitability of tracers; Eignung von Tracern

    Energy Technology Data Exchange (ETDEWEB)

    Klotz, D. [GSF - Forschungszentrum fuer Umwelt und Gesundheit GmbH, Neuherberg (Germany). Inst. fuer Hydrologie

    1999-02-01

    Hydrological tracer techniques are a means of making statements on the direction and speed of underground water. One of the simpler tasks is to find out whether there is hydrological communication between two given points. This requires a determination of the direction of flow, which places less exacting demands on the properties of the tracer than does the task of determining the flow velocity of underground water. Tracer methods can serve to infer from flow velocity the distance (flow) velocity, which is defined as the ratio between the distance between two points located in flow direction and the actual time it takes water to flow from one to the other. [Deutsch] Mit Hilfe der hydrologischen Markierungstechniken koennen Aussagen ueber die Richtung und die Geschwindigkeit von Bewegungen des unterirdischen Wassers gemacht werden. Der einfachere Fall liegt vor, wenn festgestellt werden soll, ob zwischen zwei Punkten eine hydrologische Verbindung besteht. Bei dieser Fliessrichtungsbestimmung sind die Forderungen an die Eigenschaften der einzusetzenden Tracer geringer als bei der Bestimmung der Geschwindigkeit des unterirdischen Wassers. Von den Geschwindigkeiten des unterirdischen Wassers ist die Abstands-(Fliess)geschwindigkeit, die definiert ist durch das Verhaeltnis aus dem Abstand und der wahren Fliesszeit zwischen zwei in Bewegungsrichtung gelegenen Punkten, durch Tracermethoden zu bestimmen. (orig.)

  4. 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

  5. Von Neumann's quantization of general relativity

    Science.gov (United States)

    Arbuzov, A. B.; Cherny, A. Yu.; Cirilo-Lombardo, D. J.; Nazmitdinov, R. G.; Han, Nguyen Suan; Pavlov, A. E.; Pervushin, V. N.; Zakharov, A. F.

    2017-05-01

    Von Neumann's procedure is applied to quantizing general relativity. Initial data for dynamical variables in the Planck epoch, where the Hubble parameter value coincided with the Planck mass are quantized. These initial data are defined in terms of the Fock orthogonal simplex in the tangent Minkowski spacetime and the Dirac conformal interval. The Einstein cosmological principle is used to average the logarithm of the determinant of the spatial metric over the spatial volume of the visible Universe. The splitting of general coordinate transformations into diffeomorphisms and transformations of the initial data is introduced. In accordance with von Neumann's procedure, the vacuum state is treated is a quantum ensemble that is degenerate in quantum numbers of nonvacuum states. The distribution of the vacuum state leads to the Casimir effect in gravidynamics in just the same way as in electrodynamics. The generating functional for perturbation theory in gravidynamics is found by solving the quantum energy constraint. The applicability range of gravidynamics is discussed along with the possibility of employing this theory to interpret modern observational data.

  6. Translational medicine advances in von Willebrand disease.

    Science.gov (United States)

    Lillicrap, D

    2013-06-01

    Following the recognition of von Willebrand disease (VWD) in 1926 and the cloning of the gene for von Willebrand factor (VWF) in 1985, significant advances have been made in our fundamental knowledge of both the disease and the protein. Some of this new knowledge has also begun to impact the clinical management of VWD. First, the progressive increase in our understanding of the molecular genetic basis of VWD has resulted in rational applications of molecular testing to complement the current range of phenotypic tests for VWD. These molecular genetic strategies are most effectively directed at the prenatal diagnosis of type 3 VWD and confirmatory testing for types 2B and 2N disease. In contrast, the use of molecular testing to clarify the diagnosis of type 1 VWD is of marginal benefit, at best. In terms of VWD therapies, a new recombinant VWF concentrate has recently completed successful clinical trials and is now awaiting more widespread application. There have even been some preclinical successes with VWF gene transfer although the clinical rationale for this therapeutic strategy needs careful consideration. Much more remains to be learnt about the biology of VWF and further translational advances for the enhancement of VWD care will inevitably be realized. © 2013 International Society on Thrombosis and Haemostasis.

  7. Entwicklung von Nickel-Trägerkatalysatoren für die Methanisierung von Kohlenstoffdioxid unter Anwendung von Parallelpräparation und statistischer Versuchsplanung

    OpenAIRE

    Thomys, Oliver Dieter

    2017-01-01

    Die Methanisierung von Kohlenstoffdioxid (Sabatier-Reaktion) gilt als aussichtsreiche Technologie für die chemische Speicherung überschüssigen elektrischen Stroms aus erneuerbaren Energien. Diese Arbeit befasst sich mit der Präparation von Nickel-Trägerkatalysatoren mit hoher Niedrigtemperatur-Aktivität und Langzeitstabilität. Durch Parallelsynthese-Konzepte und Methoden der statistischen Versuchsplanung konnten entsprechende Katalysatoren mit niedriger Metallbeladung präpariert werden, deren...

  8. Alexander von Humboldt in Daniel Kehlmanns Welt

    Directory of Open Access Journals (Sweden)

    Ottmar Ette

    2012-12-01

    Full Text Available Zusammenfassung Wie stark sich im Verlauf des zurückliegenden Vierteljahrhunderts der Bekanntheitsgrad Alexander von Humboldts in der deutschsprachigen Öffentlichkeit verändert hat, zeigen nicht nur Fernsehumfragen zu den berühmtesten Deutschen, in denen Alexander von Humboldt mittlerweile figuriert, oder Fernsehserien, die über aktuelle Expeditionen berichten und auf Humboldts Namen zurückgreifen. Am deutlichsten vielleicht belegt dies der enorme Erfolg von Daniel Kehlmanns Roman Die Vermessung der Welt, der ohne die zuvor skizzierte Entwicklung nicht denkbar gewesen wäre. Es ist vor diesem Hintergrund nicht nur reizvoll, sondern aufschlußreich, sich mit dem großen Erfolg dieses kleinen Romans zu beschäftigen. Worum geht es in Die Vermessung der Welt? Und wie läßt sich das „Phänomen Kehlmann“ aus etwas größerer Distanz erklären? Abstract In the last 25 years, Alexander von Humboldt‘s popularity has radically changed in the german-speaking public opinion. Proof of this are not only television surveys about the most famous germans - in which Alexander von Humboldt now regularly figures - or television series about contemporary expeditions, which constantly refer to Humboldt‘s name; perhaps what most clearly verifies this change is the great success of Daniel Kehlmann‘s novel Die Vermessung der Welt. Without the recent developments outlined above, this novel‘s degree of impact would have been unimaginable. To study the great success of this text against this backdrop is not only attractive, but also revealing. What is Die Vermessung der Welt really about? And how can we explain the „Kehlmann phenomenon“ from a greater distance? Resumen La popularidad de Alejandro de Humboldt ha cambiado profundamente dentro del último cuarto de siglo en la opinión pública de habla alemana. Prueba de esto son no sólo las encuestas televisivas sobre los alemanes más famosos, dentro de las cuales figura en estos momentos Alejandro

  9. 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.

  10. Drei Dimensionen von filmischem Archivmaterial. Die Untersuchung von Archivfilmen aus der Zeit des Holocaust

    Directory of Open Access Journals (Sweden)

    Tobias Ebbrecht-Hartmann

    2017-04-01

    Full Text Available Filmisches Archivmaterial aus der Zeit des Holocaust ist eine ambivalente Quelle. Daher sind spezifische Ansätze notwendig, um dieses Material zu ‘lesen’. Es geht darum, den besonderen Inhalt der Bilder zu analysieren, den Kontext ihrer Entstehung zu bestimmen, aber auch, ihre spätere Verwendung und Zirkulation in der visuellen Kultur und damit auch ihren wechselnden Status mit einzubeziehen. Am Beispiel ausgewählter Filmfragmente aus dem Warschauer Ghetto und dem Ghetto Theresienstadt skizziert der Artikel einen Ansatz, wie man diese drei Dimensionen von filmischem Archivmaterial analysieren kann und schlägt damit eine entsprechende Historiographie von Archivfilmen aus der Zeit des Holocaust vor.

  11. Modellierung von Angebots- und Nachfrageverhalten zur Analyse von Agrarpolitiken: Theorie, Methoden und empirische Anwendungen

    OpenAIRE

    Henningsen, Arne

    2006-01-01

    Die Analyse der Auswirkungen von Agrarpolitiken ist in der Regel sehr komplex und erfordert eine detaillierte Modellierung des Angebots- und Nachfrageverhaltens im Agrarsektor. Eine empirische Anwendung setzt daher eine angemessene ökonomische Theorie sowie fortgeschrittene quantitative Methoden voraus. Alle neun Aufsätze dieser Dissertation lassen sich in diese Themengebiete einordnen. Zunächst werden die Nachfrage nach Bananen und die Folgen der EU Bananenmarktordnung für deutsche Konsument...

  12. Charakterisierung von Mutanten im Lösungsmittelstoffwechsel von Clostridium acetobutylicum

    OpenAIRE

    Hönicke, Daniel

    2015-01-01

    Im Rahmen dieser Arbeit wurden insgesamt neun durch ClosTron-basierte Mutagenese erhaltene Insertionsmutanten von C. acetobutylicum ATCC 824 einer umfangreichen Charakterisierung unterzogen. Für alle im Batch-Fermentationsmaßstab und/oder in kontinuierlicher Kultur fermentierten Stämme erfolgte eine globale Analyse des Transkriptoms unter Verwendung der DNA-Microarray-Technologie. Für eine Analyse des Acetat- und Aceton-Stoffwechsels wurden Stämme mit einer inaktivierten Phosphotransacetyl...

  13. Informationssuchverhalten als Grundlage für die Gestaltung von Veranstaltungen zum Erwerb von Informationskompetenz

    Directory of Open Access Journals (Sweden)

    Martin Wollschläger-Tigges

    2015-09-01

    Full Text Available Für die Gestaltung bibliothekarischer Veranstaltungen zum Erwerb von Informationskompetenz stellen die bisherigen Ergebnisse und Befunde der Forschung zum Informationssuchverhalten eine wertvolle Grundlage dar, indem bestimmte und v.a. typische Verhaltensmuster, Routinen und Präferenzen im Umgang mit Informationsressourcen und Informationen in konzeptionelle und inhaltliche Anpassungen von IK- Veranstaltungen eingebracht und eingesetzt werden. Das Informationssuchverhalten untersucht sowohl individuelle als auch kollektive Informationsprozesse und Faktoren, die diese maßgeblich beeinflussen. Hierzu werden der gesamte Informationsprozess oder einzelne Abschnitte untersucht, die den Information Need, Seeking und Using (INSU-Prozess bilden. Die Befunde der einzelnen INSU-Prozesses-Einheiten zeigen, dass Faktoren wie Informationsbedarf, Informationsart und -form sowie die Einbindung in übergeordnete Arbeitsprozesse wesentlichen Einfluss auf das Informationssuchverhalten haben. Des Weiteren konnte die ISB-Forschung eine Klassifizierung von Benutzergruppen entwickeln und z.B. Fast Surfers, Broad Scanners und Deep Divers charakterisieren bzw. auch das Bouncing oder Flicking Behavior beschreiben. Hinzu kommen mehrere Modelle, die Informationssuchverhalten und Informationsverhalten in bestimmten Situationen nachbilden und darstellen können.

  14. Tragverhalten von Verbunddübeln unter Zugbelastung

    OpenAIRE

    Appl, Jörg-Jochen

    2009-01-01

    Im Bauwesen werden in zunehmendem Maße Dübel zur Einleitung von Lasten in den erhärteten Beton eingesetzt. Vor allem Befestigungssysteme auf der Grundlage chemischer Mörtel werden vermehrt verwendet. Allerdings fehlte bisher ein genügend genaues Berechnungsmodell zur Bemessung von beliebigen Befestigungen mit Verbunddübeln für unterschiedliche Verankerungstiefen und für verschiedene Verbundfestigkeiten. In der vorliegenden Arbeit wurde das Tragverhalten von Verbundübeln unter Zugbelastung...

  15. A von Bertalanffy growth model with a seasonally varying coefficient

    Science.gov (United States)

    Cloern, James E.; Nichols, Frederic H.

    1978-01-01

    The von Bertalanffy model of body growth is inappropriate for organisms whose growth is restricted to a seasonal period because it assumes that growth rate is invariant with time. Incorporation of a time-varying coefficient significantly improves the capability of the von Bertalanffy equation to describe changing body size of both the bivalve mollusc Macoma balthicain San Francisco Bay and the flathead sole, Hippoglossoides elassodon, in Washington state. This simple modification of the von Bertalanffy model should offer improved predictions of body growth for a variety of other aquatic animals.

  16. Abenteuer Alexander-von-Humboldt-Bibliographie

    Directory of Open Access Journals (Sweden)

    Christian Suckow

    2002-04-01

    Full Text Available Article in German; Abstracts in English and German.The two attempts (1860 and 1872 to compile a bibliography of all works of Alexander von Humboldt have to be regarded as failures. Due to Humboldt’s scientific methods, the contemporary popularity of his writings, and the conditions of book publishing and selling, it has been difficult to achieve an overview of his œuvre. Thus each attempt to write a reliable or at least partially complete bibliography of Humboldt’s works constituted an adventure. Horst Fiedler and Ulrike Leitner have mastered this undertaking. As a result of their efforts over more than two decades, a bibliography of those works by Humboldt which were published in book form appeared in the year 2000.

  17. Johann von Lamont: A Pioneer in Geomagnetism

    Science.gov (United States)

    Soffel, Heinrich

    2006-06-01

    The 200th birthday of John Lamont (1805-1879, Figure 1), a pioneer in the study of geomagnetism, was marked on 13 December 2005. Lamont founded the Munich Geomagnetic Observatory in 1840 and was a member of the group of scientists including Carl Friedrich Gauss, Alexander von Humboldt, Eduard Sabine, Jonas Angstrøm, Humphret Lloyd, Adolf Kupffer, Karl Kreil, and Adolphe Quetelet who composed the Göttingen Magnetic Union. They organized an international network of geomagnetic observatories [Barraclough et al., 1992]. The present knowledge of the geomagnetic field and its secular variation is largely based on the data collected by the global network of geomagnetic observatories during the last 170 years. Lamont's talents and his dedication and enthusiasm for discovery are reflected in the depth and scope of his contributions to a broad variety of natural sciences such as astronomy, meteorology, geomagnetism, and geodesy. However, this article just touches on his merits in geomagnetism.

  18. Bertha von Suttner 1843-1914

    OpenAIRE

    Hoock-Demarle, Marie-Claire; Hessel, Stéphane

    2016-01-01

    Née dans « le monde d'hier » cher à son compatriote Stefan Zweig, morte le 21 juin 1914 à la veille du déclenchement d’une guerre qu’elle appelle Weltkrieg, Bertha von Suttner témoigne d’un parcours hors du commun dans un moment crucial où s’amorcent les conflits générés par les militarismes et les nationalismes menant inexorablement à la catastrophe. Arpenteuse d’Europe, voyageuse du Nouveau Monde, elle voit dans « l’américanisation du monde » une raison de construire dans la paix et la coop...

  19. Modernisation of ventilation systems; Modernisierung von Lueftungsanlagen

    Energy Technology Data Exchange (ETDEWEB)

    Richter, W. [Technische Univ. Dresden (Germany). Inst. fuer Thermodynamik und Technische Gebaeudeausruestung

    1997-12-31

    When redeveloping buildings it is common to use window constructions with air-tight rabbets which obviate the inflow of fresh air almost entirely. This leads to the well-known structural-physics and hygienic consequences. As an added effect, the distinctly enhanced thermal insulation results in changes in dynamic heat loss. The paper focuses on the issues of how to safeguard the inflow of fresh air, and the heating capacity of radiators. (MSK) [Deutsch] Da die bei Gebaeudesanierungen eingesetzten fugendichten Fensterkonstruktionen die Nachstroemmoeglichkeiten fuer die Zuluft fast ganz unterbinden, fuehrt das zu den bekannten bauphysikalischen und hygienischen Konsequenzen. Dazu kommen veraenderte dynamische Waermverlustverhaeltnisse aufgrund der deutlich verbesserten Waermedaemmung. Im Folgenden wird schwerpunktmaessig auf die Probleme Zuluftsicherung und Waermeleistung von Heizkoerpern eingegangen.

  20. Hepatische Effekte von Wachstumshormon auf den Glukosestoffwechsel

    Directory of Open Access Journals (Sweden)

    Rufinatscha K

    2015-01-01

    Full Text Available Untherapierter Wachstumshormonmangel im Erwachsenenalter (AGHD ist mit viszeraler Adipositas, Dyslipidämie, Insulinresistenz und Fettleber verbunden. Interessanterweise finden sich viele der AGHD-Merkmale auch bei Patienten mit metabolischem Syndrom. Die nichtalkoholische Fettlebererkrankung (NAFLD gilt als hepatische Manifestation des metabolischen Syndroms. In einigen Studien wurden bei Patienten mit NAFLD verminderte Konzentrationen von zirkulierendem IGF-1, dessen Synthese zu einem großen Teil durch Wachstumshormon (GH reguliert wird, beschrieben. Mäuse, welche eine hepatische Wachstumshormondefizienz aufweisen, zeigen zahlreiche phänotypische Charakteristika des metabolischen Syndroms, unter anderen auch eine Fettlebererkrankung. Dies legt einen Zusammenhang zwischen dem Wachstumshormon und der Entstehung einer NAFLD nahe. Ziel unserer Studie ist es, in einem Zellkulturmodell die Effekte des Wachstumshormons auf den intrazellulären Glukosestoffwechsel näher zu untersuchen. Im Detail sollen Auswirkungen einer verminderten Wachstumshormonrezeptorexpression auf den Insulinsignaltransduktionsweg, den Glykogengehalt und auf Schlüsselenzyme der Glukoneogenese untersucht werden. Präliminäre Daten zeigen, dass eine verminderte Wachstumshormonrezeptorexpression mit intrazellulären Veränderungen des hepatischen Glukosestoffwechsels verbunden ist. Die verminderte Insulinsensitivität könnte auf Alterationen im Insulinsignaltransduktionsweg und Änderungen der Glukoneogenese zurückzuführen sein. Diese präliminären Daten weisen darauf hin, dass Wachstumshormon einen direkten Einfluss auf den Glukosestoffwechsel in der Leber hat. Zudem legen sie nahe, dass Veränderungen im Wachstumshormonstoffwechsel einen wichtigen pathophysiologischen Mechanismus in der Entstehung der Fettlebererkrankung bei Patienten mit metabolischem Syndrom darstellen könnten. Der folgende Artikel soll einen kurzen Überblick über die Effekte von Wachstumshormon

  1. VON WILLEBRAND DISEASE: DIAGNOSIS AND TREATMENT

    Directory of Open Access Journals (Sweden)

    Majda Benedik Dolničar

    2004-12-01

    Full Text Available Background. Von Willebrand disease (VWD is a most frequently inborn bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF. VWF promotes platelet-vessel wall (adhesion and plateletplatelet interaction (aggregation. It is also the carrier for factor VIII (F VIII in plasma. A deficiency of VWF may results in impairment of both, primary and secondary haemostasis. Therefore, patients with VWD can have bleeding symptoms typical fot the defect in primary haemostasis (mucocutaneous haemorrhages. In severe deficiency of VWF there are also haemarthroses and haematomas typical for patients with coagulation defects. Several types and subtypes of VWD have been described. The diagnosis is based on measurements of VWF concentration and activity and F VIII activity in plasma. The tests identifying VWD subtypes are ristocetin induced platelet agglutination (RIPA, multimeric analysis of VWF and measurement of the binding of VWF to F VIII.Conclusions. Due to heterogeneity of VWF defects, the correct diagnosis of types and subtypes is sometimes difficult but is important for appropriate treatment. There are two main therapeutic options for patients with VWD: desmopressin and blood derived concentrates of F VIII/VWF. In certain cases antifibrinolytics and hormones can be suitable treatment. Desmopressin is the treatment of choice in patients with type 1 VWD. It raises endogenous F VIII and VWF and thereby corrects the intrinsic coagulation defect as well as the prolonged bleeding time (BT or closure time (CT-PFA100 in most type 1 VWD patients. In type 3 and in the majority of type 2 patients desmopressin is not effective and it is necessary to use concentrates containing F VIII and VWF. These are always effective in raising of F VIII activity, whereas the BT/CT may not be completely corrected, but the normalisation of the BT/CT is not always necessary.

  2. Von Krahli Teatri lavastus pääses tippfestivalile

    Index Scriptorium Estoniae

    1999-01-01

    Von Krahli Teatri uuendatud lavastus "Eesti mängud. Pulm" esietendub festivalil Theater Der Welt Berliinis. Peeter Jalaka multimeediaetendus Eesti ajaloost ja traditsioonidest osaleb ka suveteatrite festivalil Hamburgis, seejärel antakse kuus etendust Amsterdamis

  3. La actualidad del pensamiento de Carl von Clausewitz

    National Research Council Canada - National Science Library

    Borrero Mansilla, Armando

    2003-01-01

    The article presents the validity of the thought of Carl von Clausewitz, which application, beyond the wars among national States, can be extended to the analysis of the confrontation among political...

  4. Lexikon lesbischer Frauen im Film von Daniela Sobek

    Directory of Open Access Journals (Sweden)

    Karin Windt

    2002-03-01

    Full Text Available Das Lexikon stellt ein neues Basiswerk über lesbische Figuren im Film dar. Neben zahlreichen Artikeln von Anbeginn der Filmgeschichte bis heute gibt es Features über bekannte Schauspielerinnen und lesbische role models.

  5. Magnus Georg von Paucker (1787-1855) / Eckhard Spring

    Index Scriptorium Estoniae

    Spring, Eckhard

    2013-01-01

    Eestis sündinud ja Tartu Ülikoolis õppinud silmapaistvast baltisaksa teadlasest ja tema lapselapsest Alexandrine Pauckerist. 23. novembril 2012 Jelgavas/Mitaus toimunud Magnus Georg von Pauckerile pühendatud teaduskonverentsist

  6. Von Krahli Teater toob Eestisse erakordse auhinna / Tiit Tuumalu

    Index Scriptorium Estoniae

    Tuumalu, Tiit, 1971-

    2004-01-01

    Bessie-auhinna puhul, millega New Yorgis pärjati Von Krahli Teatri lavastust "Luikede järv." Mõjukuselt on seda võrreldud Broadway teatriauhinna Tonyga. Lisatud lühiandmed P. Jalaka ja S. Pepeljajevi kohta

  7. Politische Bildung im Kontext von Regierung, Unterricht und Zucht

    National Research Council Canada - National Science Library

    Thomas Rucker

    2014-01-01

    .... 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...

  8. Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease.

    Science.gov (United States)

    Miki, Kenji; Arimura, Koichi; Nishimura, Ataru; Yoshimoto, Koji; Sayama, Tetsuro; Iihara, Koji

    2017-12-01

    Although extracranial-intracranial (EC-IC) bypass is an effective treatment strategy for symptomatic moyamoya disease, surgeons need to be cautious regarding the possibility of postoperative hemorrhagic complications in patients with a concurrent coagulation disorder. Here, we describe a case of EC-IC bypass for moyamoya disease concurrent with von Willebrand disease type 1. Following perioperative replacement of the von Willebrand factor, the patient showed an uneventful and uncomplicated clinical course. This is the first reported case of EC-IC bypass being performed for moyamoya disease in a patient with concurrent von Willebrand disease. We emphasize the importance of appropriate management with replacement of the von Willebrand factor during the perioperative period to avoid hemorrhagic complications. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Die zentrale Wirkung von Candesartan in der Schlaganfalltherapie

    OpenAIRE

    Maydowski, Katja

    2011-01-01

    Ziel der vorliegenden Arbeit war es, die Auswirkungen des AT1-Blockers Candesartan auf einen ischämischen Insult durch eine rein zentrale AT1-Blockade am Tiermodell mit direkter intracerebroventrikulärer Applikation von Candesartan zu untersuchen.

  10. Zur sportlichen Laufbahn von Marathonläufern

    OpenAIRE

    Rümmele, Edgar

    1984-01-01

    Zur sportlichen Laufbahn von Marathonläufern : e. Beitr. zur Psychologie d. Marathonläufers. - Thun u.a. : Deutsch, 1984. - 253, 14 S. - Zugl.: Tübingen, Univ., Diss. - (Beiträge zur Sportwissenschaft ; 1)

  11. Warum das Controlling den systematischen Einsatz von Simulationen vorantreiben sollte

    DEFF Research Database (Denmark)

    Spitzner, Jan; Schneider, Melanie L.

    2017-01-01

    Simulationen werden in der Unternehmenssteuerung heutzutage noch nicht systematisch eingesetzt. Dass sich jedoch die existierenden Hemmnisse durchaus überwinden lassen, legen die Antworten von Studienteilnehmern nahe, die Simulationen häufig einsetzen. Dabei kann Controlling eine Vorreiterrolle e...

  12. Von Krahli Teater viis Helsingisse kaks menulavastust / Andres Laasik

    Index Scriptorium Estoniae

    Laasik, Andres, 1960-2016

    2003-01-01

    Von Krahli Teater esineb 29. nov. Helsingis "Baltic Circle" festivalil lavastustega "Luikede järv" ja "Taksojuhid". Tutvustatakse lühidalt ka paari olulisemat soome lavastust ("Puksiirabi" ja "Hamlet"), mis tulevad festivalil esitamisele

  13. 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...

  14. Behandlung von Cybermobbing durch die Soziale Arbeit in der Schule

    OpenAIRE

    Dill, Irina; Wahl, Lisa

    2015-01-01

    Gegenstand dieser Arbeit ist die Behandlung von Cybermobbing durch die Soziale Arbeit in der Schule. Cybermobbing ist eine neuere Form von schulischer Gewalt und verlangt nach neuen Formen der Beratung und Intervention der Sozialen Arbeit in der Schule. Anhand einer Literaturrecherche gehen die Autorinnen Lisa Wahl und Irina Dill der Frage nach, inwiefern die Soziale Arbeit in der Schule Cybermobbing behandeln kann. Die Konzipierung der Sozialen Arbeit in der Schule fundiert primär auf dem Bu...

  15. Zusammenhang von Prozess, Mikrostruktur, Eigenspannungen und Eigenschaften bei Aluminiumverbundwerkstoffen

    OpenAIRE

    Kachold, Franziska

    2016-01-01

    Wo die mechanische Leistungsfähigkeit von monolithischen Materialien an ihre Grenzen stößt, bieten Verbundwerkstoffe neue Perspektiven. Besonders wenn hohe Festigkeit oder Steifigkeit bei gleichzeitig niedrigem spezifischen Gewicht gefordert ist, kommen Faserverbundwerkstoffe zum Einsatz. Faserverstärkte Polymere existieren bereits seit ca. 1900 und werden heute für ein breites Spektrum von Bauteilen und Produkten im Automobil-, Flugzeug- und auch Sportgerätebau verwendet. Die geringe T...

  16. 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.

  17. Möglichkeiten und Grenzen von Social Media Marketing

    OpenAIRE

    Kreutzer, Ralf T.; Hinz, Jule

    2010-01-01

    In diesem Arbeitspapier wird das Konzept des Social Media Marketing theoretisch dargestellt und seine Möglichkeiten und Grenzen analysiert. Dabei werden die einzelnen Instrumente des Social Media Marketings sowie die verschiedenen Nutzertypen erläutert und auf die Erfolgsmessung von Methoden des Social Media Marketings eingegangen. Schließlich wird an den Beispielen HUGO BOSS, Starbucks und Nestlé auf die Umsetzung von Maßnahmen des Social Media Marketings eingegangen und aufgezeigt, welche E...

  18. Rekonstruktion von Gletscherschwankungen mit Hilfe fossiler Hölzer

    OpenAIRE

    Holzhauser, H.

    1984-01-01

    Im vorliegenden Artikel wird gezeigt, wie mit Hilfe von fossilen Hölzern aus dem Gletschervorfeld minimale Gletscherausdehnungen und Gletschervorstöße erfaßt werden können. Einige zeitgenössische Berichte und Zeichnungen aus der Zeit um 1850, als die Alpengletscher ihren letzten neuzeitlichen Hochstand erreichten, sollen veranschaulichen, wie Gletscher in bewaldetes Gebiet vordrangen und Bäume umdrückten. Es wird im weiteren kurz auf die Lage von fossilem Holz im Gletschervo...

  19. Nationale Kapitalanlagengarantien als Instrumente zur Förderung von Direktinvestitionen

    OpenAIRE

    Stern, Thomas

    1988-01-01

    Wegen ihres hohen entwicklungspolitischen Stellenwertes ist die Steigerung von Direktinvestitionen als langfristiges Instrument zur Verbesserung der Verschuldenssituation der Länder der Dritten Welt anerkannt. Trotz dieser Erkenntnis blieben die Direktinvestitionen in Richtung der Entwicklungsländer in den letzten fünf Jahren hinter den Erwartungen zurück und erreichten lediglich einen Anteil von ca. 12 % an den Gesamtkapitalströmen. Wichtige Motive für die Zurückhaltung der Investoren in die...

  20. Kommunale Versorgung, Verortung und Steuerung von Risiken psychischer Gesundheit

    OpenAIRE

    Warner, Joanne

    2006-01-01

    Das Risikokonzept ist heute zentral für alle Bereiche von gesundheitlicher und sozialer Wohlfahrt in Großbritannien. Im Bereich psychischer Gesundheit und insbesondere seit den Maßnahmen zur kommunalen Versorgung in den 1990er Jahren kommt dem Konzept jedoch besondere Aufmerksamkeit zu. Dabei kamen bisher vor allem die Risiken in den Blick, die von Personen mit psychischen Erkrankungen oder in psychischer Not ausgehen, aber nicht die Risiken, mit denen diese selbst konfrontiert sind. Der vorl...

  1. Untersuchung der verfahrenstechnischen Potentiale von CO2-Minderungsoptionen

    OpenAIRE

    Geng, Jin

    2017-01-01

    Die vorliegende Arbeit beschäftigt sich mit der Untersuchung der verfahrenstechnischen Potentiale von CO2-Minderungsoptionen. CO2 ist ein Treibhausgas und führt zu Klimaproblemen. Wie erfolgreich der Kampf gegen den Klimawandel ist, hängt stark von den politischen Entscheidungen ab, welche auf internationalen Vereinbarungen und der wirtschaftlichen Situation basieren. Allerdings ist die technische Machbarkeit die Voraussetzung aller Entscheidungen. In der Arbeit wird diskutiert, welches P...

  2. CyLaw-Report V : "Sicherheit von ec-Karten"

    OpenAIRE

    Schmid, Viola

    2008-01-01

    Entscheidung des BGH vom 05.10.2004 - XI ZR 210/03 Die vorliegende Entscheidung des Bundesgerichtshof (BGH) bringt - nach jahrelanger juristischer Diskussion und divergierender Rechtsprechung verschiedener Gerichte - weiteren Aufschluss bei beweis- und haftungsrechtlichen Fragen von ec-Karten. Die besondere Bedeutung bargeldloser Zahlungsverfahren im Bereich von eCommerce, eGovernment etc. machen das Urteil des BGH zu einer für das Cyberlaw interessanten Entscheidung.

  3. Hochtemperaturverhalten von Stahlbetonplatten mit Textilbetonverstärkung

    OpenAIRE

    Hothan, Sascha; Ehlig, Daniel

    2011-01-01

    Die Verwendung von Endlosfilamenten aus Carbon als Bewehrungsmaterial für Beton, sogenannter Textilbeton, bietet die Möglichkeit der Sanierung und der Verstärkung bestehender Stahlbetonkonstruktionen. Dabei muss die Frage nach dem Feuerwiderstand von derart verstärkten Tragwerken beantwortet werden. Aufschluss darüber liefern Brandversuche. Mit Textilbeton verstärkte Stahlbetonplatten haben in Brandversuchen nach der Einheits- Temperaturzeitkurve bei 33 % der Traglast mehr als 60 Minuten stan...

  4. Expression von Wachstumsfaktoren unter Vakuumversiegelungstherapie in chronischen Wunden

    OpenAIRE

    Rosenberg, Birgit

    2012-01-01

    Hintergründe und Zielsetzung Die Vakuumversiegelungsmethode (V.A.C.® = Vac.) ist ein von M. Morykwas und C. Argenta 1988 entwickeltes Verfahren zur Konditionierung von akuten und chronischen Wunden, das sich in den letzten Jahren klinisch etabliert und dessen Anwendungsspektrum kontinuierlich zugenommen hat. In vielen klinischen Studien konnte die Wirksamkeit dieses Therapieverfahrens in der Wundbehandlung nachgewiesen werden, unklar ist jedoch bislang welche physiologischen Veränderungen auf...

  5. 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.

  6. Entwicklung von Cellulosefaser-Leichtbeton und Untersuchung des bruchmechanischen Verhaltens

    OpenAIRE

    Thiel, Thomas

    2016-01-01

    Im Zentrum der vorliegenden Arbeit steht ein zementgebundener Leichtbeton auf der Basis von aus Altpapier herausgelösten Cellulosefasern; hierfür wird im Folgenden die Bezeichnung CFLC (Cellulose-Fibre Lightweight Concrete) verwendet. Die Intention zur Untersuchung dieses mitunter auch als Papercrete bezeichneten und bislang nur verhältnismäßig wenig erforschten Materials beruht insbesondere darauf, dass von einer Kombination eines leicht verfügbaren pflanzlichen Faserstoffs mit einem mineral...

  7. Ludwig von Bertalanffy Forerunner of Evolutionary Systems Theory

    OpenAIRE

    Wolfgang, Hofkirchner

    2005-01-01

    Ludwig von Bertalanffy is known as founding father of the General System Theory (GST). When Ludwig von Bertalanffy created his GST amidst the last century, he was able to overcome the deep cleft between the controversial theoretical approaches to biology - mechanicism and vitalism. He did so by formulating laws of organisation ruling biota and after generalising them he successfully applied them to different domains such as medicine, psychology, psychotherapy. Methodologically, Bertalanffy re...

  8. 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.)

  9. Entwicklung einer kontaktfreien nichtdestruktiven Methode zur Messung von mechanischen und elastischen Eigenschaften von mikromechanischen Mehrschichtsystemen mit akustischen Oberflächenwellen

    OpenAIRE

    Bennis, Abdelali

    2009-01-01

    Mit dieser Arbeit wird ein Beitrag zur Weiterentwicklung der akustischen lasermesstechnischen Verfahren zur Ermittlung von mechanischen und elastischen Eigenschaften von mikromechanischen Mehrschichtsystemen geleistet. Zu diesen Eigenschaften zählen das E-Modul, die Dichte, die Dicke sowie die Poissonzahl. Die meisten akustischen lasermesstechnischen Verfahren basieren auf der optischen Erzeugung von breitbandigen akustischen Wellen in einem Schichtsystem und der Ermittlung der Geschwindig...

  10. Die graphic des ersten buches von Prekmurje

    Directory of Open Access Journals (Sweden)

    Vilko Novak

    1978-12-01

    Full Text Available Das erste Buch, geschrieben im Dialekt von Prekmurje (Übermurgebiet in Slowenien, war die Übersetzung des Kleinen Katechismus von M.Luther, angefertigt von Ferenc Temlin: Mali katechismus … erschienen in Halle, 1715. Über den Übersetzer schrieben bisher ausführlicher M. Rupel und V. Novak, s. Anmerkung 3. Der Verfasser untersucht, wie sich Temlin in seiner Schreibweise an die ungarische Graphik anlehnte, wie vor ihm schon die handschriftlichen Gesangbücher in Prekmurje und die kaj-kroatischen Schriftsteller. Vokalen.- Temlin benutzt konsequent die akutierten a und e fur lange und enge Vokale, indem ihm das nichtakutierte ein nichtakzentuiertes oder kurzakzentuiertes, niedriger aber einen breeiinten, nichtakzentuier­ten oder kurzakzentuierten Vokal bedeutet. Den Reflex von jat  schreibt er konsequent als ei, die dem Dialekt bekannten ö aus dem engen, kurzen postlabialen oder postdentalen e oder ,ü, und ü aus dem ethymologischen u (nur einige Ausnahmen in Lehnwörtern schreibt er mit diesen Buchstaben. (Beispiele für diese und die nächsten Buchstaben und Laute in der Abhandlung. Das lange o, das in seiner Sprache als Diphtong ou  reflektiert, bezeichnet er auch als solches. Konsonanten.- Für einige davon verwendet Temlin ungarische Doppelzeichen, deren Alter und Entwicklung der Verfasser der Abhandlung angibt. Das c bezeichnet T.ständig als cz, das s als /z, nur in einigen Fällen als z. Den letzt angeführten Buchstaben benutzt er konsequent für z.- Komplizierter ist die Bezeichnung der Zischlaute: für č schreibt T. sehr haufig cf, aber noch häufiger mit cs, sehr selten dagegen ch - Dies scheint aus kirchlichen Ausdrücken, aus kaj-kroatischen Büchern entnommen bzw. Durch die Kirche erlernt.- Das š bezeichnet T. mit doch nicht selten auch mit Dieselben zwei Buchstaben dienen ihm auch für die Bezeichnung des Lautes ž. Bei den Labiallauten ist zu bemerken, dass T. für die Präposition vu manch­ mal schreibt, sonst

  11. 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.

  12. Design of recuperators; Nachrechnung von Rekuperatoren. Moeglichkeiten zur Loesung der inverse Aufgabe bei waermetechnischen Berechnungen von Rekuperatoren mit Metallrohren

    Energy Technology Data Exchange (ETDEWEB)

    Stanev, R. [Univ. fuer Chemische Technologie und Metallurgie, Sofia (Bulgaria). Lehrstuhl fuer Physikalische Metalurgie und Waermeanlagen

    2004-02-01

    Possibilities for solution of the inverse task by heat-technical calculation of recuperators with metal pipes. The utilization of the waste heat in recuperators permits a decrease the fuel consumption of industrial and especially of metallurgical furnaces up to 30%. In the paper is represented a possibility for calculation of recuperators, which is useable not only for this application, than also for the design of air-coolers and other heat-exchangers. (orig.) [German] Die Abgaswaermenutzung mittels Rekuperator erlaubt eine Senkung des Brennstoffverbrauchs von Industrieoefen und insbesondere von den metallurgischen Oefen um bis zu 30%. Im Beitrag wird eine Moeglichkeit der Berechnung von Rekuperatoren vorgestellt, die nicht nur fuer diese Anwendung, sondern auch fuer die Auslegung von Luftkuehlern und anderen Waermeuebertragern verwendet werden kann. (orig.)

  13. Bitcoins. Eine Analyse von Kryptowaehrungen und deren Anwendung von kontroversiellen Angeboten im Darknet bis hin zu traditionellem Onlinehandel.

    OpenAIRE

    Linzner, Manfred

    2016-01-01

    von Manfred Linzner Arbeit an der Bibliothek noch nicht eingelangt - Daten nicht geprueft - Link noch nicht aktiv Abweichender Titel nach Übersetzung der Verfasserin/des Verfassers Technische Universität Wien, Univ., Diplomarbeit, 2016

  14. 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

  15. Electronic Resource Management System. Vernetzung von Lizenzinformationen

    Directory of Open Access Journals (Sweden)

    Michaela Selbach

    2014-12-01

    Full Text Available In den letzten zehn Jahren spielen elektronische Ressourcen im Bereich der Erwerbung eine zunehmend wichtige Rolle: Eindeutig lässt sich hier ein Wandel in den Bibliotheken (fort vom reinen Printbestand zu immer größeren E-Only-Beständen feststellen. Die stetig wachsende Menge an E-Ressourcen und deren Heterogenität stellt Bibliotheken vor die Herausforderung, die E-Ressourcen effizient zu verwalten. Nicht nur Bibliotheken, sondern auch verhandlungsführende Institutionen von Konsortial- und Allianzlizenzen benötigen ein geeignetes Instrument zur Verwaltung von Lizenzinformationen, welches den komplexen Anforderungen moderner E-Ressourcen gerecht wird. Die Deutsche Forschungsgemeinschaft (DFG unterstützt ein Projekt des Hochschulbibliothekszentrums des Landes Nordrhein-Westfalen (hbz, der Universitätsbibliothek Freiburg, der Verbundzentrale des Gemeinsamen Bibliotheksverbundes (GBV und der Universitätsbibliothek Frankfurt, in dem ein bundesweit verfügbares Electronic Ressource Managementsystem (ERMS aufgebaut werden soll. Ein solches ERMS soll auf Basis einer zentralen Knowledge Base eine einheitliche Nutzung von Daten zur Lizenzverwaltung elektronischer Ressourcen auf lokaler, regionaler und nationaler Ebene ermöglichen. Statistische Auswertungen, Rechteverwaltung für alle angeschlossenen Bibliotheken, kooperative Datenpflege sowie ein über standardisierte Schnittstellen geführter Datenaustausch stehen bei der Erarbeitung der Anforderungen ebenso im Fokus wie die Entwicklung eines Daten- und Funktionsmodells. In the last few years the importance of electronic resources in library acquisitions has increased significantly. There has been a shift from mere print holdings to both e- and print combinations and even e-only subscriptions. This shift poses a double challenge for libraries: On the one hand they have to provide their e-resource collections to library users in an appealing way, on the other hand they have to manage these

  16. Jade aus Amerika und weitere Grünsteinobjekte von Alexander von Humboldt aus dem Berliner Mineralienkabinett

    OpenAIRE

    Renate Nöller

    2009-01-01

    Alexander von Humboldt schickte aus Amerika Mineralproben, die nicht nur von naturwissenschaftlichem oder wirtschaftlichem Interesse waren. Vor allem grünes Steinmaterial, sogenannte Jade, war in Mesoamerika kulturell sehr bedeutsam und weit verbreitet, so daß sich aus diesem Rohstoff in der Sammlung auch bearbeitete Stücke vorfinden. Sie erlangten in Europa unterschiedliche Aufmerksamkeit. Die Jadeaxt und die Sonnenscheibe - beide im zweiten Weltkrieg verloren gegangen, hatten als “Humboldt-...

  17. Entwicklung von Dünnschicht-Reaktionsröhrchen zur Bestimmung von Schwefelwasserstoff, Chlor und Tetrachlorethen in Luft

    OpenAIRE

    Schwierz, Torge

    2000-01-01

    Dünnschicht-Reaktionsröhrchen zeichnen sich gegenüber konventionellen Prüfröhrchen durch höhere analytische Leistungen (Nachweisvermögen, Reproduzierbarkeit, Empfindlichkeit, objektive Auswertung) aus, ohne die Vorteile der einfachen praktischen Handhabung bei gasspurenanalytischen Messungen aufzugeben. In der vorliegenden Arbeit wird die Entwicklung von Dünnschicht-Reaktionsröhrchen für die Analyten Schwefelwasserstoff, Chlor und Tetrachlorethen beschrieben. Zum Nachweis von Schwefelwasserst...

  18. Die Rolle von Aldosteron im Knochenstoffwechsel

    Directory of Open Access Journals (Sweden)

    Tomaschitz A

    2012-01-01

    Full Text Available Das Steroidhormon Aldosteron wird in der Zona glomerulosa (ZG der Nebennierenrinde produziert. Kalzium spielt als gemeinsamer „Second Messenger“ eine zentrale Rolle in der durch Angiotensin II, ACTH und Kalium regulierten Aldosteronsynthese. Zahlreiche Studien der vergangenen Jahre dokumentierten die bedeutende Rolle des Aldosterons in der Pathogenese kardiovaskulärer Erkrankungen. Effekte von Aldosteron auf den Knochenstoffwechsel wurden bisher kaum untersucht. In humanen fetalen und adulten Knochenzellen wurde jedoch eine ausgeprägte Expression des Mineralokortikoidrezeptors (MR detektiert. In experimentellen Tierstudien wurden sowohl eine spezifische Aldosteron-MR-Interaktion im Knochengewebe als auch die osteoprotektive Wirkung der MR-Blockade mit Spironolakton beobachtet. Aldosteron kann durch die Hemmung der alkalischen Phosphatase indirekt eine gesteigerte Osteoblastenproliferation induzieren. Die wechselseitige Beeinflussung von Aldosteron und Parathormon (PTH könnte eine bedeutende Rolle in der Pathophysiologie kardiovaskulärer Erkrankungen und des Knochenstoffwechsels spielen. PTH kann sowohl über die Aktivierung spannungsabhängiger Kalziumkanäle als auch durch Bindung an den PTH/PTH-rP-Rezeptor der Zona-glomerulosa- Zellen eine Stimulation der Aldosteronsynthese induzieren. Dies bestätigt sich mit einem signifikanten Rückgang der Plasmaaldosteronkonzentration nach einer Parathyreoidektomie bei Patienten mit einem primären Hyperparathyreoidismus. In Tiermodellen der Herzinsuffizienz führt der relative Aldosteronüberschuss über eine verstärkte renale Kalziumexkretion zu einem sekundären Hyperparathyreoidismus, der durch die gesteigerte Kalziummobilisation aus dem Knochengewebe zu einem erhöhten Frakturrisiko in dieser Patientengruppe beiträgt. Der im Rahmen des primären Hyperaldosteronismus beobachtete sekundäre Hyperparathyreoidismus kann durch eine Hemmung der Aldosteronwirkung/Aldosteronsynthese supprimiert

  19. 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)

  20. GFRP life in wind rotor blades; Lebensdauer von GFK im Holmgurt und im Schubsteg von Rotorblaettern

    Energy Technology Data Exchange (ETDEWEB)

    Kensche, C.W. [Deutsche Forschungsanstalt fuer Luft- und Raumfahrt e.V. (DLR), Stuttgart (Germany). Inst. fuer Bauweisen- und Konstruktionsforschung

    1999-07-01

    Lives of GFRP rotor blade components were calculated on the basis of Woehler curves and the wind power specific standard WISPERX using the linear Palmgren-Miner rule. The Calculations were based on experiments with belts made of the L20/SL epoxy resin system at pressure ratios R=0.1, and -1 and with torsionally stressed GFRP tubes of linen tissue with the epoxy resing GE162/C260 at R=0.1 and -1. The results were incorporated into Haigh diagrams, from which the damage from the collective load was calculated by linear interpolation of the averaged stresses and amplitudes resp. the lines of constant life. The life curves calculated for different maximum stress horizons are in good agreement with experimental collective loads. A comparison of life curves showed that the linen tissue material was more fatigue-sensitive than the belt material. [German] Fuer GFK-Gurte und Schubstege von Rotorblaettern wurden Lebensdauerberechnungen auf der Basis von Woehlerkurven und dem windenergiespezifischen Standard WISPERX unter Anwendung der linearen Palmgren-Miner Regel durchgefuehrt. Bei der Betrachtung der Gurte wurde auf Versuche an UD-Proben mit dem Epoxidharzsystem L20/SL zurueckgegriffen, die bei Spannungsverhaeltnissen von R=0.1, -1 und 10 durchgefuehrt worden waren. Grundlage fuer die Lebensdauerbestimmung der Schubstege waren Ermuedungsversuche an torsionsbelasteten GFK-Rohren aus Leinengewebe mit dem Epoxidharz GE162/C260 bei R=0.1 und -1. In den daraus konstruierten Haighdiagrammen wurden die Schaedigungen durch das Lastkollektiv mittels linearer Interpolation der Mittelspannungen und Amplituden bzw. der Linien konstanter Lebensdauer ermittelt. Die Lebensdauerkurven, die fuer verschiedene Maximalspannungshorizonte ermittelt wurden, stimmen gut mit experimentellen Lastkollektivergebnissen ueberein. Beim Vergleich der Lebensdauerkurven zeigt sich, dass ein Leinengewebesteg erheblich ermuedungsgefaehrdeter ist als ein Gurt. (orig.)

  1. Entstehungsbedingungen von Übergängen von der Schule in den Beruf aus qualitativer und quantitativer Perspektive

    Directory of Open Access Journals (Sweden)

    Nora Gaupp

    2013-03-01

    Full Text Available Methodenintegration wird in den Sozialwissenschaften mit dem Argument sich ergänzender Erkenntnismöglichkeiten häufig gefordert. Die vorliegende Analyse zu Übergangswegen von der Schule in Ausbildung und Arbeit von Jugendlichen mit Hauptschulbildung beruht auf Daten einer quantitativen Panelstudie und einer qualitativen Ergänzungsstudie. Aus quantitativer und qualitativer Perspektive wird jeweils ein Einzelfall betrachtet sowie im Rahmen einer Modellbildung eine Verallgemeinerung auf Aggregatebene vorgenommen. Über ein logistisches Regressionsmodell wird die Bedeutung von zentralen individuellen, sozialen und strukturellen Merkmalen wie Schulleistungen, beruflichen Plänen, individuellen Problembelastungen, Migrationshintergrund und Arbeitslosigkeit der Eltern sowie regionaler Arbeitsmarktsituation für den Verlauf von Übergangswegen (Direkteinstieg in Ausbildung, Umweg in Ausbildung über schulische oder berufsvorbereitende Zwischenschritte, fortgesetzter mehrjähriger Schulbesuch und prekäre Wege in Ausbildungslosigkeit untersucht. Über das qualitative Paradigma konnten vier für den Verlauf von Übergängen zentrale Dimensionen identifiziert werden: Agency, Motivation, kritische biografische Ereignisse und soziale Interaktionen. Der Schritt der Modellbildung integriert die vier Erfahrungsebenen und zeigt ihre Bedeutung für Übergänge von der Schule in den Beruf. Die Diskussion fragt nach Möglichkeiten und Grenzen der Erkenntnisentwicklung der beiden Forschungszugänge. URN: http://nbn-resolving.de/urn:nbn:de:0114-fqs1302126

  2. Einfluss von verschiedenen Erodierstrukturen auf den Reibwert von Kunststoff-Kunststoff Paarungen

    OpenAIRE

    Bergmann, André

    2016-01-01

    Im Beitrag werden bei verschiedenen Lastkollektiven und zwei Reibgeschwindigkeiten die Erodierstrukturen K27, K36, K42 und die Ätzstruktur K36 mit glatten Probekörpern hinsichtlich des Reibwertes und des Verschleißverhaltens untersucht. Als strukturierte Probekörper kommen die Kunststoffe POM und PA und als Gegenkörper zwei verschiedene PE-UHMW´s zum Einsatz. Die Ergebnisse zeigen eine deutliche Abhängigkeit des Reibwertes von der Oberflächenstruktur der Probekörper, jedoch ist die Senkun...

  3. "Die Toten reiten schnelle." Literarische Zitate in Briefen von und an Alexander von Humboldt

    Directory of Open Access Journals (Sweden)

    Ingo Schwarz

    2007-04-01

    Full Text Available Article in GermanAbstract in English and GermanAlexander von Humboldt and his correspondents liked to enrich or embellish their letters with quotations from classic works of ancient literature as well as from recent poems, plays, or novels. This paper tries to show that references to literature were very often used in order to express thoughts and feelings more clearly not so much for impressing the recipients of letters with high education. In educated circles a good knowledge of ancient and modern works of literature was a standard requirement, which often allowed the letter writers to use quotations in a playful manner.

  4. Entwurf und Simulation von Makromodellen zur transienten Simulation von thermo-elektrischen Kopplungen in einem Netzwerksimulator

    OpenAIRE

    Schacht, Ralph Karl Benjamin

    2002-01-01

    In der vorliegenden Arbeit wird eine Methode vorgestellt, welche die Beschreibung und Si-mulation von thermo-elektrischen Kopplungen während des Design-Prozesses mittels Mak-romodellierung unterstützt. Das Makromodell ist für den Einsatz in dem Schaltungssimulator PSpice zugeschnitten. Es ermöglicht die rechenzeiteffiziente transiente Simulation zwischen thermo-elektrisch gekoppelten Komponenten eines komplexen Mikrosystems. Im Rahmen dieser Arbeit wurde zunächst eine für die Problemstellung ...

  5. Zur Struktur und Funktion von Synonymen

    Directory of Open Access Journals (Sweden)

    Marina Zorman

    1998-12-01

    Full Text Available Der Artikel behandelt die Synonyme im Licht der funktionell-strukturellen Sprachtheorie Coserius. 1 Die Wahl der theoretischen Grundsätze wurde durch die Festellung diktiert, daß die bisherigen Erkenntnisse über die Synonymie widersprüchlich sind und daß auch schon über alle Feststellungen berechtigte Einsprüche erhoben wurden. Deshalb wird in dieser Arbeit auf der genannten theoretischen Grundlage, die verschiedene Gesichtspunkte des Problems verbindet, anstatt sie zu trennen (s. Punkt 2, ein Modell für die Analyse von Synonymen vorgestellt (3, das die klassischen Schwächen der Semantikforschung (zu geringe Menge tatsächlicher Daten, Subjektivität und Introspektion durch eine empirische Untersuchung in einem Textkorpus zu ersetzen versucht. In die Analyse sind drei Inhaltsebenen einbezogen (Bezeichnung, Bedeutung und Sinn und ihnen sind jeweils entsprechende Untersuchungsmethoden zugeordnet. Im Sinne des Modells wurden in der Arbeit Zorman 1997 zwei slowenische Synonympaare (kuverta - ovojnica und borba - boj analysiert, die als Beispiele reiner (und totaler Synonymie gelten können. Die Analyse wird aus Platzgründen an dieser Stelle nicht detailliert dargestellt,2 veranschaulicht werden nur ihre Tragweite und die Ergebnisse (4. Im letzten Teil (5 werden die Leistungen der vorgeschlagenen Methode bewertet und einige Annahmen dargestellt, die der weiteren Erforschung der Synonyme dienen könnten. Die objektive Behandlung der Synonymie unter unterschiedlichen Gesichtspunkten scheint einige Dogmen über Synonyme in Frage zu  stellen.

  6. Polymorphism in the promoter region of von Willebrand factor gene and von Willebrand disease type 1

    Directory of Open Access Journals (Sweden)

    Daniel Simon

    2003-12-01

    Full Text Available The -1185A/G polymorphism in the 5'-regulatory region of the von Willebrand factor (VWF gene was associated with VWF plasma levels in a normal population. This study was undertaken to evaluate whether there is a relationship between this polymorphism and type 1 von Willebrand disease (VWD, a disorder characterized by a quantitative deficiency of VWF. The association between this polymorphism and plasma VWF levels in normal Brazilian individuals was also analyzed. Control subjects (n = 460 and type 1 VWD patients (n = 41 were studied. Polymerase chain reaction (PCR amplification of the 864-bp VWF promoter region followed by AccII restriction-digestion was used to identify the -1185A/G genotypes. The -1185G allele frequency was 57% in normal individuals and 63% in type 1 VWD patients, this difference was not significant (p = 0.29. No significant association was observed between -1185A/G genotypes and VWF plasma levels in normal individuals, although VWF levels were in the same direction as those reported by another study, with subjects carrying the G allele having the lower levels. These results suggest that -1185A/G polymorphism is not associated with the partial deficiency of VWF in type 1 VWD patients.

  7. Cistoadenoma papilar de epidídimo: a propósito de un caso Papillary cystadenoma of the epididymis: a case report

    Directory of Open Access Journals (Sweden)

    Daniela Stoisa

    2012-12-01

    Full Text Available Presentamos un caso de cistoadenoma papilar de epidídimo (CPE en un paciente varón de 44 años de edad con una masa palpable en el escroto derecho. La ecografía (US y la resonancia magnética (RM mostraron tres lesiones quísticas adyacentes extratesticulares de paredes gruesas, una con un fino septo parcial interno, de ubicación epididimaria y un diámetro en conjunto de 1 cm x 0,4 cm. El diagnóstico anatomopatológico realizado luego de su resección quirúrgica fue de cistoadenoma papilar de epidídimo. Éste consiste en un tumor epitelial benigno, muy poco frecuente, que se origina del epitelio ductal eferente. Se presenta preferentemente en el adulto joven y puede ser uni o bilateral (un tercio de los casos, así como también esporádico o hereditario en relación con la enfermedad de von Hippel-Lindau, particularmente en el caso de las lesiones bilaterales. Se diagnostica por palpación y métodos por imágenes, incluyendo la ecografía y la resonanacia magnética. Histológicamente se caracteriza por la presencia de espacios quísticos con proyecciones papilares internas, revestidas por células claras, que remedan a las del carcinoma renal. La diferenciación entre éste y el cisto-adenoma papilar de epidídimo debe hacerse a través de marcadores inmunohistoquímicos. El tratamiento es la exéresis quirúrgica y un posterior seguimiento, ya que, si bien su pronóstico es excelente, se ha descrito su transformación maligna a cistoadenocarcinoma.We report a case of papillary cystadenoma of the epididymis (PCE in a 44-year-old male patient with a palpable right intrascrotal mass. Ultrasound and magnetic resonance imaging showed three extratesticular intraepididymal thick wall-cystic lesions measuring 1.0 x 0.4 cm overall. After surgical resection, the pathological diagnosis was papillary cystadenoma of epididymis. This is a rare benign epithelial tumor that arises from the efferent duct epithelium. It usually occurs in young adult

  8. Entwicklungsperspektiven von Social Software und dem Web 2.0

    Science.gov (United States)

    Raabe, Alexander

    Der Artikel beschäftigt sich zunächst mit dem derzeitigen und zukünftigen Einsatz von Social Software in Unternehmen. Nach dem großen Erfolg von Social Software im Web beginnen viele Unternehmen eigene Social Software-Initiativen zu entwickeln. Der Artikel zeigt die derzeit wahrgenommenen Einsatzmöglichkeiten von Social Software im Unternehmen auf, erörtert Erfolgsfaktoren für die Einführung und präsentiert mögliche Wege für die Zukunft. Nach der Diskussion des Spezialfalles Social Software in Unternehmen werden anschließend die globalen Trends und Zukunftsperspektiven des Web 2.0 in ihren technischen, wirtschaftlichen und sozialen Dimensionen dargestellt. Wie aus den besprochenen Haupttrends hervorgeht, wird die Masse an digital im Web verfügbaren Informationen stetig weiterwachsen. So stellt sich die Frage, wie es in Zukunft möglich sein wird, die Qualität der Informationssuche und der Wissensgenerierung zu verbessern. Mit dem Einsatz von semantischen Technologien im Web wird hier eine revolutionäre Möglichkeit geboten, Informationen zu filtern und intelligente, gewissermaßen verstehende" Anwendungen zu entwerfen. Auf dem Weg zu einem intelligenten Web werden sich das Semantic Web und Social Software annähern: Anwendungen wie Semantic Wikis, Semantic Weblogs, lightweight Semantic Web-Sprachen wie Microformats oder auch kommerzielle Angebote wie Freebase von Metaweb werden die ersten Vorzeichen einer dritten Generation des Webs sein.

  9. 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.

  10. Biographical sketch: Georg Hermann von Meyer (1815-1892).

    Science.gov (United States)

    Skedros, John G; Brand, Richard A

    2011-11-01

    This biographical sketch on Georg Hermann von Meyer highlights the interactions in the 1860s that von Meyer, a famous anatomist, had with Karl Culmann, a famous structural engineer and mathematician. The published papers from this interaction caught the attention of Julius Wolff and stimulated his development of the trajectorial hypothesis of bone adaptation--now called "Wolff's Law." The corresponding translations are provided: (1) von Meyer's 1867 paper that highlights the regularity of arched trabecular patterns in various human bones, and his discussions with Culmann about their possible mechanical relevance; and (2) Wolff's 1869 paper that first mentions the correspondence of stress trajectories in a solid, crane-like structure to the arched trabecular patterns in the proximal human femur. This biographical sketch on Georg Hermann von Meyer corresponds to the historic texts, The Classic: The Architecture of the Trabecular bone (by von Meyer), and The Classic: On the Significance of the Architecture of the Spongy Substance for the Question of Bone Growth. A preliminary publication (by Wolff) available at DOIs 10.1007/s11999-011-2041-5 , 10.1007/s11999-011-2042-4 .

  11. Choroba von Willebranda – najczęstsza osoczowa skaza krwotoczna

    Directory of Open Access Journals (Sweden)

    Bożena Sokołowska

    2010-08-01

    Full Text Available Von Willebrand disease is the most common hereditary haemorrhagic disorder. A majority of patients (70%have classic mild or moderate (type I von Willebrand disease, and women are mostly affected. Clinical manifestationsinclude menorrhagia and post partum bleeding.

  12. Groves-Schemata zur Lösung von Anreizproblemen bei der Budgetierung

    OpenAIRE

    Locarek, Hermann

    1992-01-01

    Groves-Schemata zur Lösung von Anreizproblemen bei der Budgetierung / von Günter Bamberg u. Hermann Locarek. - In: Controlling / Klaus Spremann ... (Hrsg.). - Wiesbaden : Gabler, 1992. - S. 657-670. - Auch ersch. als: Arbeitspapiere zur mathematischen Wirtschaftsforschung ; 110

  13. 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.)

  14. Applikation von fermentierter Soja bei Krebspatienten zur Verminderung von Kachexie und Erhöhung der Apoptose - eine prospektive Pilotstudie

    Directory of Open Access Journals (Sweden)

    Jacob U

    2009-01-01

    Full Text Available Kachexie ist eine Begleiterkrankung von Krebs, Aids oder rheumatoider Arthritis. Andere Symptome dieser Erkrankungen sind Depression sowie chronische Erschöpfung. Für alle diese Begleiterkrankungen, die die Lebensqualität der schwererkrankten Patienten negativ beeinflussen, wird eine Erhöhung von Entzündungsmediatoren (z.B. IL-6 und TNF-α verantwortlich gemacht. Für Krebs wird eine Erniedrigung der Apoptose, ausgelöst durch eine Erhöhung von NFκB verantwortlich gemacht. Eine Gabe eines fermentierten Soja-Produktes, das in den USA seit 10 Jahren zur Verbesserung der Lebensqualität von Krebspatienten eingesetzt wird, wurde in einer prospektiven Studie untersucht: Für je 5 Patienten, die unter Prostata-, Ovar- oder Brustkrebs litten, konnte eine signifikante Verminderung von Kachexie, Stress und Depression festgestellt werden. Gleichzeitig konnte man für Prostata- und Ovarkrebs-Patienten eine Erhöhung der Genexpression apoptotischer Marker disseminierter Tumorzellen feststellen. Zusätzlich wurde eine starke Erhöhung der Genexpression des Tumorsuppressorgens p21 festgestellt. Auch wenn die prospektive Studie präliminär ist und die Anzahl der untersuchten Patienten zu klein, so widerspricht sie nicht unserer Annahme, dass es einen direkten Zusammenhang zwischen Krebs und Begleiterkrankungen, besonders der Kachexie, gibt.

  15. "Face to Interface": Zum Problem der Vertrauenskonstitution im Internet am Beispiel von elektronischen Auktionen

    OpenAIRE

    Brinkmann, Ulrich; Seifert, Matthias

    2001-01-01

    Am Beispiel von Internetauktionen geht der Beitrag der Frage nach, welche Rolle Vertrauen bei e-Commerce-Transaktionen spielt und über welche Institutionalisierungsprozesse Vertrauen befördert werden kann. Dazu wird zunächst mit Rückgriff auf den Stand der Forschung ein multidimensionales Verständnis von Vertrauen entwickelt. Anschließend wird die Spezifik von Internetauktionen als Sonderfall von e-Commerce aus der Perspektive der Vertrauensproblematik beleuchtet: beiden Transaktionsparteien ...

  16. Diurnal variation of von Willebrand factor in plasma

    DEFF Research Database (Denmark)

    Timm, Annette; Fahrenkrug, Jan; Jørgensen, Henrik L

    2014-01-01

    BACKGROUND: Quantitation of von Willebrand factor (VWF) in plasma is a central element in assessing von Willebrand disease (VWD). VWF activity is known to vary, which has partly been ascribed to biological and preanalytical variation. However, a possible diurnal expression of VWF has not been...... of light and 9 h of darkness); the plasma concentration of melatonin was used as an internal control to confirm the normal 24-h rhythms of the individual participants. RESULTS: The data, analyzed by rhythmometric statistics, revealed a significant variation (P = 0.02) and total amplitude of 22.6% in VWF...... and VWF and (ii) VWF propeptide and VWF was determined. Taken together, the data suggest changes in release and not in clearance. CONCLUSIONS: Diurnal variation in von Willebrand antigen and activity in plasma represents an important aspect of the biological variation. Standardized time-of-day plasma...

  17. Analyse von Videodokumentationen in der kunstpädagogischen Forschung

    Directory of Open Access Journals (Sweden)

    Anja Mohr

    2001-03-01

    Full Text Available Am Institut für Kunstpädagogik der Justus-Liebig-Universität werden seit 1996 unter der Leitung von Prof. Dr. A. von Criegern Untersuchungen zum kindlichen Bildverhalten am Computer durchgeführt. Aus ersten explorativen Studien ist inzwischen ein Forschungsprojekt entstanden, das auf breiterer theoretisch und empirischer Basis das bildnerische Verhalten von Vor- und frühen Grundschulkindern am Computer untersucht. Entgegen der bisher ergebnisorientierten, eher quantitativ arbeitenden Kinderzeichnungsforschung, stellte das Giessener Team sehr schnell fest, dass der gesamte Malprozess und mehr noch das gesamte ästhetische Verhalten am Computer mit qualitativen Methoden erforscht werden muss. Um diesem Anspruch gerecht zu werden, wurden die Beobachtungs-, Aufzeichnungs- und Analyseverfahren schrittweise optimiert und angepasst. Der Beitrag stellt die Bedeutung der im Projekt angewendeten Form der Videodokumentation für die Erforschung der digitalen Kinderzeichnung dar.

  18. Quantitative Image Quality Comparison of Reduced- and Standard-Dose Dual-Energy Multiphase Chest, Abdomen, and Pelvis CT.

    Science.gov (United States)

    Buty, Mario; Xu, Ziyue; Wu, Aaron; Gao, Mingchen; Nelson, Chelyse; Papadakis, Georgios Z; Teomete, Uygar; Celik, Haydar; Turkbey, Baris; Choyke, Peter; Mollura, Daniel J; Bagci, Ulas; Folio, Les R

    2017-06-01

    We present a new image quality assessment method for determining whether reducing radiation dose impairs the image quality of computed tomography (CT) in qualitative and quantitative clinical analyses tasks. In this Institutional Review Board-exempt study, we conducted a review of 50 patients (male, 22; female, 28) who underwent reduced-dose CT scanning on the first follow-up after standard-dose multiphase CT scanning. Scans were for surveillance of von Hippel-Lindau disease (N = 26) and renal cell carcinoma (N = 10). We investigated density, morphometric, and structural differences between scans both at tissue (fat, bone) and organ levels (liver, heart, spleen, lung). To quantify structural variations caused by image quality differences, we propose using the following metrics: dice similarity coefficient, structural similarity index, Hausdorff distance, gradient magnitude similarity deviation, and weighted spectral distance. Pearson correlation coefficient and Welch 2-sample t test were used for quantitative comparisons of organ morphometry and to compare density distribution of tissue, respectively. For qualitative evaluation, 2-sided Kendall Tau test was used to assess agreement among readers. Both qualitative and quantitative evaluations were designed to examine significance of image differences for clinical tasks. Qualitative judgment served as an overall assessment, whereas detailed quantifications on structural consistency, intensity homogeneity, and texture similarity revealed more accurate and global difference estimations. Qualitative and quantitative results indicated no significant image quality degradation. Our study concludes that low(er)-dose CT scans can be routinely used because of no significant loss in quantitative image information compared with standard-dose CT scans.

  19. Polycythemia and paraganglioma with a novel somatic HIF2A mutation in a male.

    Science.gov (United States)

    Toyoda, Hidemi; Hirayama, Jyunya; Sugimoto, Yuka; Uchida, Keiichi; Ohishi, Kohshi; Hirayama, Masahiro; Komada, Yoshihiro

    2014-06-01

    Recently, a new syndrome of paraganglioma, somatostatinoma, and polycythemia has been discovered (known as Pacak-Zhuang syndrome). This new syndrome, with somatic HIF2A gain-of-function mutations, has never been reported in male patients. We describe a male patient with Pacak-Zhuang syndrome who carries a newly discovered HIF2A mutation. Congenital polycythemias have diverse etiologies, including germline mutations in the oxygen-sensing pathway. These include von Hippel-Lindau (Chuvash polycythemia), prolyl hydroxylase domain-containing protein-2, and hypoxia-inducible factor-2α (HIF-2α). Somatic gain-of-function mutations in the gene encoding HIF-2α were reported in patients with paraganglioma and polycythemia and have been found exclusively in female patients. Through sequencing of the HIF2A using DNA from paraganglioma in 15-year-old male patient, we identified a novel mutation of HIF2A: a heterozygous C to A substitution at base 1589 in exon 12 of HIF2A. The mutation was not found in germline DNA from leukocytes. The C1589A mutations resulted in substitution of alanine 530 in the HIF-2α protein with glutamic acid. This mutation is undoubtedly associated with increased HIF-2α activity and increased protein half-life, because it affects the vicinity of the prolyl hydroxylase target residue, proline 531. To our knowledge, this is the first report describing Pacak-Zhuang syndrome with somatic gain-of-function mutation in HIF2A in a male patient. Congenital polycythemia of unknown origin should raise suspicion for the novel disorder Pacak-Zhuang syndrome, even in male patients. Copyright © 2014 by the American Academy of Pediatrics.

  20. Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib.

    Science.gov (United States)

    Jedeszko, Christopher; Paez-Ribes, Marta; Di Desidero, Teresa; Man, Shan; Lee, Christina R; Xu, Ping; Bjarnason, Georg A; Bocci, Guido; Kerbel, Robert S

    2015-04-08

    Renal cell carcinoma (RCC), normally considered an intrinsically chemotherapy-resistant cancer, is currently treated with targeted biologic therapies, including antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib. The efficacy of these agents is limited by both intrinsic and acquired resistance. Death is almost always due to advanced metastatic disease, a treatment circumstance seldom modeled in preclinical (mouse) drug testing. Similarly, therapy results using postsurgical adjuvant therapy models of microscopic disease have not been reported. Using in vivo selection and transfection of established human RCC cell lines (786-0 and SN12-PM6), we derived clonal luciferase-expressing variants capable of spontaneous metastasis from an orthotopic primary tumor to organs typical of clinical RCC, including bone, lungs, and brain. The bioluminescence and consistent metastatic spread of von Hippel-Lindau-wild type SN12-PM6-1 cells allowed for the establishment of perioperative therapy models of RCC. We report that the combination of daily low-dose metronomic topotecan with pazopanib has highly potent antiprimary tumor as well as both postsurgical adjuvant and metastatic therapy efficacy despite lack of an antimetastatic effect of pazopanib monotherapy. The combination therapy resulted in sustained metastatic tumor cell dormancy, but tumor progression occurred upon treatment cessation. We also obtained evidence for a direct effect of pazopanib on RCC cells, resulting in increased intracellular concentration of topotecan. Our results suggest that this type of treatment combination should be considered for clinical evaluation in early- or late-stage metastatic disease, even for tumors seemingly intrinsically "resistant" to antiangiogenic TKIs or chemotherapy. Copyright © 2015, American Association for the Advancement of Science.