Sample records for background von hippel-lindau

  1. Von Hippel-Lindau Disease

    MedlinePlus

    What is Von Hippel-Lindau disease (VHL)? Von Hippel-Lindau disease (VHL) is a rare disease that causes tumors and cysts to grow in your body. They ... can become cancerous. What causes Von Hippel-Lindau disease (VHL)? Von Hippel-Lindau disease (VHL) is a ...

  2. PT2385 for the Treatment of Von Hippel-Lindau Disease-Associated Clear Cell Renal Cell Carcinoma

    ClinicalTrials.gov

    2017-08-23

    VHL Gene Mutation; VHL; VHL Syndrome; VHL Gene Inactivation; Von Hippel; Von Hippel-Lindau Disease; Von Hippel's Disease; Von Hippel-Lindau Syndrome, Modifiers of; Clear Cell Renal Cell Carcinoma; Clear Cell RCC; ccRCC

  3. Genetics Home Reference: von Hippel-Lindau syndrome

    MedlinePlus

    ... more common in particular ethnic groups? Genetic Changes Mutations in the VHL gene cause von Hippel-Lindau ... dividing too rapidly or in an uncontrolled way. Mutations in this gene prevent production of the VHL ...

  4. Haemangioblastoma of a cervical sensory nerve root in Von Hippel-Lindau syndrome.

    PubMed

    McEvoy, A W; Benjamin, E; Powell, M P

    2000-10-01

    Spinal haemangioblastomas are rare, accounting for only about 7% of all central nervous system cases. The case of a 40-year-old woman with a haemangioblastoma arising solely from a cervical sensory nerve root is presented. At operation via a cervical laminectomy, it was possible to resect the tumour en masse with the sensory ramus, by extending the laminectomy through the exit foramen for C6. Haemangioblastomas are commonly intramedullary, and have only been reported in this location on one previous occasion. The patient has Von Hippel-Lindau syndrome and a history of multiple solid tumours. The possible role of the Von Hippel-Lindau tumour suppressor gene in the pathogenesis of these neoplasms is discussed.

  5. Molecular-genetic diagnostics of von Hippel-Lindau syndrome (VHL) in Bulgaria: first complex mutation event in the VHL gene.

    PubMed

    Glushkova, Maria; Dimova, Petia; Yordanova, Iglika; Todorov, Tihomir; Tourtourikov, Ivan; Mitev, Vanyo; Todorova, Albena

    2018-02-01

    Von Hippel-Lindau syndrome is an autosomal-dominant disease characterized by the formation of various tumours and cysts in many different parts of the body. Von Hippel-Lindau syndrome is caused by VHL gene mutations leading to production of impaired tumor suppressor Von Hippel-Lindau syndrome protein or its complete absence. To study five patients with clinically suspected Von Hippel-Lindau syndrome, who were referred for molecular genetic testing. Sanger sequencing of the coding regions of the VHL gene. Five clinically relevant germline mutations were detected. One of the pathogenic variants has not been previously reported. This novel mutation is a complex mutation event combining a duplication and an indel, rearranging exon 3 of the VHL gene - c. [516_517dupGTCAAGCCT; 532_542delCTGGACATCGTinsATTA], p. (Glu173Serfs*4). Overall, our results showed that the diagnosis of Von Hippel-Lindau syndrome in our country is difficult most probably because of its heterogeneous clinical manifestation and insufficient knowledge on the diagnostic criteria for the disease. From genetic point of view our results add some novel data on the mutation profile of the VHL gene. In order to prove or revise the diagnosis, early genetic testing is strongly recommended in affected patients and their family members to ensure appropriate follow-up and treatment of the malignancies.

  6. Hypoxia and cell cycle regulation of the von Hippel-Lindau tumor suppressor

    PubMed Central

    Liu, Weijun; Xin, Hong; Eckert, David T.; Brown, Julie A.; Gnarra, James R.

    2010-01-01

    Inactivation of von Hippel-Lindau tumor suppressor protein (pVHL) is associated with von Hippel-Lindau disease, an inherited cancer syndrome, as well as the majority of patients with sporadic clear cell renal carcinoma (RCC). While the involvement of pVHL in oxygen sensing through targeting HIFα subunits to ubiquitin-dependent proteolysis has been well documented, less is known about pVHL regulation under both normoxic and hypoxic conditions. We found that pVHL levels decreased in hypoxia and that hypoxia-induced cell cycle arrest is associated with pVHL expression in RCC cells. pVHL levels fluctuate during the cell cycle, paralleling cyclin B1 levels, with decreased levels in mitosis and G1. pVHL contains consensus Destruction box sequences, and pVHL associates with Cdh1, an activator of the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. We show that pVHL has a decreased half-life in G1, Cdh1 downregulation results in increased pVHL expression, while Cdh1 overexpression results in decreased pVHL expression. Taken together these results suggest that pVHL is a novel substrate of APC/CCdh1. Destruction box-independent pVHL degradation was also detected, indicating that other ubiquitin ligases are also activated for pVHL degradation. PMID:20802534

  7. Clinical features and natural history of von Hippel-Lindau disease.

    PubMed

    Maher, E R; Yates, J R; Harries, R; Benjamin, C; Harris, R; Moore, A T; Ferguson-Smith, M A

    1990-11-01

    The clinical features, age at onset and survival of 152 patients with von Hippel-Lindau disease were studied. Mean age at onset was 26.3 years and 97 per cent of patients had presented by aged 60 years. Retinal angioma was the first manifestation in 65 patients (43 per cent), followed by cerebellar haemangioblastoma (n = 60, 39 per cent) and renal cell carcinoma (n = 15, 10 per cent). Overall, 89 patients (59 per cent) developed a cerebellar haemangioblastoma, 89 (59 per cent) a retinal angioma, 43 (28 per cent) renal cell carcinoma, 20 (13 per cent) spinal haemangioblastoma and 11 (7 per cent) a phaeochromocytoma. Renal, pancreatic and epididymal cysts were frequent findings but their exact incidence was not accurately assessed. Mean age at diagnosis of renal cell carcinoma (44.0 +/- 10.9 years) was significantly older than that for cerebellar haemangioblastoma (29.0 +/- 10.0 years) and retinal angioma (25.4 +/- 12.7 years). The probability of a patient with von Hippel-Lindan disease developing a cerebellar haemangioblastoma, retinal angioma or renal cell carcinoma by age 60 years was 0.84, 0.7 and 0.69, respectively. A comprehensive screening protocol for affected patients and at-risk relatives is presented, based on detailed analysis of age at onset data for each of the major complications. Median actuarial survival was 49 years, with renal cell carcinoma the leading cause of death.

  8. Posterior fossa scintiangiography: documentation of genetic penetrance of von Hippel--Lindau syndrome in a clinically unaffected girl and her father

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hattner, R.S.

    1975-09-01

    The syndrome of von Hippel and Lindau is a rare hereditary disorder constituted by retinal angiomata, posterior fossa and spinal cord hemangioblastomata, cystic and adenomatous dysplasia of major organs, and occasionally renal cell carcinomata. Although the syndrome is transmitted by an autosomal dominant gene, the penetrance is variable and affected persons may have any or all of the elements of the disease. The 16-year-old clinically normal daughter of a patient with the von Hippel--Lindau syndrome demonstrated a vascular posterior fossa lesion on /sup 99m/Tc-DTPA scintiangiography that failed detection in delayed images. Contrast arteriography corroborated the presence of a hemangioblastoma. Noninvasivemore » demonstration of the genetic penetrance of this disorder offers its victims an opportunity for low morbidity early surgical cure of the associated brain lesions. (auth)« less

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

    PubMed

    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

  10. Drosophila Mgr, a Prefoldin subunit cooperating with von Hippel Lindau to regulate tubulin stability

    PubMed Central

    Delgehyr, Nathalie; Wieland, Uta; Rangone, Hélène; Pinson, Xavier; Mao, Guojie; Dzhindzhev, Nikola S.; McLean, Doris; Riparbelli, Maria G.; Llamazares, Salud; Callaini, Giuliano; Gonzalez, Cayetano; Glover, David M.

    2012-01-01

    Mutations in Drosophila merry-go-round (mgr) have been known for over two decades to lead to circular mitotic figures and loss of meiotic spindle integrity. However, the identity of its gene product has remained undiscovered. We now show that mgr encodes the Prefoldin subunit counterpart of human von Hippel Lindau binding-protein 1. Depletion of Mgr from cultured cells also leads to formation of monopolar and abnormal spindles and centrosome loss. These phenotypes are associated with reductions of tubulin levels in both mgr flies and mgr RNAi-treated cultured cells. Moreover, mgr spindle defects can be phenocopied by depleting β-tubulin, suggesting Mgr function is required for tubulin stability. Instability of β-tubulin in the mgr larval brain is less pronounced than in either mgr testes or in cultured cells. However, expression of transgenic β-tubulin in the larval brain leads to increased tubulin instability, indicating that Prefoldin might only be required when tubulins are synthesized at high levels. Mgr interacts with Drosophila von Hippel Lindau protein (Vhl). Both proteins interact with unpolymerized tubulins, suggesting they cooperate in regulating tubulin functions. Accordingly, codepletion of Vhl with Mgr gives partial rescue of tubulin instability, monopolar spindle formation, and loss of centrosomes, leading us to propose a requirement for Vhl to promote degradation of incorrectly folded tubulin in the absence of functional Prefoldin. Thus, Vhl may play a pivotal role: promoting microtubule stabilization when tubulins are correctly folded by Prefoldin and tubulin destruction when they are not. PMID:22451918

  11. [Genetic analysis of a family with Von Hippel-Lindau syndrome].

    PubMed

    Lafuente-Sanchis, Aránzazu; Cuevas, José M; Alemany, Pilar; Cremades, Antonio; Zúñiga, Ángel

    Von Hippel-Lindau syndrome (VHL) is an autosomal dominant inherited disease associated with mutations in the VHL tumour suppressor gene located on chromosome 3p25. VHL is characterized by the development of multiple malignant and benign tumours in the central nervous system and internal organs, including liver, pancreas and the adrenal gland. More than 823 different mutations of the VHL gene have currently been identified. In the present study we describe the case of a family affected by VHL treated at the University Hospital of La Ribera and the results of the genetic analysis of three relatives, identifying the mutation R167G in exon 3 of VHL gene as the cause of VHL syndrome in this family. Copyright © 2016 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.

  12. Diagnostic Genetics at a Distance: Von Hippel-Lindau Disease and a Novel Mutation

    PubMed Central

    Prosser, Debra O.; Love, Jennifer M.; Gardner, R. J. McKinlay; Love, Donald R.

    2013-01-01

    Genetic testing at a distance is commonplace where members of a family with a segregating germline mutation are geographically separated. For the most part, this challenge is addressed through the intervention of health professionals in taking and/or processing blood samples for subsequent couriering of DNA to a referral laboratory. In some circumstances, however, the collecting of pivotal clinical material may involve direct patient involvement. We describe such a situation where noninvasive saliva samples were provided by members of a family manifesting Von Hippel-Lindau (VHL) disease. The analysis identified a novel mutation in the VHL gene that was used to exclude other family members as being at risk of VHL disease. PMID:24062953

  13. Management of uncommon disorders in pregnancy: Von Hippel-Lindau disease, Gitelman syndrome, and Nutcracker syndrome.

    PubMed

    Merhi, Basma; Miller, Margaret; Lanis, Aviya; Katz, Brittany; Hsu, Tiffany; Tong, Iris

    2017-09-01

    Uncommon renal disorders in pregnancy can be challenging to manage given limited evidence in the literature to guide management. We present a series of three uncommon renal disorders in pregnancy: Von Hippel-Lindau disease, Gitelman syndrome, and Nutcracker syndrome. Previously published case reports with differing outcomes offer some guidance to the management of these disorders in pregnancy. In this case series, we address the management of these syndromes during pregnancy and discuss the maternal and fetal outcomes. All three of our patients had good maternal and fetal outcomes, which will contribute to current data on maternal and fetal outcomes in these rare diseases, which is limited.

  14. Molecular analysis of the von hippel-lindau disease gene.

    PubMed

    Chernoff, A; Kasparcova, V; Linehan, W M; Stolle, C A

    2001-01-01

    Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that predisposes the affected individual to develop characteristic tumors. These include CNS hemangioblastoma, retinal angiomas, endolymphatic sac tumors, pancreatic cysts and tumors, epididymal cystadenomas, pheochromocytomas, renal cysts, and clear-cell renal carcinoma. The VHL gene was localized to 3p25 and then isolated by Latif et al. (1). The gene contains three exons with an open reading frame of 852 nucleotides, which encode a predicted protein of 284 amino acids. The VHL protein is believed to have several functions. It is involved in transcription regulation through its inhibition of elongation by binding to the B and C subunits of elongin. Mutations of VHL allow the B and C subunits to bind with the A subunit. This complex then overcomes "pausing" of RNA polymerase during mRNA transcription (2,3). Several studies suggest that the VHL protein is also involved in regulation of hypoxia-inducible transcripts, particularly vascular endothelial growth factor (VEGF), by altering mRNA stability (4,5). Therefore, VHL gene mutations permit the overexpression of VEGF under normoxic conditions, which leads to the angiogenesis believed to be required for tumor growth. The VHL-elongin BC complex (VBC) also binds two other proteins-CUL2 and Rbx1-in a complex that has structural similarity to other E3 ubiquitin ligase complexes (6). Such complexes mediate the degradation of cell-cycle regulatory proteins.

  15. Phosphorylation-dependent cleavage regulates von Hippel Lindau proteostasis and function

    PubMed Central

    German, Peter; Bai, Shanshan; Liu, Xian-De; Sun, Mianen; Zhou, Lijun; Kalra, Sarathi; Zhang, Xuesong; Minelli, Rosalba; Scott, Kenneth L.; Mills, Gordon B.; Jonasch, Eric; Ding, Zhiyong

    2016-01-01

    Loss of von Hippel Lindau (VHL) protein function is a key driver of VHL diseases, including sporadic and inherited clear cell renal cell carcinoma. Modulation of the proteostasis of VHL, especially missense point-mutated VHL, is a promising approach to augmenting VHL levels and function. VHL proteostasis is regulated by multiple mechanisms including folding, chaperone binding, complex formation, and phosphorylation. Nevertheless, many details underlying the regulations of VHL proteostasis are unknown. VHL is expressed as two variants, VHL30 and VHL19. Furthermore, the long form variant of VHL was often detected as multiple bands by Western blotting. However, how these multiple species of VHL are generated and whether the process regulates VHL proteostasis and function are unknown. We hypothesized that the two major species are generated by VHL protein cleavage, and the cleavage regulates VHL proteostasis and subsequent function. We characterized VHL species using genetic and pharmacologic approaches and showed that VHL was first cleaved at the N-terminus by chymotrypsin C before being directed for proteasomal degradation. Casein kinase 2-mediated phosphorylation at VHL N-terminus was required for the cleavage. Furthermore, inhibition of cleavage stabilized VHL protein, thereby promoting HIF downregulation. Our study reveals a novel mechanism regulating VHL proteostasis and function, which is significant for identifying new drug targets and developing new therapeutic approaches targeting VHL deficiency in VHL diseases. PMID:26973240

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

    PubMed

    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.

  17. Glucocorticoids promote Von Hippel Lindau degradation and Hif-1α stabilization

    PubMed Central

    Greenald, David; Wilson, Garrick K.; Peron, Margherita; Markham, Eleanor; Sinnakaruppan, Mathavan; Matthews, Laura C.; McKeating, Jane A.; Argenton, Francesco; van Eeden, Fredericus J. M.

    2017-01-01

    Glucocorticoid (GC) and hypoxic transcriptional responses play a central role in tissue homeostasis and regulate the cellular response to stress and inflammation, highlighting the potential for cross-talk between these two signaling pathways. We present results from an unbiased in vivo chemical screen in zebrafish that identifies GCs as activators of hypoxia-inducible factors (HIFs) in the liver. GCs activated consensus hypoxia response element (HRE) reporters in a glucocorticoid receptor (GR)-dependent manner. Importantly, GCs activated HIF transcriptional responses in a zebrafish mutant line harboring a point mutation in the GR DNA-binding domain, suggesting a nontranscriptional route for GR to activate HIF signaling. We noted that GCs increase the transcription of several key regulators of glucose metabolism that contain HREs, suggesting a role for GC/HIF cross-talk in regulating glucose homeostasis. Importantly, we show that GCs stabilize HIF protein in intact human liver tissue and isolated hepatocytes. We find that GCs limit the expression of Von Hippel Lindau protein (pVHL), a negative regulator of HIF, and that treatment with the c-src inhibitor PP2 rescued this effect, suggesting a role for GCs in promoting c-src–mediated proteosomal degradation of pVHL. Our data support a model for GCs to stabilize HIF through activation of c-src and subsequent destabilization of pVHL. PMID:28851829

  18. [Clinical study on patients with renal-cell carcinoma accompanied with Von Hippel-Lindau disease treated with radiofrequency ablation].

    PubMed

    Nao, Tomoya; Shimamoto, Tsutomu; Karashima, Takashi; Kamei, Maiko; Fukuhara, Hideo; Fukata, Satoshi; Satake, Hirofumi; Ashida, Shingo; Yamasaki, Ichiro; Kamata, Masayuki; Inoue, Keiji; Yamanishi, Tomoaki; Ogawa, Yasuhiro; Ito, Satoshi; Shuin, Taro

    2014-09-01

    We report 12 renal cell carcinomas in 6 patients with Von Hippel-Lindau (VHL) disease treated with radiofrequency ablation (RFA). The mean age of the patients was 46 (range 38-53) years (male : 4, female : 2). Computed tomography (CT)-guided transcutaneous RFA was performed under conscious sedation with local anesthetics. The mean size of the tumors was 2.4 (range 0.7-8.1) cm. Nine of the 12 tumors (75%) were locally well controlled. However, 3 tumors in 2 patients developed visceral metastases after RFA. While minimal flank pain, nausea, perinephritic hematoma and lumbago were observed, there was no major complication during or after the procedure. The therapy with CT-guided transcutaneous RFA is efficient and minimal invasive for renal cell carcinoma in patients with VHL, leading to preservation of renal function.

  19. Cloning and characterization of a mouse gene with homology to the human von Hippel-Lindau disease tumor suppressor gene: implications for the potential organization of the human von Hippel-Lindau disease gene.

    PubMed

    Gao, J; Naglich, J G; Laidlaw, J; Whaley, J M; Seizinger, B R; Kley, N

    1995-02-15

    The human von Hippel-Lindau disease (VHL) gene has recently been identified and, based on the nucleotide sequence of a partial cDNA clone, has been predicted to encode a novel protein with as yet unknown functions [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. The length of the encoded protein and the characteristics of the cellular expressed protein are as yet unclear. Here we report the cloning and characterization of a mouse gene (mVHLh1) that is widely expressed in different mouse tissues and shares high homology with the human VHL gene. It predicts a protein 181 residues long (and/or 162 amino acids, considering a potential alternative start codon), which across a core region of approximately 140 residues displays a high degree of sequence identity (98%) to the predicted human VHL protein. High stringency DNA and RNA hybridization experiments and protein expression analyses indicate that this gene is the most highly VHL-related mouse gene, suggesting that it represents the mouse VHL gene homologue rather than a related gene sharing a conserved functional domain. These findings provide new insights into the potential organization of the VHL gene and nature of its encoded protein.

  20. TLX controls angiogenesis through interaction with the von Hippel-Lindau protein.

    PubMed

    Zeng, Zhao-Jun; Johansson, Erik; Hayashi, Amiko; Chavali, Pavithra L; Akrap, Nina; Yoshida, Takeshi; Kohno, Kimitoshi; Izumi, Hiroto; Funa, Keiko

    2012-06-15

    TLX is known as the orphan nuclear receptor indispensable for maintaining neural stem cells in adult neurogenesis. We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL), which stabilizes TLX. In turn, TLX competes with hydroxylated hypoxia-inducible factor (HIF-α) for binding to pVHL, which contributes to the stabilization of HIF-2α in neuroblastoma during normoxia. Upon hypoxia, TLX increases in the nucleus where it binds in close proximity of the HIF-response element on the VEGF-promoter chromatin, and, together with HIF-2α, recruits RNA polymerase II to induce VEGF expression. Conversely, depletion of TLX by shRNA decreases the expression of HIF-2α and VEGF as well as the growth-promoting and colony-forming capacity of the neuroblastoma cell lines IMR-32 and SH-SY5Y. On the contrary, silencing HIF-2α will slightly increase TLX, suggesting that TLX acts to maintain a hypoxic environment when HIF-2α is decreasing. Our results demonstrate TLX to play a key role in controlling angiogenesis by regulating HIF-2α. TLX and pVHL might counterbalance each other in important fate decisions such as self-renewal and differentiation, as well as angiogenesis and anti-angiogenesis.

  1. TLX controls angiogenesis through interaction with the von Hippel-Lindau protein

    PubMed Central

    Zeng, Zhao-jun; Johansson, Erik; Hayashi, Amiko; Chavali, Pavithra L.; Akrap, Nina; Yoshida, Takeshi; Kohno, Kimitoshi; Izumi, Hiroto; Funa, Keiko

    2012-01-01

    Summary TLX is known as the orphan nuclear receptor indispensable for maintaining neural stem cells in adult neurogenesis. We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL), which stabilizes TLX. In turn, TLX competes with hydroxylated hypoxia-inducible factor (HIF-α) for binding to pVHL, which contributes to the stabilization of HIF-2α in neuroblastoma during normoxia. Upon hypoxia, TLX increases in the nucleus where it binds in close proximity of the HIF-response element on the VEGF-promoter chromatin, and, together with HIF-2α, recruits RNA polymerase II to induce VEGF expression. Conversely, depletion of TLX by shRNA decreases the expression of HIF-2α and VEGF as well as the growth-promoting and colony-forming capacity of the neuroblastoma cell lines IMR-32 and SH-SY5Y. On the contrary, silencing HIF-2α will slightly increase TLX, suggesting that TLX acts to maintain a hypoxic environment when HIF-2α is decreasing. Our results demonstrate TLX to play a key role in controlling angiogenesis by regulating HIF-2α. TLX and pVHL might counterbalance each other in important fate decisions such as self-renewal and differentiation, as well as angiogenesis and anti-angiogenesis. PMID:23213445

  2. Renal Cell Carcinoma Programmed Death-ligand 1, a New Direct Target of Hypoxia-inducible Factor-2 Alpha, is Regulated by von Hippel-Lindau Gene Mutation Status.

    PubMed

    Messai, Yosra; Gad, Sophie; Noman, Muhammad Zaeem; Le Teuff, Gwenael; Couve, Sophie; Janji, Bassam; Kammerer, Solenne Florence; Rioux-Leclerc, Nathalie; Hasmim, Meriem; Ferlicot, Sophie; Baud, Véronique; Mejean, Arnaud; Mole, David Robert; Richard, Stéphane; Eggermont, Alexander M M; Albiges, Laurence; Mami-Chouaib, Fathia; Escudier, Bernard; Chouaib, Salem

    2016-10-01

    Clear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene. To elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression. A series of 32 renal tumors composed of 11 VHL tumor-associated and 21 sporadic RCCs were used to evaluate PD-L1 expression levels after sequencing of the three exons and exon-intron junctions of the VHL gene. The 786-O, A498, and RCC4 cell lines were used to investigate the mechanisms of PD-L1 regulation. Fisher's exact test was used for VHL mutation and Kruskal-Wallis test for PD-L1 expression. If no covariate accounted for the association of VHL and PD-L1, then a Kruskal-Wallis test was used; otherwise Cochran-Mantel-Haenzsel test was used. We also used the Fligner-Policello test to compare two medians when the distributions had different dispersions. We demonstrated that tumors from ccRCC patients with VHL biallelic inactivation (ie, loss of function) display a significant increase in PD-L1 expression compared with ccRCC tumors carrying one VHL wild-type allele. Using the inducible VHL 786-O-derived cell lines with varying hypoxia-inducible factor-2 alpha (HIF-2α) stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2α expression. Targeting HIF-2α decreased PD-L1, while HIF-2α overexpression increased PD-L1 mRNA and protein levels in ccRCC cells. Interestingly, chromatin immunoprecipitation and luciferase assays revealed a direct binding of HIF-2α to a transcriptionally active hypoxia-response element in the human PD-L1 proximal promoter in 786-O cells. Our work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy. We investigated the relationship between von Hippel-Lindau mutations and programmed death-ligand 1 expression. We

  3. Epidemiological study of a von Hippel-Lindau family in northwest China.

    PubMed

    Zhang, Jingyao; Wu, Dapeng; Ai, Hong; Bai, Jigang; Dong, Shunbin; Yang, Qinling; Qu, Kai; Zhou, Lei; Xu, Xinsen; Liu, Chang

    2013-09-01

    von Hippel-Lindau (VHL) disease is a rare, inherited neoplastic disease characterized by hemangioblastomas (HBL) of the central nervous system (CNS), retinal angiomas, renal cell carcinomas (RCC), pancreatic endocrine tumors (PETs), pheochromocytomas, paragangliomas, and visceral cysts. We encountered a large VHL family in northwest China and conducted a systematic screening of the family members based on their epidemiological and clinical characteristics. A self-designed questionnaire was used to collect the general sociodemographic and health information of the family members. For the preliminary family screening, physical examination and abdomen B ultrasonography were performed. The suspected patients were subjected to cranial computerized tomography and fundus examination. The clinical data of the patients with confirmed VHL disease were collected from hospital records. A total of 63 lineal descendants in six generations were observed in the family (generations O, A, B, C, D, E), including 9 dead suspected cases (6 males, 3 females) and 10 living cases (2 males, 8 females). Among the 10 living cases, 4, 2, 1, 3, 4, 8, and 2 manifested HBLs of the CNS, PETs, RCC, pancreatic cysts, renal cysts, pheochromocytomas (4 hemi and 4 bilateral), and paragangliomas, respectively. Data showed that the morbidity of VHL disease in generation C was lower than that in generation B, but the age of onset was younger. This study is the first to report VHL disease in northwest China and VHL-associated PET cases in Chinese. Therefore, follow-up checkups of the family should be focused on younger generations. Proper family screening protocols should be followed for the treatment of patients with VHL disease.

  4. [Hereditary pheochromocytoma--a family affected by von Hippel-Lindau disease].

    PubMed

    Mertl, J; Rovný, A; Krepelová, A; Prásek, J

    2003-07-01

    The authors present a case of a 37 year old male (proband) with a 13 year history of progressive sight impairment leading to blindness and a 4 year history of a mild hypertension. He was incidentally found to have large adrenal tumors after an ultrasound kidney examination. The tumors were confirmed with CT scan and magnetic resonance imaging. A bilateral pheochromocytoma was biochemically demonstrated and successfully removed. The eye diagnosis of angiomatosis retinae von Hippel-Lindau was ascertained after a search of the patient files in other medical departments, which led to a family screening. Proband's brother, having hypertension and a history of a cerebellar astrocytoma operation, was also diagnosed with CT scan to have a bilateral pheochromocytoma. Unfortunately, at the same time he was found to have a large irremovable neuroendocrine pancreatic carcinoma, which caused complications and his eventual death. Both proband and his brother were affected by the same CGG(Arg167)->CAG(Gln) mutation in the exon 3 of the VHL gene. Other living and examined family members were not affected, which was confirmed by negative genetic testing. One year after the pheochromocytoma operation, proband was diagnosed to have a retroperitoneal tumor left to the aorta, clinically silent, with slightly and non-constantly elevated urine norepinephrine and normetanephrine. Metaiodobenzylguanidine scintigraphy showed that it was a paraganglioma. The old CT and magnetic resonance picture review demonstrated that the tumor had already been present at the time of the operation. It was surgically removed and histologically verified. It is a pity that proband had not been sent by his ophthalmologist for an endocrine examination when the eye diagnosis was determined. Affection of the family would have been discovered earlier, and proband's brother might have possibly been saved.

  5. Pheochromocytoma Screening Initiation and Frequency in von Hippel-Lindau Syndrome

    PubMed Central

    Aufforth, Rachel D.; Ramakant, Pooja; Sadowski, Samira M.; Mehta, Amit; Trebska-McGowan, Katarzyna; Nilubol, Naris; Pacak, Karel

    2015-01-01

    Context: Patients with von Hippel-Lindau (VHL) syndrome have a 25–30% chance of developing pheochromocytoma. Although practice guidelines recommend biochemical and radiological screening every 1–2 years for pheochromocytoma in patients with VHL, there are limited data on the optimal age and frequency for screening. Objective: Our objective was to determine the earliest age of onset and frequency of contralateral and recurrent pheochromocytomas in patients with VHL syndrome. Methods: This is a retrospective analysis of a prospective cohort of patients with VHL enrolled in a natural history study. Results: A total of 273 patients diagnosed with VHL were enrolled in a natural history clinical study. Thirty-one percent (84) were diagnosed with pheochromocytoma. The mean age of diagnosis was 28.8 ± 13.9 years. The earliest age at diagnosis was 5.5 years. Median follow-up for the cohort was 116.6 months (range, 0.1–613.2). Ninety-nine percent (83) of patients underwent adrenalectomy. Fifty-eight and 32% of patients had metanephrines and/or catecholamines elevated more than two times and more than four times the upper limit of normal, respectively. Twenty-five percent (21) of pheochromocytomas were diagnosed in pediatric patients younger than 19 years of age, and 86% and 57% of pediatric patients had an elevation more than two times and more than four times upper limit of normal, respectively. Eight patients had a total of nine recurrences. The median age at recurrence was 33.5 years (range, 8.8–51.9). Recurrences occurred as short as 0.5 years and as long as 39.7 years after the initial operation. Conclusions: Our findings among VHL pediatric patients supports the need for biochemical screening starting at age 5 with annual lifelong screening. PMID:26451910

  6. Metastatic phaeochromocytoma in a 23-year-old woman with an unclassified variant in the von Hippel Lindau disease gene: how can the pathogenicity of this variant be determined?

    PubMed

    Russell, Nicholas; Delatycki, Martin; Grossmann, Mathis

    2015-07-01

    A 23-year-old woman with metastatic phaeochromocytoma was found to have a previously unclassified variant in the von Hippel Lindau disease gene (c.361G>C). We use this case to highlight the issue of unclassified single nucleotide variants and the approaches to help predict whether they are disease causing or neutral. With increasing use of genetic testing, and widespread clinical use of next-generation sequencing around the corner, this issue is likely to become more prominent. © 2015 John Wiley & Sons Ltd.

  7. Design and analysis of a Petri net model of the Von Hippel-Lindau (VHL) tumor suppressor interaction network.

    PubMed

    Minervini, Giovanni; Panizzoni, Elisabetta; Giollo, Manuel; Masiero, Alessandro; Ferrari, Carlo; Tosatto, Silvio C E

    2014-01-01

    Von Hippel-Lindau (VHL) syndrome is a hereditary condition predisposing to the development of different cancer forms, related to germline inactivation of the homonymous tumor suppressor pVHL. The best characterized function of pVHL is the ubiquitination dependent degradation of Hypoxia Inducible Factor (HIF) via the proteasome. It is also involved in several cellular pathways acting as a molecular hub and interacting with more than 200 different proteins. Molecular details of pVHL plasticity remain in large part unknown. Here, we present a novel manually curated Petri Net (PN) model of the main pVHL functional pathways. The model was built using functional information derived from the literature. It includes all major pVHL functions and is able to credibly reproduce VHL syndrome at the molecular level. The reliability of the PN model also allowed in silico knockout experiments, driven by previous model analysis. Interestingly, PN analysis suggests that the variability of different VHL manifestations is correlated with the concomitant inactivation of different metabolic pathways.

  8. Spectrum of magnetic resonance imaging findings in pancreatic and other abdominal manifestations of Von Hippel-Lindau disease in a series of 23 patients: a pictorial review.

    PubMed

    Graziani, Rossella; Mautone, Simona; Vigo, Mario; Manfredi, Riccardo; Opocher, Giuseppe; Falconi, Massimo

    2014-01-10

    Von Hippel Lindau disease is a rare autosomal dominantly inherited multisystem disorder characterized by development of benign and malignant tumors. The abdominal manifestation of the syndrome are protean. Magnetic resonance plays an important role in identification of abdominal abnormalities and follow-up of lesions. To describe magnetic resonance imaging findings and patterns of pancreatic and other principal abdominal manifestations in a series of von Hippel-Lindau (VHL) disease patients and to review literature. We retrospectively reviewed abdominal magnetic resonance studies performed in 23 patients (10 males, 13 females) diagnosed of VHL. In all examined patients abdominal involvement was present. The pancreatic imaging findings detected were: unilocular cystic lesions (6/23: 26.1%); serous cystadenomas (11/23: 47.8%), including diffuse lesions (8/23: 34.8%); solid neuroendocrine tumors (8/23: 34.8%); cystic neuroendocrine tumors (1/23: 4.3%). The renal findings detected were: simple renal cysts (18/23: 78.3%); complex renal cysts (13/23: 56.5%), including benign lesions (10/23: 43.5%) and malignant lesions (3/23: 13.0%); renal carcinomas (11/23: 47.8%) and 5 of these (45.5%) were multiple and bilateral. Five patients (21.7%) presented pheochromocytoma (4 of these were bilateral; 80.0%) and 1 patient (4.3%) presented cystadenoma of the epididymis. In VHL disease patients, magnetic resonance imaging plays an essential role in the identification of pancreatic and other abdominal lesions, in their follow-up, in the screening of asymptomatic gene carriers, and in their long-term surveillance.

  9. Preventive medicine for von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

    PubMed

    Krauss, Tobias; Ferrara, Alfonso Massimiliano; Links, Thera P; Wellner, Ulrich; Bancos, Irina; Kvachenyuk, Andrey; Villar Gómez de Las Heras, Karina; Yukina, Marina; Petrov, Roman; Bullivant, Garrett; von Duecker, Laura; Jadhav, Swati S; Ploeckinger, Ursula; Welin, Staffan; Schalin-Jantti, Camilla; Gimm, Oliver; Pfeifer, Marija; Ngeow, Joanne; Hasse-Lazar, Kornelia; Sanso, Gabriela; Qi, Xiao-Ping; Ugurlu, Umit; Diaz, Rene Eduardo; Wohllk, Nelson; Peczkowska, Mariola; Aberle, Jens; Lourenço, Delmar Muniz; Pereira, Maria Adelaide; Fragoso, Maria Candida Barisson Villares; Hoff, Ana O; Almeida, Madson Queiroz; Violante, Alice H D; Quidute, Ana R P; Zhang, Zheiwei; Recasens, Monica; Robles Diaz, Luis; Kunavisarut, Tada; Wannachalee, Taweesak; Sirinvaravong, Sirinart; Jonasch, Eric; Grozinsky-Glasberg, Simona; Fraenkel, Merav; Beltsevich, Dmitry; Egorov, Viacheslav I; Bausch, Dirk; Schott, Matthias; Tiling, Nikolaus; Pennelli, Gianmaria; Zschiedrich, Stefan; Därr, Roland; Ruf, Juri; Denecke, Timm; Link, Karl-Heinrich; Zovato, Stefania; von Dobschuetz, Ernst; Yaremchuk, Svetlana; Amthauer, Holger; Makay, Ozer; Patocs, Attila; Walz, Martin K; Huber, Tobias B; Seufert, Jochen; Hellman, Per; Kim, Raymond H; Kuchinskaya, Ekaterina; Schiavi, Francesca; Malinoc, Angelica; Reisch, Nicole; Jarzab, Barbara; Barontini, Marta; Januszewicz, Andrzej; Shah, Nalini; Young, William; Opocher, Giuseppe; Eng, Charis; Neumann, Hartmut P H; Bausch, Birke

    2018-05-10

    Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2,330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cutoff ≥2.8 cm, 44% and 91% for TVDT cutoff of ≤24 months). In 117/273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8 cm (94% vs 85% by 10 years; P=0.020; 80% vs 50% at 10 years; P=0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

  10. What the neurosurgeon should know about hemangioblastoma, both sporadic and in Von Hippel-Lindau disease: A literature review

    PubMed Central

    Bamps, Sven; Calenbergh, Frank Van; Vleeschouwer, Steven De; Loon, Johannes Van; Sciot, Raf; Legius, Eric; Goffin, Jan

    2013-01-01

    Background: Hemangioblastomas are associated with Von Hippel-Lindau disease (VHLD) in 10-40% of cases. Based upon a literature review we state the core features the neurosurgeon should be aware of. Methods: We performed a selective literature (Cochrane and Medline) search for hemangioblastoma, both sporadic and VHL associated. We reviewed general characteristics (epidemiology, symptomatology, diagnosis, and management) and focused on follow-up as well as screening modalities for sporadic and VHL associated lesions. Results: Based upon our literature search, we established guidelines for screening and follow-up in both sporadic and VHL associated hemangioblastoma patients. Conclusions: Screening for retinal angiomas, abdominal masses, and pheochromocytomas as well as genetic analysis is recommended for every patient with a newly diagnosed hemangioblastoma. Follow-up is by magnetic resonance imaging (MRI) of the clinical neuronal region at 6 and at 12-24 months postoperatively. For VHL-associated hemangioblastomas yearly investigation for craniospinal hemangioblastoma by MRI and yearly screening and follow-up for retinal angiomas is recommended. Annual abdominal ultrasound with triennial computed tomography (CT) imaging for abdominal masses is postulated. Annual audiometry is to be performed for possible endolymphatic sac tumor, detailed radiographic imaging of the skull base should be performed upon abnormality in auditory testing. Investigations for cystadenomas of the epidydimis and broad ligament only are mandatory on indication. Annual investigation for pheochromocytoma is recommended. PMID:24340227

  11. Design and Analysis of a Petri Net Model of the Von Hippel-Lindau (VHL) Tumor Suppressor Interaction Network

    PubMed Central

    Minervini, Giovanni; Panizzoni, Elisabetta; Giollo, Manuel; Masiero, Alessandro; Ferrari, Carlo; Tosatto, Silvio C. E.

    2014-01-01

    Von Hippel-Lindau (VHL) syndrome is a hereditary condition predisposing to the development of different cancer forms, related to germline inactivation of the homonymous tumor suppressor pVHL. The best characterized function of pVHL is the ubiquitination dependent degradation of Hypoxia Inducible Factor (HIF) via the proteasome. It is also involved in several cellular pathways acting as a molecular hub and interacting with more than 200 different proteins. Molecular details of pVHL plasticity remain in large part unknown. Here, we present a novel manually curated Petri Net (PN) model of the main pVHL functional pathways. The model was built using functional information derived from the literature. It includes all major pVHL functions and is able to credibly reproduce VHL syndrome at the molecular level. The reliability of the PN model also allowed in silico knockout experiments, driven by previous model analysis. Interestingly, PN analysis suggests that the variability of different VHL manifestations is correlated with the concomitant inactivation of different metabolic pathways. PMID:24886840

  12. Pancreatic mixed serous neuroendocrine neoplasm with clear cells leading to diagnosis of von Hippel Lindau disease.

    PubMed

    Kakkar, Aanchal; Sharma, Mehar C; Yadav, Rajni; Panwar, Rajesh; Mathur, Sandeep R; Iyer, Venkateswaran K; Sahni, Peush

    2016-08-01

    Mixed serous neuroendocrine neoplasms are extremely rare tumors that are usually seen in female patients and are often associated with von Hippel Lindau (VHL) disease. We describe the case of a 38-year-old male who presented with complaints of anorexia, weight loss, and abdominal pain. CT abdomen showed a mass in the head of the pancreas, multiple small nodules in the body of pancreas, and bilateral adrenal masses. Fine needle aspiration cytology (FNAC) from the mass showed features of a neuroendocrine tumor, with many of the cells demonstrating abundant clear cytoplasm. Histopathological examination of the pancreaticoduodenectomy specimen showed a mixed serous neuroendocrine neoplasm with two components viz. serous cystadenoma and neuroendocrine tumor (NET) World Health Organization (WHO) grade 2. In addition, he was diagnosed to have bilateral pheochromocytomas and a paraganglioma. The synchronicity of these tumors suggested the possibility of VHL disease. Thus, identification of a NET with clear cells or of a mixed serous neuroendocrine neoplasm should raise suspicion of VHL disease. In a mixed tumor, FNAC may identify only one of the two components. Thorough processing of all pancreatic serous tumors for pathological examination is recommended, as NET may occur as a small nodule within the serous cystadenoma. Copyright © 2016 Elsevier GmbH. All rights reserved.

  13. Agents that Stabilize Mutated von Hippel Lindau Protein Result in Differential Post-Translational Modification and Subcellular Localization

    PubMed Central

    Ding, Zhiyong; German, Peter; Bai, Shanshan; Feng, Zhehui; Gao, Meng; Si, Wendy; Sobieski, Mary M.; Stephan, Clifford C.; Mills, Gordon B.; Jonasch, Eric

    2014-01-01

    Background von Hippel Lindau (VHL) disease is an autosomal dominant inherited disorder that results in multiple organ systems being affected. Treatment is mainly surgical, however, effective systemic therapies are needed. We developed and tested a cell-based screening tool to identify compounds that stabilize or upregulate full-length, point mutated VHL. Methods The 786-0 cell line was infected with full-length W117A mutated VHL linked to a C-terminal Venus fluorescent protein. This VHL-W117A-Venus line was used to screen the Prestwick drug library and was tested against the known proteasome inhibitors MG132 and bortezomib. Western blot validation and evaluation of downstream functional readouts, including HIF and GLUT1 levels, were performed. Results Bortezomib, MG132, and the Prestwick compounds 8-azaguanine, thiostrepton and thioguanosine were found to reliably upregulate VHL-W117A-Venus in 786-0 cells. 8-azaguanine was found to downregulate HIF2α levels, and was augmented by the presence of VHL W117A. VHL p30 band intensities varied as a function of compound used, suggesting alternate post-translational processing. In addition, nuclear-cytoplasmic localization of pVHL varied amongst the different compounds. Conclusion 786-0 cells containing VHL-W117A-Venus can be successfully used to identify compounds that upregulate VHL levels, and that have a differential effect on pVHL intracellular localization and posttranslational processing. Further screening efforts will broaden the number of pharmacophores available to develop therapeutic agents that will upregulate and refunctionalize mutated VHL. PMID:22357874

  14. Long-term outcome after resection of brainstem hemangioblastomas in von Hippel-Lindau disease

    PubMed Central

    Wind, Joshua J.; Bakhtian, Kamran D.; Sweet, Jennifer A.; Mehta, Gautam U.; Thawani, Jayesh P.; Asthagiri, Ashok R.; Oldfield, Edward H.; Lonser, Russell R.

    2016-01-01

    Object Brainstem hemangioblastomas are frequently encountered in patients with von Hippel-Lindau (VHL) disease. These tumors can cause significant morbidity, and their optimal management has not been defined. To better define the outcome and management of these tumors, the authors analyzed the long-term results in patients who underwent resection of brainstem hemangioblastomas. Methods Consecutive patients with VHL disease who underwent resection of brainstem hemangioblastomas with a follow-up of 12 months or more were included in this study. Serial functional assessments, radiographic examinations, and operative records were analyzed. Results Forty-four patients (17 male and 27 female) underwent 51 operations for resection of 71 brainstem hemangioblastomas. The most common presenting symptoms were headache, swallowing difficulties, singultus, gait difficulties, and sensory abnormalities. The mean follow-up was 5.9 ± 5.0 years (range 1.0–20.8 years). Immediately after 34 operations (66.7%), the patients remained at their preoperative functional status; they improved after 8 operations (15.7%) and worsened after 9 operations (17.6%) as measured by the McCormick scale. Eight (88.9%) of the 9 patients who were worse immediately after resection returned to their preoperative status within 6 months. Two patients experienced functional decline during long-term follow-up (beginning at 2.5 and 5 years postoperatively) caused by extensive VHL disease–associated CNS disease. Conclusions Generally, resection of symptomatic brainstem hemangioblastomas is a safe and effective management strategy in patients with VHL disease. Most patients maintain their preoperative functional status, although long-term decline in functional status may occur due to VHL disease–associated progression. PMID:20932100

  15. Coexistence of sporadic cerebellar hemangioblastoma and pituitary null cell adenoma: simultaneous expression of von Hippel-Lindau gene product. Case report.

    PubMed

    Shimoda, Yoshiteru; Ogawa, Yoshikazu; Endo, Hidenori; Watanabe, Mika; Tominaga, Teiji

    2012-01-01

    Coexistence of brain tumors of different pathologies is rare, and the majority of the cases were related to genetic disorders or secondary tumors occurring after radiotherapy. A 73-year-old man was introduced to the outpatient department suffering from severe nausea and vertigo. Magnetic resonance imaging showed a cystic tumor in the left cerebellar hemisphere and another lesion in the sella turcica. There was no evident family history of von Hippel-Lindau (VHL) disease, and the systemic investigation failed to detect any other tumors or signs of VHL disease. Treatment was performed in two stages, and he was discharged with remaining slight ataxic gait. The diagnoses were cerebellar hemangioblastoma and pituitary null cell adenoma. Additional immunohistochemical investigation using VHL disease gene-related protein in both tumors showed minute granular positive staining in the cytoplasm of stromal cells in the former, and diffuse and strong granular cytoplasmic positive staining in the latter. Further analysis is required to confirm the true implication of the VHL gene mutation, and the possible involvement of VHL gene-related protein in the pathogenesis of these coexisting tumors.

  16. Clinicopathologic correlation of argon laser photocoagulation of retinal angiomas in a patient with von Hippel-Lindau disease followed for more than 20 years.

    PubMed

    Rosa, R H; Goldberg, M F; Green, W R

    1996-01-01

    The authors review the histopathologic findings in the eyes of a patient with multiple retinal angiomas and von Hippel-Lindau disease, who underwent treatment with argon laser photocoagulation with follow-up of more than 20 years. The patient was studied ophthalmoscopically and by fluorescein angiography before and after argon laser photocoagulation of retinal angiomas. The eyes were obtained postmortem, and the central portion of the right eye, including the macula and optic nerve head, was sectioned serially for light microscopy. The pupil-optic nerve segment of the left eye was step-sectioned serially for light microscopy. Histopathologic study of the right eye disclosed mild cystoid macular edema and focal areas of exudation in the midperiphery possibly secondary to irradiation of the head. A 1.5 x 0.3-mm area of residual angioma was present in the nasal peripapillary retina. Superotemporally, four chorioretinal scars were present in one photocoagulated area. These scars were composed of dense fibrous tissue with vascularization and variable retinal pigment epithelium hyperplasia. Large, nonangiomatous vessels within each of the scars were continuous with other retinal vessels. Inferotemporally, two chorioretinal scars were present in one photocoagulated area. Histopathologically, these scars were similar to the superotemporal scars, except that no patent retinal vessels traversed the inferotemporal scars. Neovascularization of the retina was associated with one superotemporal and one inferotemporal scar. No residual angiomatous tissue was present in the supero- or inferotemporal areas. Histopathologic examination of the left eye disclosed extensive vitreous organization and periretinal fibrovascular proliferation, extensive gliosis of the retina, and a 4.5 x 2-mm schisis cavity filled with fibrinous exudate. Three angiomas with variable fibrosis were present in the left eye. Despite a poor clinical course in one eye treated with xenon arc photocoagulation

  17. Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes

    PubMed Central

    Ivanov, Sergey V.; Kuzmin, Igor; Wei, Ming-Hui; Pack, Svetlana; Geil, Laura; Johnson, Bruce E.; Stanbridge, Eric J.; Lerman, Michael I.

    1998-01-01

    To discover genes involved in von Hippel-Lindau (VHL)-mediated carcinogenesis, we used renal cell carcinoma cell lines stably transfected with wild-type VHL-expressing transgenes. Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12. The deduced protein sequence was classified as a one-pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module. Reintroduced wild-type VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines. Similar results were obtained with CA9, encoding another transmembrane CA with an intact catalytic domain. Although both domains of the VHL protein contribute to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression. We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21.2 respectively, regions prone to amplification in some human cancers. Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth. PMID:9770531

  18. The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL).

    PubMed

    Guo, Y; Schoell, M C; Freeman, R S

    2009-04-23

    von Hippel-Lindau (VHL) disease is caused by germ-line mutations in the VHL tumor suppressor gene and is the most common cause of inherited renal cell carcinoma (RCC). Mutations in the VHL gene also occur in a large majority of sporadic cases of clear-cell RCC, which have high intrinsic resistance to chemotherapy and radiotherapy. Here we show that VHL-deficient RCC cells express lower levels of the proapoptotic Bcl-2 family protein BIM(EL) and are more resistant to etoposide and UV radiation-induced death compared to the same cells stably expressing the wild-type VHL protein (pVHL). Reintroducing pVHL into VHL-null cells increased the half-life of BIM(EL) protein without affecting its mRNA expression, and overexpressing pVHL inhibited BIM(EL) polyubiquitination. Suppressing pVHL expression with RNA interference resulted in a decrease in BIM(EL) protein and a corresponding decrease in the sensitivity of RCC cells to apoptotic stimuli. Directly inhibiting BIM(EL) expression in pVHL-expressing RCC cells caused a similar decrease in cell death. These results demonstrate that pVHL acts to promote BIM(EL) protein stability in RCC cells, and that destabilization of BIM(EL) in the absence of pVHL contributes to the increased resistance of VHL-null RCC cells to certain apoptotic stimuli.

  19. Tumors in von Hippel-Lindau Syndrome: From Head to Toe-Comprehensive State-of-the-Art Review.

    PubMed

    Ganeshan, Dhakshinamoorthy; Menias, Christine O; Pickhardt, Perry J; Sandrasegaran, Kumaresan; Lubner, Meghan G; Ramalingam, Preetha; Bhalla, Sanjeev

    2018-01-01

    Von Hippel-Lindau syndrome (VHL) is an autosomal-dominant hereditary tumor disease that arises owing to germline mutations in the VHL gene, located on the short arm of chromosome 3. Patients with VHL may develop multiple benign and malignant tumors involving various organ systems, including retinal hemangioblastomas (HBs), central nervous system (CNS) HBs, endolymphatic sac tumors, pancreatic neuroendocrine tumors, pancreatic cystadenomas, pancreatic cysts, clear cell renal cell carcinomas, renal cysts, pheochromocytomas, paragangliomas, and epididymal and broad ligament cystadenomas. The VHL/hypoxia-inducible factor pathway is believed to play a key role in the pathogenesis of VHL-related tumors. The diagnosis of VHL can be made clinically when the characteristic clinical history and findings have manifested, such as the presence of two or more CNS HBs. Genetic testing for heterozygous germline VHL mutation may also be used to confirm the diagnosis of VHL. Imaging plays an important role in the diagnosis and surveillance of patients with VHL. Familiarity with the clinical and imaging manifestations of the various VHL-related tumors is important for early detection and guiding appropriate management. The purpose of this article is to discuss the molecular cytogenetics and clinical manifestations of VHL, review the characteristic multimodality imaging features of the various VHL-related tumors affecting multiple organ systems, and discuss the latest advances in management of VHL, including current recommendations for surveillance and screening. © RSNA, 2018 An earlier incorrect version of this article appeared online. This article was corrected on April 9, 2018.

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

    PubMed Central

    2010-01-01

    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 procedures in non

  1. Shorter telomere length increases age-related tumor risks in von Hippel-Lindau disease patients.

    PubMed

    Wang, Jiang-Yi; Peng, Shuang-He; Ning, Xiang-Hui; Li, Teng; Liu, Sheng-Jie; Liu, Jia-Yuan; Hong, Bao-An; Qi, Nie-Nie; Peng, Xiang; Zhou, Bo-Wen; Zhang, Jiu-Feng; Cai, Lin; Gong, Kan

    2017-09-01

    Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome caused by alterations of VHL gene. Patients are predisposed to develop pheochromocytomas and solid or cystic tumors of the central nervous system, kidney, pancreas, and retina. Remarkable phenotypic heterogeneity exits in organ involvement and tumor onset age between and within VHL families. However, no reliable markers have been found to predict the age-related tumor risks in VHL patients. A large Chinese cohort composed of 300 VHL patients and 92 healthy family controls was enrolled in our study. Blood relative telomere length was measured in 184 patients and all the controls available for genomic DNA samples. Age-related risks for the five major VHL-associated tumors were evaluated using Kaplan-Meier plots and Cox regression analysis. Differences in clinical phenotype were observed between Chinese cohort and the United Kingdom cohort. VHL patients showed significantly shorter telomere length than healthy family controls(P = 0.0183), and a positive correlation was found between telomere length and onset age of the five major tumors, respectively. Moreover, patients in the shorter telomere group (age-adjusted telomere length ≤ 0.44) suffered higher age-related risks for VHL-associated central nervous system hemangioblastomas (HR: 1.879, P = 0.004), renal cell carcinoma (HR: 2.126, P = 0.002) and pancreatic cyst and neuroendocrine tumors (HR: 2.093, P = 0.001). These results indicate that blood shorter telomere length is a new biomarker for age-related tumor risks in VHL patients, which will be crucial to genetic counseling and future research about the role of telomere shortening in the pathogenesis of VHL-associated tumors. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  2. MicroRNAs Associated with Von Hippel-Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review.

    PubMed

    Schanza, Lisa-Maria; Seles, Maximilian; Stotz, Michael; Fosselteder, Johannes; Hutterer, Georg C; Pichler, Martin; Stiegelbauer, Verena

    2017-11-22

    Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel-Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets.

  3. Treatment of multiple synchronous misdiagnosed renal cell cancers in a young patient affected by a "de novo" Von Hippel-Lindau syndrome.

    PubMed

    Allasia, Marco; Battaglia, Antonino; Pasini, Barbara; Gazzera, Carlo; Calandri, Marco; Bosio, Andrea; Gontero, Paolo; Destefanis, Paolo

    2017-02-28

    Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited syndrome occurring in one out of 36,000 live births. Diagnosis could be a challenge in patients with no familial VHL history. Renal cancer (RCC) represents one of the most important manifestations. RCC is usually recurrent and multifocal. Actually treating RCC in VHL patients represent a clinical dilemma: the oncological outcomes must be balanced against renal function preservation. A young man with a negative familial history was referred to our department with seven misdiagnosed renal masses. VHL disease was determined through genetic test. The multiple RCCs were treated by surgery and percutaneous thermal ablation by radiofrequency ablation (RFA) with complete control of RCC and no impairment of renal function. This case history confirms that VHL disease has to be suspected in young patients with evidence of synchronous multiple renal masses and in presence of specific clinical criteria.RFA appears to be safe in terms of oncological radicalism and in renal function preservation.In hereditary RCC, we should purpose, whenever it is possible, minimally invasive treatment in terms of low hospital stay and a minimal loss of renal tissue.

  4. Genetic and Pharmacological Strategies to Refunctionalize the von Hippel Lindau R167Q Mutant Protein

    PubMed Central

    Ding, Zhiyong; German, Peter; Bai, Shanshan; Reddy, A. Srinivas; Liu, Xian-De; Sun, Mianen; Zhou, Lijun; Chen, Xiaohua; Zhao, Xiaobei; Wu, Chengbiao; Zhang, Shuxing; Mills, Gordon B.; Jonasch, Eric

    2014-01-01

    Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations. PMID:24755468

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

    PubMed

    Wang, Wen-Chung; Chen, Hui-Ju; Shu, Wei-Pang; Tsai, Yi-Chang; Lai, Yen-Chein

    2011-10-01

    The von Hippel-Lindau (VHL) tumor suppressor gene located on chromosome 3p25-26 is implicated in VHL disease. Two informative single nucleotide polymorphisms are at positions 19 and 1149 on the nucleotide sequence from Gene Bank NM_000551. In this study we examined the allele frequencies at these two loci in the Taiwanese population and compared the results to those from European ethnic populations. The allele frequency was examined in 616 healthy individuals including 301 university students and 315 neonates. Both A/G polymorphisms were investigated using restriction fragment length polymorphism analysis created by restriction enzymes, BsaJ I and Acc I. Among these subjects, the allele frequencies at 19 SNP and 1149 SNP for variant G were 0.130 and 0.133, respectively. And these results were significant differences from those of the Caucasian populations. In addition, 90% of the tested subjects had identical genotypes at these two loci suggesting the existence of nonrandom association of alleles. 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. Copyright © 2011. Published by Elsevier B.V.

  6. Developmentally arrested structures preceding cerebellar tumors in von Hippel–Lindau disease

    PubMed Central

    Shively, Sharon B; Falke, Eric A; Li, Jie; Tran, Maxine G B; Thompson, Eli R; Maxwell, Patrick H; Roessler, Erich; Oldfield, Edward H; Lonser, Russell R; Vortmeyer, Alexander O

    2011-01-01

    There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel–Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma. However, in von Hippel–Lindau disease, hemangioblastomas are frequently observed in the cerebellum, suggesting an origin in the central nervous system. We performed a structural and topographic analysis of cerebellar tissues obtained from von Hippel–Lindau disease patients to identify and characterize developmentally arrested structural elements in the central nervous system. We examined the entire cerebella of five tumor-free von Hippel–Lindau disease patients and of three non-von Hippel–Lindau disease controls. In all, 9 cerebellar developmentally arrested structural elements were detected and topographically mapped in 385 blocks of von Hippel–Lindau disease cerebella. No developmentally arrested structural elements were seen in 214 blocks from control cerebella. Developmentally arrested structural elements are composed of poorly differentiated cells that express hypoxia-inducible factor (HIF)2α, but not HIF1α or brachyury, and preferentially involve the molecular layer of the dorsum cerebelli. For the first time, we identify and characterize developmentally arrested structural elements in the central nervous system of von Hippel–Lindau patients. We provide evidence that developmentally arrested structural elements in the cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer of the dorsum cerebelli. PMID:21499240

  7. Deletion of the von Hippel-Lindau Gene in Hemangioblasts Causes Hemangioblastoma-like Lesions in Murine Retina.

    PubMed

    Wang, Herui; Shepard, Matthew J; Zhang, Chao; Dong, Lijin; Walker, Dyvon; Guedez, Liliana; Park, Stanley; Wang, Yujuan; Chen, Shida; Pang, Ying; Zhang, Qi; Gao, Chun; Wong, Wai T; Wiley, Henry; Pacak, Karel; Chew, Emily Y; Zhuang, Zhengping; Chan, Chi-Chao

    2018-03-01

    von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. LOH of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl -Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl -Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl -mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histologic analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by "tumorlet" cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in "tumorlet" cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL. Significance: This study describes a model that phenotypically recapitulates a form of retinal pathogenesis that is driven by genetic loss of the VHL tumor suppressor, providing a useful tool for its study and therapeutic intervention. Cancer Res; 78(5); 1266-74. ©2018 AACR . ©2018 American Association for Cancer Research.

  8. Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development.

    PubMed

    Lange, Clemens A K; Luhmann, Ulrich F O; Mowat, Freya M; Georgiadis, Anastasios; West, Emma L; Abrahams, Sabu; Sayed, Haroon; Powner, Michael B; Fruttiger, Marcus; Smith, Alexander J; Sowden, Jane C; Maxwell, Patrick H; Ali, Robin R; Bainbridge, James W B

    2012-07-01

    Molecular oxygen is essential for the development, growth and survival of multicellular organisms. Hypoxic microenvironments and oxygen gradients are generated physiologically during embryogenesis and organogenesis. In the eye, oxygen plays a crucial role in both physiological vascular development and common blinding diseases. The retinal pigment epithelium (RPE) is a monolayer of cells essential for normal ocular development and in the mature retina provides support for overlying photoreceptors and their vascular supply. Hypoxia at the level of the RPE is closely implicated in pathogenesis of age-related macular degeneration. Adaptive tissue responses to hypoxia are orchestrated by sophisticated oxygen sensing mechanisms. In particular, the von Hippel-Lindau tumour suppressor protein (pVhl) controls hypoxia-inducible transcription factor (HIF)-mediated adaptation. However, the role of Vhl/Hif1a in the RPE in the development of the eye and its vasculature is unknown. In this study we explored the function of Vhl and Hif1a in the developing RPE using a tissue-specific conditional-knockout approach. We found that deletion of Vhl in the RPE results in RPE apoptosis, aniridia and microphthalmia. Increased levels of Hif1a, Hif2a, Epo and Vegf are associated with a highly disorganised retinal vasculature, chorioretinal anastomoses and the persistence of embryonic vascular structures into adulthood. Additional inactivation of Hif1a in the RPE rescues the RPE morphology, aniridia, microphthalmia and anterior vasoproliferation, but does not rescue retinal vasoproliferation. These data demonstrate that Vhl-dependent regulation of Hif1a in the RPE is essential for normal RPE and iris development, ocular growth and vascular development in the anterior chamber, whereas Vhl-dependent regulation of other downstream pathways is crucial for normal development and maintenance of the retinal vasculature.

  9. Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease.

    PubMed

    Knickelbein, Jared E; Jacobs-El, Naima; Wong, Wai T; Wiley, Henry E; Cukras, Catherine A; Meyerle, Catherine B; Chew, Emily Y

    2017-01-01

    To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling. Observational case review. Three patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate. Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits. Visual acuity, size of RCH, and degree of exudation. Three patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction. Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other

  10. Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease

    PubMed Central

    Knickelbein, Jared E.; Jacobs-El, Naima; Wong, Wai T.; Wiley, Henry E.; Cukras, Catherine A.; Meyerle, Catherine B.; Chew, Emily Y.

    2016-01-01

    Purpose To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling. Design Observational case review. Participants Three patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate. Methods Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits. Main Outcome Measures Visual acuity, size of RCH, and degree of exudation. Results Three patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction. Conclusions Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this

  11. 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

    PubMed Central

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

    2013-01-01

    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. PMID:23506478

  12. Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHL-haplotype analysis in patients with presumable congenital erythrocytosis.

    PubMed

    Cario, Holger; Schwarz, Klaus; Jorch, Norbert; Kyank, Ulrike; Petrides, Petro E; Schneider, Dominik T; Uhle, Renate; Debatin, Klaus-Michael; Kohne, Elisabeth

    2005-01-01

    Congenital erythrocytoses or polycythemias are rare and heterogeneous. A homozygous mutation (C598T->Arg200Trp) in the von Hippel-Lindau (VHL) gene was originally identified as the cause of the endemic Chuvash polycythemia. Subsequently this and other mutations in the VHL gene were also detected in several patients of different ethnic origin. Haplotype analyses of the VHL gene suggested a common origin for the Chuvash-type mutation. Thirty-four patients with presumable congenital erythrocytosis due to an unknown underlying disorder were examined for VHL gene mutations and VHL region haplotypes. Four patients were homozygous and one patient heterozygous for the Chuvash-type mutation. One additional patient presented a previously not described heterozygous mutation G311->T VHL in exon 1. The haplotype analyses were in agreement with recently published data for three of the four patients with homozygous mutations as well as for the patient with a heterozygous Chuvash-type mutation. One patient of Turkish origin with homozygous Chuvash-type mutation had a haplotype not previously found in individuals with Chuvash-type mutation. These results confirm that mutations in the VHL gene are responsible for a substantial proportion of patients with congenital erythrocytoses. Erythrocytoses due to a C598->T mutation of the VHL gene are not geographically restricted. The majority of patients with Chuvash polycythemia share a common VHL gene haplotype. The different haplotype in one of the patients with Chuvash-type mutation indicates that this mutation was not spread only from a single founder but developed independently in other individuals.

  13. Psychological impact of von Hippel-Lindau genetic screening in patients with a previous history of hemangioblastoma of the central nervous system.

    PubMed

    Rochette, Claire; Baumstarck, Karine; Canoni-Zattara, Hélène; Abdullah, Ahmad Esmaeel; Figarella-Branger, Dominique; Pertuit, Morgane; Barlier, Anne; Castinetti, Frédéric; Pacak, Karel; Metellus, Philippe; Taïeb, David

    2018-05-15

    Von Hippel-Lindau (VHL) syndrome is a hereditary cancer syndrome characterized by a high risk of developing benign and malignant tumors, including central nervous system hemangioblastomas (CNS HBs). For an early diagnosis of VHL, before the occurrence of cancers (especially renal cell carcinoma), it is of huge importance to initiate VHL genetic testing in at-risk patients. The aim of the study was to assess the psychological impact of VHL genetic testing in patients previously diagnosed with a CNS HB. From 1999 until 2015, 55 patients underwent surgery for CNS HBs. Eleven patients were already screened for VHL mutations and 3 patients deceased before the start of the study. From the remaining 42 patients, 24 were accepted to be enrolled in the study. Assessment of psychological impact of VHL genetic testing was performed by measuring anxiety levels, mood disorders, quality of life, and psychological consequences of genetic screening. Twenty-one of the enrolled 24 patients underwent VHL genetic testing and 12 patients came back for the communication of positive genetic results. The baseline psychological status did not differ between these 2 groups. Patients who attended the visit of communication of genetic results had similar anxiety levels compared to those who had not. Furthermore, they also experienced an improvement in the level of anxiety and two QoL dimension scores compared to their baseline status. In summary, there is no evidence of a negative psychosocial impact of VHL genetic testing in patients with a previous history of CNS HB. We, therefore, recommend the recall of patients who have not been previously screened.

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

    PubMed

    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.

  15. Constitutional von Hippel-Lindau (VHL) gene deletions detected in VHL families by fluorescence in situ hybridization.

    PubMed

    Pack, S D; Zbar, B; Pak, E; Ault, D O; Humphrey, J S; Pham, T; Hurley, K; Weil, R J; Park, W S; Kuzmin, I; Stolle, C; Glenn, G; Liotta, L A; Lerman, M I; Klausner, R D; Linehan, W M; Zhuang, Z

    1999-11-01

    von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited cancer syndrome predisposing to a variety of tumor types that include retinal hemangioblastomas, hemangioblastomas of the central nervous system, renal cell carcinomas, pancreatic cysts and tumors, pheochromocytomas, endolymphatic sac tumors, and epididymal cystadenomas [W. M. Linehan et al., J. Am. Med. Assoc., 273: 564-570, 1995; E. A. Maher and W. G. Kaelin, Jr., Medicine (Baltimore), 76: 381-391, 1997; W. M. Linehan and R. D. Klausner, In: B. Vogelstein and K. Kinzler (eds.), The Genetic Basis of Human Cancer, pp. 455-473, McGraw-Hill, 1998]. The VHL gene was localized to chromosome 3p25-26 and cloned [F. Latif et al., Science (Washington DC), 260: 1317-1320, 1993]. Germline mutations in the VHL gene have been detected in the majority of VHL kindreds. The reported frequency of detection of VHL germline mutations has varied from 39 to 80% (J. M. Whaley et al., Am. J. Hum. Genet., 55: 1092-1102, 1994; Clinical Research Group for Japan, Hum. Mol. Genet., 4: 2233-2237, 1995; F. Chen et al., Hum. Mutat., 5: 66-75, 1995; E. R. Maher et al., J. Med. Genet., 33: 328-332, 1996; B. Zbar, Cancer Surv., 25: 219-232, 1995). Recently a quantitative Southern blotting procedure was found to improve this frequency (C. Stolle et al., Hum. Mutat., 12: 417-423, 1998). In the present study, we report the use of fluorescence in situ hybridization (FISH) as a method to detect and characterize VHL germline deletions. We reexamined a group of VHL patients shown previously by single-strand conformation and sequencing analysis not to harbor point mutations in the VHL locus. We found constitutional deletions in 29 of 30 VHL patients in this group using cosmid and P1 probes that cover the VHL locus. We then tested six phenotypically normal offspring from four of these VHL families: two were found to carry the deletion and the other four were deletion-free. In addition, germline mosaicism of the VHL gene was identified in

  16. [A Case of Von Hippel-Lindau Disease with Nonfunctioning Pancreatic Neuroendocrine Tumors Treated by Duodenum-Preserving Resection of the Head of the Pancreas and Spleen-Preserving Resection of the Tail of the Pancreas].

    PubMed

    Umehara, Yutaka; Umehara, Minoru; Tokura, Tomohisa; Yachi, Takafumi; Takahashi, Kenichi; Morita, Takayuki; Hakamada, Kenichi

    2015-10-01

    A 26-year-old woman presented to our department with a diagnosis of multiple nonfunctioning pancreatic neuroendocrine tumors. She had a family history of pheochromocytoma and a medical history of bilateral adrenalectomy for pheochromocytoma at the age of 25 years. During follow-up treatment for adrenal insufficiency after the surgery, highly enhanced tumors in the pancreas were detected on contrast-enhanced CT. Other examinations found that the patient did not satisfy the clinical criteria for von Hippel-Lindau (VHL) disease. Considering her age and risk of developing multiple heterotopic and heterochronous tumors, we performed a duodenum-preserving resection of the head of the pancreas and spleen-preserving resection of the tail of the pancreas with informed consent. The histopathological findings revealed that all of the tumors were NET G1. She underwent genetic testing postoperatively and was diagnosed with VHL disease. This diagnosis meant that we were able to create an optimal treatment plan for the patient. If a tumor predisposition syndrome is suspected, VHL disease should be borne in mind and genetic testing after genetic counseling should be duly considered.

  17. Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein.

    PubMed

    Liu, Sheng-Jie; Wang, Jiang-Yi; Peng, Shuang-He; Li, Teng; Ning, Xiang-Hui; Hong, Bao-An; Liu, Jia-Yuan; Wu, Peng-Jie; Zhou, Bo-Wen; Zhou, Jing-Cheng; Qi, Nie-Nie; Peng, Xiang; Zhang, Jiu-Feng; Ma, Kai-Fang; Cai, Lin; Gong, Kan

    2018-03-29

    PurposeVon Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL).MethodsVHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.ResultsMissense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations.ConclusionThe modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.Genetics in Medicine advance online publication, 29 March 2018; doi:10.1038/gim.2017.261.

  18. Hydrogen Sulfide Inhibits Hypoxia- But Not Anoxia-Induced Hypoxia-Inducible Factor 1 Activation in a von Hippel-Lindau- and Mitochondria-Dependent Manner

    PubMed Central

    Kai, Shinichi; Tanaka, Tomoharu; Daijo, Hiroki; Harada, Hiroshi; Kishimoto, Shun; Suzuki, Kengo; Takabuchi, Satoshi; Takenaga, Keizo; Fukuda, Kazuhiko

    2012-01-01

    Abstract Aims: In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H2S) is an endogenously synthesized gaseous molecule that acts as an important signaling molecule in the living body. Transcription factor hypoxia-inducible factor 1 (HIF-1) is known to respond to intracellular reduced oxygen (O2) availability, which is regulated by an elaborate balance between O2 supply and demand. However, the effect of H2S on HIF-1 activity under hypoxic conditions is largely unknown in mammalian cells. In this study, we tried to elucidate the effect of H2S on hypoxia-induced HIF-1 activation adopting cultured cells and mice. Results: The H2S donors sodium hydrosulfide and sodium sulfide in pharmacological concentrations reversibly reduced cellular O2 consumption and inhibited hypoxia- but not anoxia-induced HIF-1α protein accumulation and expression of genes downstream of HIF-1 in established cell lines. H2S did not affect HIF-1 activation induced by the HIF-α hydroxylases inhibitors desferrioxamine or CoCl2. Experimental evidence adopting von Hippel-Lindau (VHL)- or mitochondria-deficient cells indicated that H2S did not affect neosynthesis of HIF-1α protein but destabilized HIF-1α in a VHL- and mitochondria-dependent manner. We also demonstrate that exogenously administered H2S inhibited HIF-1–dependent gene expression in mice. Innovation: For the first time, we show that H2S modulates intracellular O2 homeostasis and regulates activation of HIF-1 and the subsequent gene expression induced by hypoxia by using an in vitro system with established cell lines and an in vivo system in mice. Conclusions: We demonstrate that H2S inhibits hypoxia-induced HIF-1 activation in a VHL- and mitochondria-dependent manner. Antioxid. Redox Signal. 16, 203–216. PMID:22004513

  19. Genetic screening for von Hippel-Lindau gene mutations in non-syndromic pheochromocytoma: low prevalence and false-positives or misdiagnosis indicate a need for caution.

    PubMed

    Eisenhofer, G; Vocke, C D; Elkahloun, A; Huynh, T-T; Prodanov, T; Lenders, J W M; Timmers, H J; Benhammou, J N; Linehan, W M; Pacak, K

    2012-05-01

    Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs. © Georg Thieme Verlag KG Stuttgart · New York.

  20. The von Hippel-Lindau (VHL) tumor-suppressor gene is down-regulated by selenium deficiency in Caco-2 cells and rat colon mucosa.

    PubMed

    Uthus, Eric; Begaye, Adrienne; Ross, Sharon; Zeng, Huawei

    2011-08-01

    To test the hypothesis that selenium affects DNA methylation and hence gene regulation, we employed a methylation array (Panomics) in the human colonic epithelial Caco-2 cell model. The array profiles DNA methylation from promoter regions of 82 human genes. After conditioning cells to repeatedly reduced concentrations of fetal bovine serum, a serum-free culture was established. Se-methylselenocysteine (SeMSC) was added at 0 (deficient Se) or 250 (control Se) nM to cells maintained in DMEM. After 7 days, cells were collected and stored at -80 °C until analysis; experiments were replicated three times. Glutathione peroxidase activity was significantly decreased in cells grown in low SeMSC. Cells grown in 250 nM SeMSC had maximal GPx activity. Genomic DNA from cells grown in the low-SeMSC media and media containing 250 nM SeMSC was incubated with methylation-binding protein followed by isolation of methylated DNA. The methylated DNA was labeled with biotin and hybridized to the methylation array. Thus, genes with promoter methylation will produce a higher chemiluminescence signal than those genes with no promoter methylation. Of the genes profiled, the von Hippel-Lindau (VHL) gene was most different as indicated by quantification following chemiluminescence detection demonstrating that the promoter region of VHL was hypermethylated in cells from the low-SeMSC media. To determine whether promoter methylation affected transcription, we isolated RNA from replicate samples and performed real-time RT PCR. VHL (mRNA) was down-regulated (fold change significantly <1) in cells grown in low SeMSC compared to cells grown in 250 nM SeMSC (control; fold change = 1). We also show that (mRNA) Vhl expression is significantly reduced in mucosa from rats fed a diet deficient in Se. Our results suggest that low Se status affects DNA promoter region methylation and that this can result in down-regulation of the tumor suppressor gene VHL.

  1. Specific Inhibition of HER-2/neu Transcription Initiation

    DTIC Science & Technology

    2006-07-01

    normoxia due to posttranslational processing involving proline hy- droxylation and the von Hippel Lindau (VHL) protein, a multifunctional adapter...inducible factor 1 alpha; VHL, Von Hippel Lindau; HRE, hypoxia response element; VEGF, vascular endothelial growth factor; PI3K, phosphatidyl inositol...Biol. 13, 167-171. 3. Zhong, H., De Marzo, A. M., Laughner, E., Lim, M., Hilton , D. A., Zagzag, D., Buechler, P ., Isaacs, W. B., Semenza, G. L., and

  2. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma.

    PubMed

    Liang, Yingjian; Zheng, Tongsen; Song, Ruipeng; Wang, Jiabei; Yin, Dalong; Wang, Luoluo; Liu, Haitao; Tian, Lantian; Fang, Xiang; Meng, Xianzhi; Jiang, Hongchi; Liu, Jiaren; Liu, Lianxin

    2013-05-01

    The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world. Although sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects, currently sets the new standard for advanced HCC, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical if outcomes are to be improved. In this study we tested the hypothesis that hypoxia caused by the antiangiogenic effects of sustained sorafenib therapy could induce sorafenib resistance as a cytoprotective adaptive response, thereby limiting sorafenib efficiency. We found that HCCs, clinically resistant to sorafenib, exhibit increased intratumor hypoxia compared with HCCs before treatment or HCCs sensitive to sorafenib. Hypoxia protected HCC cells against sorafenib and hypoxia-inducible factor 1 (HIF-1α) was required for the process. HCC cells acquired increased P-gp expression, enhanced glycolytic metabolism, and increased nuclear factor kappa B (NF-κB) activity under hypoxia. EF24, a molecule having structural similarity to curcumin, could synergistically enhance the antitumor effects of sorafenib and overcome sorafenib resistance through inhibiting HIF-1α by sequestering it in cytoplasm and promoting degradation by way of up-regulating Von Hippel-Lindau tumor suppressor (VHL). Furthermore, we found that sustained sorafenib therapy led to increased intratumor hypoxia, which was associated with sorafenib sensitivity in HCC subcutaneous mice tumor models. The combination of EF24 and sorafenib showed synergistically effects against metastasis both in vivo and in vitro. Synergistic tumor growth inhibition effects were also observed in subcutaneous and orthotopic hepatic tumors. Hypoxia induced by sustained sorafenib treatment confers sorafenib resistance to HCC through HIF-1α and NF-κB activation. EF24 overcomes sorafenib resistance through VHL-dependent HIF-1

  3. Sporadic Hemangioblastoma Arising from the Infundibulum.

    PubMed

    Pakdaman, Michael N; Austin, Matthew J; Bannykh, Serguei; Pressman, Barry D

    2017-05-01

    Hemangioblastomas are rare vascular tumors most often found in the posterior fossa and cervical spinal cord and commonly associated with von Hippel-Lindau Disease. We report a case of sporadic hemangioblastoma in a patient without von Hippel-Lindau Disease. Imaging characteristics included a solid, suprasellar mass that was homogeneously enhancing. These findings most resembled a pituicytoma or choroid glioma because of the close association with the infundibulum and the homogeneous avid enhancement. Microscopically, the neoplasm was seen to be composed of vascular channels associated with foamy stromal cells, containing clear cytoplasmic vacuoles. Microscopic and immunohistochemical findings were consistent with hemangioblastoma. Hemangioblastomas are a rare form of vascular tumor most commonly associated with von-Hippel Lindau disease. Our finding of non-cystic hemangioblastoma arising from the infundibulum demonstrates that, while rare, hemangioblastomas should be considered on the differential diagnosis for an avidly enhancing suprasellar mass.

  4. Sporadic Hemangioblastoma Arising from the Infundibulum

    PubMed Central

    Pakdaman, Michael N; Austin, Matthew J; Bannykh, Serguei; Pressman, Barry D

    2017-01-01

    Hemangioblastomas are rare vascular tumors most often found in the posterior fossa and cervical spinal cord and commonly associated with von Hippel-Lindau Disease. We report a case of sporadic hemangioblastoma in a patient without von Hippel-Lindau Disease. Imaging characteristics included a solid, suprasellar mass that was homogeneously enhancing. These findings most resembled a pituicytoma or choroid glioma because of the close association with the infundibulum and the homogeneous avid enhancement. Microscopically, the neoplasm was seen to be composed of vascular channels associated with foamy stromal cells, containing clear cytoplasmic vacuoles. Microscopic and immunohistochemical findings were consistent with hemangioblastoma. Hemangioblastomas are a rare form of vascular tumor most commonly associated with von-Hippel Lindau disease. Our finding of non-cystic hemangioblastoma arising from the infundibulum demonstrates that, while rare, hemangioblastomas should be considered on the differential diagnosis for an avidly enhancing suprasellar mass. PMID:29299088

  5. Von Hippel-Lindau Syndrome

    MedlinePlus

    ... examination to look for retinal tumors, beginning around age 2 Yearly physical examination Yearly blood test and/or 24-hour urine test to screen for elevated catecholamines, beginning around age 5 Yearly abdominal ultrasound to look at the ...

  6. [Papillary cystadenoma of the epididymis. 2 case reports].

    PubMed

    Raimoldi, A; Berti, G L; Canclini, L; Giola, V; Leidi, G L; Maccaroni, A; Sironi, M; Veneroni, L; Bacchioni, A M; Assi, A

    1997-12-01

    Tumors of the epididymis are very rare. They are benign tumors in 75 per cent of the cases. Papillary cystadenoma represents 4-9 per cent of epididymal benign tumors. Often associated with the syndrome of von Hippel Lindau and infertility, histologically it can be confused with metastatic renal cell carcinoma. We report two cases of papillary cystadenoma located in the head of the right epididymis, with no concomitance with the syndrome of von Hippel Lindau, cured by the removal of the neoplastic nodule. There was no recidivation, in confirmation of the neoplastic benignity.

  7. Von Hippel-Lindau Disease (VHL)

    MedlinePlus

    ... tumors can be treated with focused high-dose irradiation. Individuals with VHL need careful monitoring by a ... tumors can be treated with focused high-dose irradiation. Individuals with VHL need careful monitoring by a ...

  8. Extraneuraxial hemangioblastoma: A clinicopathologic study of 10 cases with molecular analysis of the VHL gene.

    PubMed

    Muscarella, Lucia Anna; Bisceglia, Michele; Galliani, Carlos A; Zidar, Nina; Ben-Dor, David Jonathan; Pasquinelli, Gianandrea; la Torre, Annamaria; Sparaneo, Angelo; Fanburg-Smith, Julie C; Lamovec, Janez; Michal, Michal; Bacchi, Carlos E

    2018-05-29

    Less than 250 extraneuraxial hemangioblastomas occurring in paraneuraxial or peripheral sites have been reported to date, sporadically or in the setting of von Hippel-Lindau disease. Seventeen such cases underwent molecular genetic analysis, using either the patient's peripheral blood in 9 cases or paraffin embedded tumor tissue in the rest. VHL gene mutations were documented in 3/9 cases in which DNA from peripheral blood lymphocytes was used, all with clinically manifest von Hippel-Lindau disease; instead, no VHL gene alterations were found in all of the 8 cases with sporadic extraneuraxial hemangioblastoma in which DNA from tumor tissue was analyzed. Our aim is to investigate the molecular genetic profile of the VHL gene in extraneuraxial hemangioblastoma using paraffin embedded tumor tissues. The clinical features, histopathology, and molecular investigations of 10 extraneuraxial hemangioblastomas (7 females, 3 males; median age: 47 years) are presented herein. The histopathologic diagnosis was supported by immunohistochemistry (10/10) and electron microscopy (4/10). Molecular genetic analysis was conducted (10/10) for VHL gene mutations, LOH, and gene promoter methylation. Two of the present cases were already published with only limited or no molecular investigations. Four tumors of the present series were paraneuraxial, and 6 peripheral (2 involved soft tissues, and 4 the kidney). One tumor was von Hippel-Lindau disease-associated, 1 was classified as "hemangioblastoma-only VHLD", 7 were sporadic, and one was unknown. All were histopathologically analogous to their counterpart located inside the central nervous system. Immunophenotypically, all tumors expressed vimentin, S-100, NSE, and alpha-inhibin (10/10). Ultrastructurally, unbound lipid droplets filled the cytoplasms of the stromal cells. Molecular analysis revealed 3 inactivating mutations (1 germline, two somatic) in the coding sequence of the VHL gene in 2 different extraneuraxial hemangioblastomas

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

    ClinicalTrials.gov

    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. von Hippel–Lindau binding protein 1-mediated degradation of integrase affects HIV-1 gene expression at a postintegration step

    PubMed Central

    Mousnier, Aurélie; Kubat, Nicole; Massias-Simon, Aurélie; Ségéral, Emmanuel; Rain, Jean-Christophe; Benarous, Richard; Emiliani, Stéphane; Dargemont, Catherine

    2007-01-01

    HIV-1 integrase, the viral enzyme responsible for provirus integration into the host genome, can be actively degraded by the ubiquitin–proteasome pathway. Here, we identify von Hippel–Lindau binding protein 1(VBP1), a subunit of the prefoldin chaperone, as an integrase cellular binding protein that bridges interaction between integrase and the cullin2 (Cul2)-based von Hippel–Lindau (VHL) ubiquitin ligase. We demonstrate that VBP1 and Cul2/VHL are required for proper HIV-1 expression at a step between integrase-dependent proviral integration into the host genome and transcription of viral genes. Using both an siRNA approach and Cul2/VHL mutant cells, we show that VBP1 and the Cul2/VHL ligase cooperate in the efficient polyubiquitylation of integrase and its subsequent proteasome-mediated degradation. Results presented here support a role for integrase degradation by the prefoldin–VHL–proteasome pathway in the integration–transcription transition of the viral replication cycle. PMID:17698809

  11. Spinal Cord Tumor

    MedlinePlus

    ... are linked to known inherited syndromes, such as neurofibromatosis 2 and von Hippel-Lindau disease. Risk factors ... tumors are more common in people who have: Neurofibromatosis 2. In this hereditary disorder, benign tumors develop ...

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

    PubMed Central

    Xue, Xin; Zhao, Ning-Yi; Yu, Hai-Tao; Sun, Yuan; Kang, Chen; Huang, Qiong-Bin; Sun, Hao-Peng

    2016-01-01

    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. PMID:27994971

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

    Cancer.gov

    Genetics of Kidney Cancer (Renal Cell) includes the hereditary cancer syndromes von Hippel-Lindau disease, hereditary leiomyomatosis and renal cell cancer, Birt-Hogg-Dubé syndrome, and hereditary papillary renal carcinoma. Get comprehensive information on these syndromes in this clinician summary.

  14. Pazopanib therapy for cerebellar hemangioblastomas in von Hippel–Lindau disease

    PubMed Central

    Kim, Betty Y. S.; Jonasch, Eric

    2016-01-01

    von Hippel–Lindau (VHL) disease is a genetically acquired multisystem tumor syndrome of the viscera and central nervous system (CNS). The most common tumors associated with this disease are histologically benign, slow-growing CNS hemangioblastomas affecting the retina, cerebellum, brainstem, spinal cord or nerve roots. With mean age at diagnosis of 30 years, CNS hemangioblastomas are usually the first manifestation of the disease. Ongoing clinical and radiological surveillance is required, with symptomatic lesions necessitating treatment. As tumor growth is inevitable during the lifetime of most VHL patients, and the multiplicity of tumors may preclude surgical cure, the search for effective therapies is ongoing. Here we provide the first report demonstrating clinical and radiological anti-tumor response using pazopanib, a small molecule multi-receptor tyrosine kinase inhibitor, in a patient with treatment-refractory VHL-associated CNS hemangioblastoma. Treatment initiation with daily oral pazopanib (800 mg/day) resulted in significant neurologic improvement and radiologic tumor volume reduction. PMID:22374327

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

    Cancer.gov

    Hereditary kidney 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 kidney cancer syndromes in this expert-reviewed summary.

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

    PubMed

    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.

  17. Mutation of von Hippel–Lindau Tumour Suppressor and Human Cardiopulmonary Physiology

    PubMed Central

    Smith, Thomas G; Brooks, Jerome T; Balanos, George M; Lappin, Terence R; Layton, D. Mark; Leedham, Dawn L; Liu, Chun; Maxwell, Patrick H; McMullin, Mary F; McNamara, Christopher J; Percy, Melanie J; Pugh, Christopher W; Ratcliffe, Peter J; Talbot, Nick P; Treacy, Marilyn; Robbins, Peter A

    2006-01-01

    Background The von Hippel–Lindau tumour suppressor protein–hypoxia-inducible factor (VHL–HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL–HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL–HIF pathway in systemic human cardiopulmonary physiology. Methods and Findings Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. Conclusions The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF. PMID:16768548

  18. [Cystic renal neoplasms. New entities and molecular findings].

    PubMed

    Moch, H

    2010-10-01

    Renal neoplasms with dominant cysts represent a broad spectrum of known as well as novel renal tumor entities. Established renal tumors with dominant cysts include cystic nephroma, mixed epithelial and stromal tumor, synovial sarcoma and multilocular cystic renal cancer (WHO classification 2004). Novel tumor types have recently been reported, which are also characterized by marked cyst formation. Examples are tubulocystic renal cancer and renal cancer in end-stage renal disease. These tumors are very likely to be included in a future WHO classification due to their characteristic phenotype and molecular features. Cysts and clear cell renal cell carcinoma frequently coexist in the kidneys of patients with von Hippel-Lindau disease. Cysts are also a component of many sporadic clear cell renal cell carcinomas. Multilocular cystic renal cell carcinoma is composed almost exclusively of cysts and is regarded as a specific subtype of clear cell renal cancer. Recent molecular findings suggest that clear cell renal cancer may develop via a cyst-dependent mechanism in von Hippel-Lindau syndrome as well as via cyst-independent molecular pathways in sporadic clear cell renal cancer.

  19. Dysregulation of HIF2α and autophagy in renal cell carcinoma

    PubMed Central

    Liu, Xian-De; Zhu, Haifeng; DePavia, Adela; Jonasch, Eric

    2015-01-01

    Our recent study shows that autophagy collaborates with proteasomes to degrade endothelial PAS domain-containing protein 1 (EPAS1, also known as HIF2α) in a manner dependent on Von Hippel-Lindau (VHL) and sequestosome 1 (SQSTM1/p62). The genetic dysregulation of autophagy is a common feature of different subtypes of renal cell carcinoma (RCC). PMID:27308417

  20. Edema is a precursor to central nervous system peritumoral cyst formation.

    PubMed

    Lonser, Russell R; Vortmeyer, Alexander O; Butman, John A; Glasker, Sven; Finn, Michael A; Ammerman, Joshua M; Merrill, Marsha J; Edwards, Nancy A; Zhuang, Zhengping; Oldfield, Edward H

    2005-09-01

    Despite the common occurrence and frequent clinical effects of peritumoral cysts in the central nervous system (CNS), the mechanism underlying their development and evolution is not understood. Because they commonly produce peritumoral cysts and because serial magnetic resonance imaging (MRI) is obtained in von Hippel-Lindau disease patients, hemangioblastomas provide an opportunity to examine the pathophysiology of CNS peritumoral cyst formation. Serial MRI was correlated with the clinical findings in 16 von Hippel-Lindau disease patients with 22 CNS hemangioblastomas (11 spinal cord; 11 cerebellar) that were associated with the appearance and evolution of peritumoral cysts. Hemangioblastoma-associated cyst wall histomorphological analysis was performed on postmortem tissues from three von Hippel-Lindau disease patients (not in the clinical series). Comparative proteomic profiling was performed on peritumoral cyst fluid and serum. Vascular endothelial growth factor levels were determined in peritumoral cysts. MRI clearly showed peritumoral edema that developed and slowly and progressively evolved into enlarging hemangioblastoma-associated cysts in all tumors (mean follow-up, 130 +/- 38 months; mean +/- standard deviation). Postcontrast MRI demonstrated convective leakage of gadolinium into cysts. Mean time required for edema to evolve into a cyst was 36 +/- 23 months (range, 8-72 months). Thirteen (59%) hemangioblastoma-cysts became symptomatic (mean time to symptom formation after cyst development, 35 +/- 32 months; range, 3-102 months) and required resection. Protein profiles of cyst fluid and serum were similar. Mean cyst fluid vascular endothelial growth factor concentration was 1.5 ng/ml (range, 0-5.4 ng/ml). Histology of the cyst walls was consistent with reactive gliosis. CNS peritumoral cyst formation is initiated by increased tumor vascular permeability, increased interstitial pressure in the tumor, and plasma extravasation with convective distribution

  1. Classification and management of hereditary retinal angiomas.

    PubMed

    Augsburger, J J; Shields, J A; Goldberg, R E

    1981-08-01

    Two distinct types of retinal angiomas are currently recognized. Capillary hemangiomas occur most characteristically as part of the von Hippel-Lindau syndrome. The retinal capillary hemangiomas typically appear as globular red-orange tumors with dilated and tortuous afferent arterioles and efferent venules. Cavernous hemangiomas typically appear as grape-like clusters of dilated vascular sacs without pronounced alteration in the adjacent arterioles and venules. The spectrum of clinical features of these two types of hemangiomatosis and current approaches to management of patients with these disorders is reviewed.

  2. Different Angiogenic Potential in Low and High Grade Sporadic Clear Cell Renal Cell Carcinoma Is Not Related to Alterations in the von Hippel–Lindau Gene

    PubMed Central

    Baldewijns, Marcella M.; van Vlodrop, Iris J. H.; Smits, Kim M.; Vermeulen, Peter B.; Van den Eynden, Gert G.; Schot, Fiona; Roskams, Tania; van Poppel, Hein; van Engeland, Manon; de Bruïne, Adriaan P.

    2009-01-01

    Background: von Hippel–Lindau (VHL) inactivation is common in sporadic clear cell renal cell carcinomas (ccRCC). pVHL is part of the ubiquitin ligase complex that targets the alpha subunits of hypoxia-inducible transcription factor (HIF) for degradation under well-oxygenated conditions. In the absence of wild-type pVHL, as observed in VHL patients and most sporadic ccRCCs, constitutive upregulation of HIF results in transcriptional activation of angiogenesis-related genes, such as VEGF. Differences in angiogenic activity within the group of ccRCCs were reported and strong genotype-phenotype correlations were found in patients with VHL disease, raising a question about the importance of VHL inactivation status in angiogenic behaviour and tumour progression. Methods: To address this question, we investigated the influence of VHL mutation (direct sequencing)/hypermethylation (methylation-specific PCR) on angiogenesis/tumour parameters (immunohistochemistry) in 150 patients with sporadic ccRCC. Results: We found no significant association between VHL mutation or methylation and angiogenesis/tumour parameters. Conclusions: These data indicate that tumour progression and angiogenesis are not directly influenced by VHL alterations and that additional genetic/epigenetic events should be considered to explain the diverse angiogenic and proliferative behaviour during tumour progression. PMID:19759417

  3. The Opposing Roles of Nucleophosmin and the ARF Tumor Suppressor in Breast Cancer

    DTIC Science & Technology

    2007-04-01

    P ., R. K. Busch, B. C. Valdez, and H. Busch. 1996 . C23 interacts with B23, a putative nucleolar...beneficial anti-cancer activity of peptides in vivo. Injection of a peptide from the von Hippel -Lindau (VHL) tumor suppressor inhibited the growth and... 240 WT Arf -/- 1 2 3 4 5 0 C y to s o lic 3 H -M e th y l M e th io n in e c p m ( x 1 0 3 ) A 28S 18S WT chase (min): Arf -/- 120 240 120 240 N

  4. Prognostic and predictive value of VHL gene alteration in renal cell carcinoma: a meta-analysis and review.

    PubMed

    Kim, Bum Jun; Kim, Jung Han; Kim, Hyeong Su; Zang, Dae Young

    2017-02-21

    The von Hippel-Lindau (VHL) gene is often inactivated in sporadic renal cell carcinoma (RCC) by mutation or promoter hypermethylation. The prognostic or predictive value of VHL gene alteration is not well established. We conducted this meta-analysis to evaluate the association between the VHL alteration and clinical outcomes in patients with RCC. We searched PUBMED, MEDLINE and EMBASE for articles including following terms in their titles, abstracts, or keywords: 'kidney or renal', 'carcinoma or cancer or neoplasm or malignancy', 'von Hippel-Lindau or VHL', 'alteration or mutation or methylation', and 'prognostic or predictive'. There were six studies fulfilling inclusion criteria and a total of 633 patients with clear cell RCC were included in the study: 244 patients who received anti-vascular endothelial growth factor (VEGF) therapy in the predictive value analysis and 419 in the prognostic value analysis. Out of 663 patients, 410 (61.8%) had VHL alteration. The meta-analysis showed no association between the VHL gene alteration and overall response rate (relative risk = 1.47 [95% CI, 0.81-2.67], P = 0.20) or progression free survival (hazard ratio = 1.02 [95% CI, 0.72-1.44], P = 0.91) in patients with RCC who received VEGF-targeted therapy. There was also no correlation between the VHL alteration and overall survival (HR = 0.80 [95% CI, 0.56-1.14], P = 0.21). In conclusion, this meta-analysis indicates that VHL gene alteration has no prognostic or predictive value in patients with clear cell RCC.

  5. Prognostic and predictive value of VHL gene alteration in renal cell carcinoma: a meta-analysis and review

    PubMed Central

    Kim, Bum Jun; Kim, Jung Han; Kim, Hyeong Su; Zang, Dae Young

    2017-01-01

    The von Hippel-Lindau (VHL) gene is often inactivated in sporadic renal cell carcinoma (RCC) by mutation or promoter hypermethylation. The prognostic or predictive value of VHL gene alteration is not well established. We conducted this meta-analysis to evaluate the association between the VHL alteration and clinical outcomes in patients with RCC. We searched PUBMED, MEDLINE and EMBASE for articles including following terms in their titles, abstracts, or keywords: ‘kidney or renal’, ‘carcinoma or cancer or neoplasm or malignancy’, ‘von Hippel-Lindau or VHL’, ‘alteration or mutation or methylation’, and ‘prognostic or predictive’. There were six studies fulfilling inclusion criteria and a total of 633 patients with clear cell RCC were included in the study: 244 patients who received anti-vascular endothelial growth factor (VEGF) therapy in the predictive value analysis and 419 in the prognostic value analysis. Out of 663 patients, 410 (61.8%) had VHL alteration. The meta-analysis showed no association between the VHL gene alteration and overall response rate (relative risk = 1.47 [95% CI, 0.81-2.67], P = 0.20) or progression free survival (hazard ratio = 1.02 [95% CI, 0.72-1.44], P = 0.91) in patients with RCC who received VEGF-targeted therapy. There was also no correlation between the VHL alteration and overall survival (HR = 0.80 [95% CI, 0.56-1.14], P = 0.21). In conclusion, this meta-analysis indicates that VHL gene alteration has no prognostic or predictive value in patients with clear cell RCC. PMID:28103578

  6. New lessons from an old gene: complex splicing and a novel cryptic exon in VHL gene cause erythrocytosis and VHL disease.

    PubMed

    Lenglet, Marion; Robriquet, Florence; Schwarz, Klaus; Camps, Carme; Couturier, Anne; Hoogewijs, David; Buffet, Alexandre; Knight, Samantha Jl; Gad, Sophie; Couvé, Sophie; Chesnel, Franck; Pacault, Mathilde; Lindenbaum, Pierre; Job, Sylvie; Dumont, Solenne; Besnard, Thomas; Cornec, Marine; Dreau, Helene; Pentony, Melissa; Kvikstad, Erika; Deveaux, Sophie; Burnichon, Nelly; Ferlicot, Sophie; Vilaine, Mathias; Mazzella, Jean-Michaël; Airaud, Fabrice; Garrec, Céline; Heidet, Laurence; Irtan, Sabine; Mantadakis, Elpis; Bouchireb, Karim; Debatin, Klaus-Michael; Redon, Richard; Bezieau, Stéphane; Bressac-de Paillerets, Brigitte; Teh, Bin Tean; Girodon, François; Randi, Maria-Luigia; Putti, Maria Caterina; Bours, Vincent; Van Wijk, Richard; Göthert, Joachim R; Kattamis, Antonis; Janin, Nicolas; Bento, Celeste; Taylor, Jenny C; Arlot-Bonnemains, Yannick; Richard, Stéphane; Gimenez-Roqueplo, Anne-Paule; Cario, Holger; Gardie, Betty

    2018-06-11

    Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. Since this discovery, additional VHL mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. VHL is a major tumor suppressor gene, mutations in which were first described in patients presenting with von Hippel-Lindau disease, which is characterized by the development of highly vascularized tumors. Here, we identified a new VHL cryptic-exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identified mutations in E1' in seven families with erythrocytosis (one homozygous case and six compound-heterozygous cases with a mutation in E1' in addition to a mutation in VHL coding sequences) and in one large family with typical VHL disease but without any alteration in the other VHL exons. In this study we have shown that the mutations induced a dysregulation of the VHL splicing with excessive retention of E1' and are associated with a downregulation of VHL protein expression. In addition, we have demonstrated a pathogenic role for synonymous mutations in VHL-Exon 2 that alter splicing through E2-skipping in five families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially impact splicing, correlating with phenotype severity. This study demonstrates that cryptic-exon-retention or exon-skipping are new VHL alterations and reveals a novel complex splicing regulation of the VHL gene. These findings open new avenues for diagnosis and research into the VHL-related-hypoxia-signaling pathway. Copyright © 2018 American Society of Hematology.

  7. Status Epilepticus Secondary to Pseudonodular Hemorragic Occipital Lesion with Edema: "Non Semper Ea Sunt, Quae Videntur, Decipit Frons Prima Multos" (Things Are Not Always What They Seem; The First Appearance Deceives Many).

    PubMed

    Nasi, Davide; Servadei, Franco; Romano, Antonio

    2017-08-01

    We report a case in which common radiologic images masked a rare case of supratentorial hemangioblastoma (HBL). Other peculiarities of this case are the clinical presentation with status epilepticus and the occurrence of a supratentorial HBL unrelated to von Hippel-Lindau syndrome. Based on clinical and radiologic findings, including massive cerebral edema and hemorrhagic presentation, our preoperative diagnosis was a cerebral metastasis. In this scenario, physicians must take into account the words of the Roman fabulist Phaedrus: "Non semper ea sunt, quae videntur, decipit frons prima multos" (things are not always what they seem; the first appearance deceives many). Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Impact of Genetics on the Diagnosis and Treatment of Renal Cancer

    PubMed Central

    Singer, Eric A.; Bratslavsky, Gennady; Middelton, Lindsay; Srinivasan, Ramaprasad; Linehan, W. Marston

    2011-01-01

    Kidney cancer is a heterogeneous disease comprised of a number of histologic subtypes, each associated with unique genetic mutations, clinical features, and sensitivity to treatment. By examining families affected with the hereditary kidney cancer syndromes von Hippel-Lindau, hereditary papillary renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma, and Birt-Hogg-Dube', researchers have been able to identify the genes responsible for these syndromes. This work has revealed that kidney cancer is fundamentally a metabolic disorder, and as such, novel targeted therapies specific to their molecular biology have been developed and employed in both the hereditary and sporadic forms of renal cell carcinoma. PMID:21128028

  9. Renal Cell Carcinoma in a Young Adult – Do We Need Further Investigations?

    PubMed Central

    Walter, Matthias; Wetterauer, Christian; Bruder, Elisabeth; Obermann, Ellen C.; Subotic, Svetozar; Wyler, Stephen

    2016-01-01

    Renal cell carcinomas (RCC), mostly occurring in adults aged 60–70 years, can result from well-known factors like cigarette smoking, obesity and hypertension. However, they have been associated with genetic alterations in children and young adults. A 28 year-old male patient with a confirmed RCC underwent biomolecular and immunohistochemical analyses due to his young age. A point mutation of the von Hippel-Lindau tumor suppressor gene was identified. Young patients under 40 years with diagnosed RCC should undergo additional diagnostic investigation, hence the discovery of an underlying cause. This could be important for further treatment and counseling of these young patients. PMID:27169022

  10. pVHL's kryptonite: E2-EPF UCP.

    PubMed

    Ohh, Michael

    2006-08-01

    E2-EPF ubiquitin carrier protein (UCP) is a member of an E2 family of enzymes that catalyzes the ligation of ubiquitin to proteins targeted for destruction by the proteasome. UCP is overexpressed in common human cancers, suggesting its involvement in oncogenesis, but a physiologic target of UCP has not been identified. In a recent report published in Nature Medicine, Jung et al. identified von Hippel-Lindau (VHL) tumor suppressor protein, which targets the alpha subunit of hypoxia-inducible factor (HIF) for ubiquitin-mediated destruction, as a bona fide substrate of UCP and demonstrated a potential pVHL-HIF pathway-dependent role for UCP in cancer development.

  11. The Opposing Roles of Nucleophosmin and the ARF Tumor Suppressor in Breast Cancer

    DTIC Science & Technology

    2006-04-01

    born to be weak. Trends Cell Biol. 15:121–124. 26. Li, Y. P ., R. K. Busch, B. C. Valdez, and H. Busch. 1996 . C23 interacts with B23, a putative...peptides in vivo. Injection of a peptide from the von Hippel -Lindau (VHL) tumor suppressor inhibited the growth and invasiveness of renal tumor...NPM IB: NPM IB: p19ARF 1° 2° 3° 4° 5° s up er na ta nt 2 5 % i n p u t 28S 18S WT Arf -/- 120 240 120 240chase (min) N C N CN C N C

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

    PubMed

    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.

  13. BIlateral juxtapapillary retinal capillary haemangioma: Usefulness of aflibercept in the management of its complications.

    PubMed

    Campos Polo, R; Rubio Sánchez, C; García Guisado, D M; Díaz Luque, M J

    2017-10-01

    A 45 year-old man with a history of adrenal phaeochromocytoma presented with a subretinal juxtapapillary haemorrhage on his left eye and a small asymptomatic vascular tumour in the contralateral eye. With the mentioned findings, the patient was diagnosed with bilateral retinal capillary haemangioma in the context of a von Hippel Lindau disease. Intravitreal aflibercept was prescribed, with a good outcome of the disease. Many treatments have been proposed for the management of juxtapapillary retinal capillary haemangioma with variable results. Intravitreal aflibercept can be a useful treatment with a good safety profile. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  14. A HIF-1alpha-related gene involved in cell protection from hypoxia by suppression of mitochondrial function.

    PubMed

    Kakinuma, Yoshihiko; Katare, Rajesh G; Arikawa, Mikihiko; Muramoto, Kazuyo; Yamasaki, Fumiyasu; Sato, Takayuki

    2008-01-23

    Recently, we reported that acetylcholine-induced hypoxia-inducible factor-1alpha protects cardiomyocytes from hypoxia; however, the downstream factors reducing hypoxic stress are unknown. We identified apoptosis inhibitor (AI) gene as being differentially expressed between von Hippel Lindau (VHL) protein-positive cells with high levels of GRP78 expression and VHL-negative cells with lower GRP levels, using cDNA subtraction. AI decreased GRP78 level, suppressed mitochondrial function, reduced oxygen consumption and, ultimately, suppressed hypoxia-induced apoptosis. By contrast, knockdown of the AI gene increased mitochondrial function. Hypoxic cardiomyocytes and ischemic myocardium showed increased AI mRNA expression. These findings suggest that AI is involved in suppressing mitochondrial function, thereby leading to cellular stress eradication and consequently to protection during hypoxia.

  15. International workshop on chromosome 3. Final report, April 15, 1991--April 14, 1992

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gemmill, R.M.

    1992-07-01

    The Second Workshop on Human Chromosome 3 was held on April 4--5, 1991 at Denver, Colorado. There were 43 participants representing 8 nations. The workshop participants reviewed the current state of the chromosome 3 map, both physical and genetic, and prepared lists of markers and cell lines to be made commonly available. These markers and cell lines should be incorporated into the mapping efforts of diverse groups to permit the integration of data and development of consensus maps at future workshops. Region specific efforts were described for sections of the chromosome harboring genes thought to be involved in certain diseasesmore » including Von Hippel-Lindau disease, 3p-syndrome, lung cancer and renal cancer. Selected papers have been processed separately for inclusion in the Energy Science and Technology Database.« less

  16. Familial Renal Cancer: Molecular Genetics and Surgical Management

    PubMed Central

    Barrisford, Glen W.; Singer, Eric A.; Rosner, Inger L.; Linehan, W. Marston; Bratslavsky, Gennady

    2011-01-01

    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. PMID:22312516

  17. VHL and Hypoxia Signaling: Beyond HIF in Cancer

    PubMed Central

    Zhang, Jing

    2018-01-01

    Von Hippel-Lindau (VHL) is an important tumor suppressor that is lost in the majority of clear cell carcinoma of renal cancer (ccRCC). Its regulatory pathway involves the activity of E3 ligase, which targets hypoxia inducible factor α (including HIF1α and HIF2α) for proteasome degradation. In recent years, emerging literature suggests that VHL also possesses other HIF-independent functions. This review will focus on VHL-mediated signaling pathways involving the latest identified substrates/binding partners, including N-Myc downstream-regulated gene 3 (NDRG3), AKT, and G9a, etc., and their physiological roles in hypoxia signaling and cancer. We will also discuss the crosstalk between VHL and NF-κB signaling. Lastly, we will review the latest findings on targeting VHL signaling in cancer. PMID:29562667

  18. Familial Investigations of Childhood Cancer Predisposition

    ClinicalTrials.gov

    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

  19. Joint Capabilities for Post-Conflict Operations

    DTIC Science & Technology

    2004-05-01

    Political Geography (NY: John Wiley & Sons, 1989), 37. 2 Karin von Hippel , “Democracy by Force: A Renewed Commitment to Nation Building,” The...fear. Democratic states are vital to international security. In an article adapted from her book, Democracy by Force, Karin von Hippel , a civil...Parameters 33 (Autumn 2003) 101. 5 Karin von Hippel , “Democracy by Force: A Renewed Commitment to Nation Building,” The Washington Quarterly 23 (Winter

  20. Von Hippel–Lindau and myotonic dystrophy of Steinert along with pancreatic neuroendocrine tumor and renal clear cell carcinomal neoplasm: Case report and review of the literature

    PubMed Central

    Addeo, A.; Bini, R.; Viora, T.; Bonaccorsi, L.; Leli, R.

    2013-01-01

    INTRODUCTION Myotonic dystrophy of Steinert, DM1, is the most common adult muscular dystrophy and generally is not associated to development on multiple site neoplasm. Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome that is associated to tumors such as hemangioblastoma of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. No data exist in literature describing the coexistence of both DM1 and VHL. PRESENTATION OF CASE Herein we report a case of renal and pancreatic neoplasm in a young adult female affected by DM1 and VHL simultaneously. DISCUSSION DM1 is due to an unstable trinucleotide (CTG) expansion in the 30 antranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, located on chromosome 19q13.3. Several molecular mechanisms thought to be determining the classical DM phenotype have been shown. VHL disease is characterized by marked phenotypic variability and the most common tumors are hemangioblastomas of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. The pancreatic manifestations seen in patients with VHL disease are divided into 2 categories: pancreatic neuroendocrine tumor (PNET) as solid tumors, and cystic lesions, including a simple cyst and serous cystadenoma. The surgical approach for these cistic lesions is to consider as golden standard. Blansfield has proposed 3 criteria to predict metastatic disease of PNET in patients with VHL disease: (1) tumor size greater than or equal to 3 cm; (2) presence of a mutation in exon 3; and (3) tumor doubling time less than 500 d. If the patient has none of these criteria the patient could be followed with physical examination and radiological surveillance on a 2/3 years base.4 If the patient has 1 criterion, the patient

  1. Recurrent hemorrhage in hemangioblastoma involving the posterior fossa: Case report

    PubMed Central

    Marvin, Eric; Akhter, Asad S.; Coppens, Jeroen R.

    2017-01-01

    Background: Hemangioblastomas (HGBs) are the most common primary intra-axial posterior fossa tumor in adults. Although spontaneous hemorrhage of these tumors is exceedingly rare, despite their vascular nature, we describe a case of recurrent hemorrhage with associated tonsillar herniation, and demonstrate that a surgical approach can provide a suitable outcome. Case Description: A 54-year-old female with von Hippel-Lindau (VHL) syndrome presented with acute loss of consciousness and Glasgow Coma Scale (GCS) was 4. Computed tomographic (CT) images demonstrated large volume subarachnoid hemorrhage of the posterior fossa with intraventricular extension and intraparenchymal hemorrhage involving the right cerebellar tonsil. Magnetic resonance imaging (MRI) displayed three lesions in the posterior fossa, two near the hemorrhage site. Patient underwent suboccipital craniectomy with a decent recovery followed by radiosurgery as she refused resection. A second hemorrhage occurred ultimately prompting surgical resection of the three posterior fossa lesions, with a reasonable postoperative course. Conclusion: Hemorrhage of HGBs of the posterior fossa can present in conjunction of tonsillar herniation. Re-hemorrhage appears to be likely if prior acute hemorrhage has occurred. A stepwise approach of surgical decompression and resection may provide the best outcome. PMID:28713626

  2. [Molecular biology of renal cancer: bases for genetic directed therapy in advanced disease].

    PubMed

    Maroto Rey, José Pablo; Cillán Narvaez, Elena

    2013-06-01

    There has been expansion of therapeutic options in the management of metastatic renal cell carcinoma due to a better knowledge of the molecular biology of kidney cancers. There are different tumors grouped under the term renal cell carcinoma, being clear cell cancer the most frequent and accounting for 80% of kidney tumors. Mutations in the Von Hippel-Lindau gene can be identified in up to 80% of sporadic clear cell cancer, linking a genetically inheritable disease where vascular tumors are frequent, with renal cell cancer. Other histologic types present specific alterations in molecular pathways, like c-MET in papillary type I tumors, and Fumarase Hydratase in papillary type II tumors. Identification of the molecular alteration for a specific tumor may offer an opportunity for treatment selection based on biomarkers, and, in the future, for developing an engineering designed genetic treatment.

  3. Mitochondrial Reactive Oxygen Species Trigger Hypoxia-Inducible Factor-Dependent Extension of the Replicative Life Span during Hypoxia▿

    PubMed Central

    Bell, Eric L.; Klimova, Tatyana A.; Eisenbart, James; Schumacker, Paul T.; Chandel, Navdeep S.

    2007-01-01

    Physiological hypoxia extends the replicative life span of human cells in culture. Here, we report that hypoxic extension of replicative life span is associated with an increase in mitochondrial reactive oxygen species (ROS) in primary human lung fibroblasts. The generation of mitochondrial ROS is necessary for hypoxic activation of the transcription factor hypoxia-inducible factor (HIF). The hypoxic extension of replicative life span is ablated by a dominant negative HIF. HIF is sufficient to induce telomerase reverse transcriptase mRNA and telomerase activity and to extend replicative life span. Furthermore, the down-regulation of the von Hippel-Lindau tumor suppressor protein by RNA interference increases HIF activity and extends replicative life span under normoxia. These findings provide genetic evidence that hypoxia utilizes mitochondrial ROS as signaling molecules to activate HIF-dependent extension of replicative life span. PMID:17562866

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

    PubMed

    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.

  5. 18F-FDG avidity of pheochromocytomas and paragangliomas: a new molecular imaging signature?

    PubMed

    Taïeb, David; Sebag, Frederic; Barlier, Anne; Tessonnier, Laurent; Palazzo, Fausto F; Morange, Isabelle; Niccoli-Sire, Patricia; Fakhry, Nicolas; De Micco, Catherine; Cammilleri, Serge; Enjalbert, Alain; Henry, Jean-François; Mundler, Olivier

    2009-05-01

    Our objective was to evaluate (18)F-FDG PET uptake in patients with nonmetastatic and metastatic chromaffin-derived tumors. Twenty-eight consecutive unrelated patients with chromaffin tumors, including 9 patients with genetically determined disease, were studied. A combination of preoperative imaging work-up, surgical findings, and pathologic analyses was used to classify the patients into 2 groups: those with nonmetastatic disease (presumed benign, n = 18) and those with metastatic tumors (n = 10). (18)F-FDG PET was performed in all cases. Visual and quantitative analyses were individually graded for each tumor. Somatic mutations of the succinate dehydrogenase subunits B and D and Von-Hippel Lindau genes were also evaluated in 6 benign sporadic tumor samples. All but 2 patients showed significantly increased (18)F-FDG uptake on visual analysis. The maximum standardized uptake value (SUVmax) ranged from 1.9 to 42 (mean +/- SD, 8.2 +/- 9.7; median, 4.6) in nonmetastatic tumors and 2.3 to 29.3 (mean +/- SD, 9.7 +/- 8.4; median, 7.4) in metastatic tumors. No statistical difference was observed between the groups (P = 0.44), but succinate dehydrogenase-related tumors were notable in being the most (18)F-FDG-avid tumors (SUVmax, 42, 29.3, 21, 17, and 5.3). Succinate dehydrogenase and Von-Hippel Lindau-related tumors had a significantly higher SUVmax than did neurofibromatosis type 1 and multiple endocrine neoplasia type 2A syndrome-related tumors (P = 0.02). (18)F-FDG PET was superior to (131)I-metaiodobenzylguanidine in all metastatic patients but one. By contrast, (18)F-FDG PET underestimated the extent of the disease, compared with 6-(18)F-fluorodopa PET, in 5 patients with metastatic pheochromocytoma. However, succinate dehydrogenase mutations (germline and somatic) and functional dedifferentiation do not adequately explain (18)F-FDG uptake since most tumors were highly avid for (18)F-FDG. (18)F-FDG PET positivity is almost a constant feature of pheochromocytomas

  6. Stabilization of a progressive hemangioblastoma under treatment with thalidomide.

    PubMed

    Piribauer, Maria; Czech, Thomas; Dieckmann, Karin; Birner, Peter; Hainfellner, Johannes A; Prayer, Daniela; Fazeny-Dörner, Barbara; Weinländer, Georg; Marosi, Christine

    2004-02-01

    After the second recurrence of spinal seeding in hemangioblastoma not associated to von-Hippel-Lindau disease, we treated an adult female patient with thalidomide 200 mg orally/day at night for longer than 1 year. The patient reported subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI) controls 1,6 and 11 months after begin of thalidomide treatment did not show further tumor progression. She remained wheelchair-bound, but mobility of her arms continuously improved. There was no thalidomide associated side-effect in this patient until her death from pneumonia due to legionnaire's disease. Antiangiogenic treatment with interferon (IFN) alpha-2a and IFN alpha-2b and with SU 5416 has been reported to be effective and well tolerated in several patients with previously progressive angioblastomas and hemangioblastomas. This case adds further evidence of the efficacy of an antiangiogenic treatment concept in a progressive hemangioblastoma.

  7. VHL-regulated miR-204 Suppresses Tumor Growth through Inhibition of LC3B-mediated Autophagy in Renal Clear Cell Carcinoma

    PubMed Central

    Mikhaylova, Olga; Stratton, Yiwen; Hall, Daniel; Kellner, Emily; Ehmer, Birgit; Drew, Angela F.; Gallo, Catherine A.; Plas, David R.; Biesiada, Jacek; Meller, Jarek; Czyzyk-Krzeska, Maria F.

    2012-01-01

    Summary The von Hippel-Lindau tumor-suppressor gene (VHL) is lost in most clear cell renal cell carcinomas (ccRCC). Here, using human ccRCC specimens, VHL-deficient cells, and xenograft models, we show that miR-204 is a VHL-regulated tumor suppressor acting by inhibiting macroautophagy, with MAP1LC3B (LC3B) as a direct and functional target. Importantly, higher tumor grade of human ccRCC was correlated with a concomitant decrease in miR-204 and increase in LC3B levels, indicating that LC3B-mediated macroautophagy is necessary for RCC progression. VHL, in addition to inducing endogenous miR-204, triggered the expression of LC3C, an HIF-regulated LC3B paralog, that suppressed tumor growth. These data reveal a function of VHL as a tumor suppressing regulator of autophagic programs. PMID:22516261

  8. TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma

    PubMed Central

    Hall, Daniel P.; Cost, Nicholas G.; Hegde, Shailaja; Kellner, Emily; Mikhaylova, Olga; Stratton, Yiwen; Ehmer, Birgit; Abplanalp, William A.; Pandey, Raghav; Biesiada, Jacek; Harteneck, Christian; Plas, David R.; Meller, Jarek; Czyzyk-Krzeska, Maria F.

    2014-01-01

    Summary Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca2+ influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca2+ and Zn2+ fluxes inhibit miR-214 which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 through miR-204 directly and indirectly through another miR-204 target, Caveolin 1 (CAV1). PMID:25517751

  9. Balanced branching in transcription termination.

    PubMed

    Harrington, K J; Laughlin, R B; Liang, S

    2001-04-24

    The theory of stochastic transcription termination based on free-energy competition [von Hippel, P. H. & Yager, T. D. (1992) Science 255, 809-812 and von Hippel, P. H. & Yager, T. D. (1991) Proc. Natl. Acad. Sci. USA 88, 2307-2311] requires two or more reaction rates to be delicately balanced over a wide range of physical conditions. A large body of work on glasses and large molecules suggests that this balancing should be impossible in such a large system in the absence of a new organizing principle of matter. We review the experimental literature of termination and find no evidence for such a principle, but do find many troubling inconsistencies, most notably, anomalous memory effects. These effects suggest that termination has a deterministic component and may conceivably not be stochastic at all. We find that a key experiment by Wilson and von Hippel [Wilson, K. S. & von Hippel, P. H. (1994) J. Mol. Biol. 244, 36-51] thought to demonstrate stochastic termination was an incorrectly analyzed regulatory effect of Mg(2+) binding.

  10. Role of HIF-1α in skeletal development

    PubMed Central

    Wan, Chao; Shao, Jin; Gilbert, Shawn R.; Riddle, Ryan C.; Long, Fanxin; Johnson, Randall S.; Schipani, Ernestina; Clemens, Thomas L.

    2011-01-01

    Angiogenesis and osteogenesis are tightly coupled during bone development and regeneration. Mesenchymal cells in the developing stroma elicit angiogenic signals to recruit new blood vessels into bone. Reciprocal signals, likely emanating from the incoming vascular endothelium, stimulate mesenchymal cell specification through additional interactions with cells within the vascular stem cell niche. The hypoxia-inducible factor-1 alpha (HIF-1) pathway has been identified as a key component in this process. We demonstrated that overexpression of HIF-1 in mature osteoblasts through disruption of the von Hippel-Lindau protein profoundly increases angiogenesis and osteogenesis; these processes appear to be coupled by cell nonautonomous mechanisms involving the action of vascular endothelial growth factor (VEGF) on the endothelial cells. The same occurred in the model of injury-mediated bone regeneration (distraction osteogenesis). Surprisingly, manipulation of HIF-1 does not influence angiogenesis of the skull bones, where earlier activation of HIF-1 in the condensing mesenchyme upregulates osterix during cranial bone formation. PMID:20392254

  11. Spinal capillary hemangiomas: Two cases reports and review of the literature

    PubMed Central

    Tunthanathip, Thara; Rattanalert, Sanguansin; Oearsakul, Thakul; Kanjanapradit, Kanet

    2017-01-01

    Hemangiomas have rarely been found in the spinal cord. A few cases of spinal capillary hemangioma have been reported since 1987. The authors reported the two cases of capillary hemangioma including the tumor at conus medullaris and the another mimicked von Hippel-Lindau disease. A 15-year-old man was presented with coccydynia and left leg pain. A magnetic resonance imaging (MRI) revealed an intradural extramedullary enhancing mass at conus medullaris. Another case, a 31-year-old man was presented with a history of familial history of brain tumor, retinal hemangioma both eyes, multiple pancreatic cyst and syringobulbia with syringohydromyelia. On MRI, a well-circumscribed intramedullary nodule was detected at C5-6 level and multiple subpial nodule along cervicothoracic spinal cord. All patients underwent surgery, and the histological diagnosis confirmed capillary hemangioma. Although rare and indistinguishable from other tumors, capillary hemangioma should be in the differential diagnosis of the spinal cord tumor. PMID:28761543

  12. Genomic imprinting and dermatological disease.

    PubMed

    Millington, G W M

    2006-09-01

    Imprinting is the process whereby genetic alleles responsible for a phenotype are derived from one parent only. It is an epigenetic phenomenon resulting from DNA methylation or modification of protruding histones. When imprinted genes are disrupted, syndromes with characteristic patterns of inheritance and multisystem phenotype occur. Those detailed in this article have some quite characteristic cutaneous features and patterns of inheritance. These diseases include Beckwith-Wiedmann, Silver-Russell, Prader-Willi, McCune-Albright and Angelman syndromes, Albright's hereditary osteodystrophy, and progressive osseous heteroplasia. In the case of Von Hippel-Lindau syndrome, hypomelanosis of Ito and dermatopathia pigmentosa reticularis, imprinting may play a part in the inheritance. With neurofibromatosis type 1, a nonimprinted condition, the expression of the phenotype could be affected by interaction with imprinted gene loci. Imprinted genes could also play a part in the polygenetic inheritance of more common diseases also, as atopic eczema and psoriasis may have predominantly maternal and paternal modes of transmission, respectively.

  13. Concurrent bilateral pheochromocytoma and thoracic paraganglioma during pregnancy.

    PubMed

    Snabboon, Thiti; Plengpanich, Wanee; Houngngam, Natnicha; Buranasupkajorn, Patinut; Plengvidhya, Nattachet; Sereepapong, Wisan; Sunthornyothin, Sarat; Shotelersuk, Vorasuk

    2010-04-01

    Although hypertension occurring during pregnancies is not uncommon and its prognosis is generally excellent, some of its unusual causes can lead to catastrophic consequences, especially in undiagnosed cases. Here, we report a pregnant woman who presented with hypertension in her early pregnancy. It was subsequently found to be caused by bilateral pheochromocytoma. After removal of both tumors, catecholamine levels unexpectedly and unexplainably remained elevated. At 23 weeks of gestation, the fetus was found dead in utero. After the fetal death, additional studies were performed and revealed a thoracic paraganglioma. To our knowledge, this is the first report of a case of three catecholamine-producing tumors occurring concurrently during a pregnancy. Genetic analysis helped identify this unprecedented condition; the patient harbored a heterozygous missense mutation c.482G>A in exon 3 of the VHL gene, indicating von Hippel-Lindau syndrome. Physicians who care for hypertensive pregnant patients should be aware of this condition as its diagnosis would probably lead to a better outcome.

  14. E2-EPF UCP targets pVHL for degradation and associates with tumor growth and metastasis.

    PubMed

    Jung, Cho-Rok; Hwang, Kyung-Sun; Yoo, Jinsang; Cho, Won-Kyung; Kim, Jin-Man; Kim, Woo Ho; Im, Dong-Soo

    2006-07-01

    The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including hypoxia-inducible factor-1alpha (HIF-1alpha), which is involved in tumor progression and angiogenesis. It remains unclear, however, how pVHL is destabilized. Here we show that E2-EPF ubiquitin carrier protein (UCP) associates with and targets pVHL for ubiquitin-mediated proteolysis in cells, thereby stabilizing HIF-1alpha. UCP is detected coincidently with HIF-1alpha in human primary liver, colon and breast tumors, and metastatic cholangiocarcinoma and colon cancer cells. UCP level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of UCP boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway. Our results suggest that UCP helps stabilize HIF-1alpha and may be a new molecular target for therapeutic intervention in human cancers.

  15. A Test Fixture for Detecting the Presence of Water in Buoyant Cables

    DTIC Science & Technology

    1990-06-14

    Systems Branch, along with Messrs. Craig L. Flynn, Eric von Winkle and Phillip Watrous of the Pressure Lab for their assistance in the measurements...Report No. 4051; 2 April 1971, p. 110. [7] Tareev, B. Physics of Dielectrics. (Moscow, USSR: Mir Publishers, 1979), pp. 116- 134. [81 von Hippel , A.R...34 Telephony, August 10, 1981; pp. 58 - 60, 149. Von Hippel , Arthur R. Dielectrics and Waves. (New York: John Wiley and Sons, 1954). Wentworth, F.L. and M. Cohn

  16. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies

    PubMed Central

    Jensen, Robert T.; Berna, Marc J.; Bingham, David B; Norton, Jeffrey A.

    2008-01-01

    Pancreatic endocrine tumors (PETs) can occur in as part of four inherited disorders including: Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1(NF-1) [von Recklinghausen’s disease] and the tuberous sclerosis complex (TSC). The relative frequency with which patients with these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization, medical and surgical treatment of the PETs in these patients. The study of the PETs in these disorders has not only provided insights into the possible pathogenesis of sporadic PETs, but have also presented a number of unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore the study of PETs in these uncommon disorders has provided valuable insights that in many cases are applicable to the general group of patients with sporadic PETs. In this article these areas are briefly reviewed as well as the current state of knowledge of the PETs in these disorders and the controversies that exist in their management are briefly summarized and discussed. PMID:18798544

  17. Acute Inactivation of the VHL gene Contributes to Protective Effects of Ischemic Preconditioning in the Mouse Kidney

    PubMed Central

    Iguchi, Mitsuko; Kakinuma, Yoshihiko; Kurabayashi, Atsushi; Sato, Takayuki; Shuin, Taro; Hong, Seung-Beom; Schmidt, Laura S.; Furihata, Mutsuo

    2009-01-01

    Background/Aims The von Hippel-Lindau (pVHL) protein functions as an E3 ubiquitin ligase, controlling the stability of hypoxia inducible factor (HIF). Pre-induction of HIF-1α before pathological insult activates a self-defense mechanism and suppresses further aggravation of organ or cellular injury by ischemia. We investigated whether acute inactivation of the VHL gene might play a role in the response of mice to ischemic renal injury. Methods We generated tamoxifen-inducible conditional VHL knockout (VHL-KO) mice to inactivate the VHL gene in an acute manner during renal ischemia-reperfusion injury (IRI) induced by bilateral clamping of kidney arteries. Renal IRI is characterized by renal dysfunction and tubular damage. Results After the procedure of IRI, blood urea nitrogen (BUN) and creatinine (CRN) levels in control mice were significantly higher (BUN, 138.10±13.03 mg/dL; CRN, 0.72±0.16 mg/dL) than in VHL-KO mice (BUN, 52.12±6.61 mg/dL; CRN, 0.24±0.04 mg/dL; BUN: p<0.05; CRN: p<0.05). Histologically, tubular injury scores were higher in control mice than in VHL-KO mice (p<0.05). Conclusion We suggest that the acute inactivation of the VHL gene contributes to protective effects of ischemic preconditioning in renal tubules of the mouse. PMID:18957870

  18. Stereotactic radiosurgery in hemangioblastoma: Experience over 14 years

    PubMed Central

    Goyal, Nishant; Agrawal, Deepak; Singla, Raghav; Kale, Shashank Sharad; Singh, Manmohan; Sharma, Bhawani Shankar

    2016-01-01

    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. PMID:26933339

  19. The 2008 Lindau Nobel Laureate Meeting: Robert Huber, Chemistry 1988

    PubMed Central

    Huber, Robert

    2008-01-01

    Robert Huber and his colleagues, Johann Deisenhofer and Hartmut Michel, elucidated the three-dimensional structure of the Rhodopseudomonas viridis photosynthetic reaction center. This membrane protein complex is a basic component of photosynthesis – a process fundamental to life on Earth – and for their work, Huber and his colleagues received the 1988 Nobel Prize in Chemistry. Because structural information is central to understanding virtually any biological process, Huber likens their discovery to “switching on the light” for scientists trying to understand photosynthesis. Huber marvels at the growth of structural biology since the time he entered the field, when crystallographers worked with hand-made instruments and primitive computers, and only “a handful” of crystallographers would meet annually in the Bavarian Alps. In the “explosion” of structural biology since his early days of research, Huber looks to the rising generation of scientists to solve the remaining mysteries in the field – such as the mechanisms that underlie protein folding. A strong proponent of science mentorship, Huber delights in meeting young researchers at the annual Nobel Laureate Meetings in Lindau, Germany. He hopes that among these young scientists is an “Einstein of biology” who, he says with a twinkle in his eye, “doesn’t know it yet.” The interview was conducted by JoVE co-founder Klaus J. Korak at the Lindau Nobel Laureate Meeting 2008 in Lindau, Germany. PMID:19066525

  20. Re-Architecting the DOD Acquisition Process: Transition to the Information Age

    DTIC Science & Technology

    2006-06-01

    Testimony before the subcommittee on AirLand Committee on Armed Services Unites States Senate, CSIS Report, 15 Nov 2005. Hippel , Eric von ...both the military and commercial communities that users are the innovators of the world. ( Hippel ) 4.2 - Dynamics of Army Transformation

  1. Hereditary Pheochromocytoma.

    PubMed

    Santos, Pedro; Pimenta, Tiago; Taveira-Gomes, Antonio

    2014-08-01

    Pheochromocytomas (PHEO) and paragangliomas (PGL) are rare neuroendocrine tumors with an estimated occurrence of 2 to 5 patients per million per year and an incidence of about 1 per 100 000 in the general population. These tumors may arise sporadically or be associated to various syndromes, namely multiple endocrine neoplasia type 2, neurofibromatosis type 1, Von Hippel-Lindau syndrome, and hereditary paraganglioma-pheochromocytoma syndromes. This article aims to review the current epidemiology, pathogenesis, clinical presentation, and genetic aspects of syndromes associated with hereditary PHEO/PGL. The literature research, conducted at PubMed database, included review articles, published from February 2009 to February 2014, written in English or Portuguese, using as query: "Hereditary AND Pheochromocytoma." These tumors can be part of a myriad hereditary conditions that are not yet fully understood. Nevertheless, important systemic symptoms and even fatal outcomes can occur. Knowledge of these hereditary conditions can ensure a more efficient detection, treatment, and even prevention of these neuroectodermal tumors, thus new tests and studies should be conducted. © The Author(s) 2014.

  2. Regulation of endocytosis via the oxygen-sensing pathway.

    PubMed

    Wang, Yi; Roche, Olga; Yan, Mathew S; Finak, Greg; Evans, Andrew J; Metcalf, Julie L; Hast, Bridgid E; Hanna, Sara C; Wondergem, Bill; Furge, Kyle A; Irwin, Meredith S; Kim, William Y; Teh, Bin T; Grinstein, Sergio; Park, Morag; Marsden, Philip A; Ohh, Michael

    2009-03-01

    Tumor hypoxia is associated with disease progression, resistance to conventional cancer therapies and poor prognosis. Hypoxia, by largely unknown mechanisms, leads to deregulated accumulation of and signaling via receptor tyrosine kinases (RTKs) that are critical for driving oncogenesis. Here, we show that hypoxia or loss of von Hippel-Lindau protein--the principal negative regulator of hypoxia-inducible factor (HIF)--prolongs the activation of epidermal growth factor receptor that is attributable to lengthened receptor half-life and retention in the endocytic pathway. The deceleration in endocytosis is due to the attenuation of Rab5-mediated early endosome fusion via HIF-dependent downregulation of a critical Rab5 effector, rabaptin-5, at the level of transcription. Primary kidney and breast tumors with strong hypoxic signatures show significantly lower expression of rabaptin-5 RNA and protein. These findings reveal a general role of the oxygen-sensing pathway in endocytosis and support a model in which tumor hypoxia or oncogenic activation of HIF prolongs RTK-mediated signaling by delaying endocytosis-mediated deactivation of receptors.

  3. Erythrocytosis associated with a novel missense mutation in the HIF2A gene

    PubMed Central

    van Wijk, Richard; Sutherland, Scott; Van Wesel, Annet C.W.; Huizinga, Eric G.; Percy, Melanie J.; Bierings, Marc; Lee, Frank S.

    2010-01-01

    The ERYTHROPOIETIN (EPO) gene is regulated by the transcription factor Hypoxia Inducible Factor-α (HIF-α). In this pathway, Prolyl Hydroxylase Domain protein 2 (PHD2) hydroxylates two prolyl residues in HIF-α, which in turn promotes HIF-α degradation by the von Hippel Lindau (VHL) protein. Evidence that HIF-2α is the important isoform for EPO regulation in humans comes from the recent observation that mutations in the HIF2A gene are associated with cases of erythrocytosis. We report here a new erythrocytosis-associated mutation, p.Asp539Glu, in the HIF2A gene. Similar to all reported cases, the affected residue is in close vicinity and C-terminal to the primary hydroxylation site in HIF-2α, Pro531. This mutation, however, is notable in producing a rather subtle amino acid substitution. Nonetheless, we find that this mutation compromises binding of HIF-2α to both PHD2 and VHL, and we propose that this mutation is the cause of erythrocytosis in this individual. PMID:20007141

  4. Insights into Cullin-RING E3 ubiquitin ligase recruitment: structure of the VHL-EloBC-Cul2 complex.

    PubMed

    Nguyen, Henry C; Yang, Haitao; Fribourgh, Jennifer L; Wolfe, Leslie S; Xiong, Yong

    2015-03-03

    The von Hippel-Lindau tumor suppressor protein (VHL) recruits a Cullin 2 (Cul2) E3 ubiquitin ligase to downregulate HIF-1α, an essential transcription factor for the hypoxia response. Mutations in VHL lead to VHL disease and renal cell carcinomas. Inhibition of this pathway to upregulate erythropoietin production is a promising new therapy to treat ischemia and chronic anemia. Here, we report the crystal structure of VHL bound to a Cul2 N-terminal domain, Elongin B, and Elongin C (EloC). Cul2 interacts with both the VHL BC box and cullin box and a novel EloC site. Comparison with other cullin E3 ligase structures shows that there is a conserved, yet flexible, cullin recognition module and that cullin selectivity is influenced by distinct electrostatic interactions. Our structure provides a structural basis for the study of the pathogenesis of VHL disease and rationale for the design of novel compounds that may modulate cullin-substrate receptor interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Bilateral pheochromocytoma associated with paraganglioma and papillary thyroid carcinoma: report of an unusual case.

    PubMed

    Yang, Jeong Hoon; Bae, Sung Jin; Park, Sanghui; Park, Hyun-Kyung; Jung, Hye Seung; Chung, Jae Hoon; Min, Yong-Ki; Lee, Myung-Shik; Kim, Kwang-Won; Lee, Moon-Kyu

    2007-04-01

    A 42-year old woman presented with headache, palpitation and facial flushing. Ultrasonograms and computed tomograms revealed tumors in both of the adrenal glands, anterior aspect of the inferior vena cava, and the right lobe of the thyroid gland. Fine needle aspiration biopsy of the thyroid nodule revealed papillary thyroid carcinoma. Serum calcitonin, CEA, intact PTH and calcium levels were within normal limits. Markedly elevated levels of urinary normetanephrine and vanillylmandelic acid, and the result of 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy indicated that both adrenal masses were pheochromocytoma. Bilateral adrenalectomy, paracaval mass removal and total thyroidectomy together with central lymph node dissection were performed. The final pathological diagnosis was bilateral adrenal pheochromocytoma, paraganglioma, papillary thyroid carcinoma and either parathyroid adenoma or hyperplasia. Analysis of the RET proto-oncogene mutation, von Hippel Lindau mutation, succinate dehydrogenase subunit B mutation, and succinate dehydrogenase subunit D mutation yielded negative results. The relationship of these lesions could not be determined. This is the first report of a combination of bilateral pheochromocytoma, abdominal paraganglioma, papillary thyroid carcinoma and either parathyroid adenoma or hyperplasia without hyperparathyroidism.

  6. Hydroxyl-HIF2-alpha is potential therapeutic target for renal cell carcinomas

    PubMed Central

    Isono, Takahiro; Chano, Tokuhiro; Yoshida, Tetsuya; Kageyama, Susumu; Kawauchi, Akihiro; Suzaki, Masafumi; Yuasa, Takeshi

    2016-01-01

    Dormant cancer cells are deprivation-resistant, and cause a number of problems for therapeutic approaches for cancers. Renal cell carcinomas (RCCs) include deprivation-resistant cells that are resistant to various treatments. In this study, the specific characteristics of deprivation-resistant cells were transcriptionally identified by next generation sequencing. The hypoxia-inducible factors (HIF) transcription factor network was significantly enhanced in deprivation-resistant RCCs compared to the sensitive RCCs. Deprivation-resistant RCCs, that had lost Von Hippel-Lindau tumor suppressor expression, expressed hydroxyl-HIF2-alpha in the nucleus, but not sensitive-RCCs. Hydroxyl-HIF-alpha was also expressed in nuclei of RCC tissue samples. Knockdown for HIF2-alpha, but not HIF1-alpha, induced cell death related to a reduction in HIF-related gene expression in deprivation-resistant RCC cells. Chetomin, a nuclear HIF-inhibitor, induced marked level of cytotoxicity in deprivation-resistant cells, similar to the knockdown of HIF2-alpha. Therefore, hydroxyl-HIF2-alpha might be a potential therapeutic target for RCCs. PMID:27822416

  7. Cystic renal tumors: new entities and novel concepts.

    PubMed

    Moch, Holger

    2010-05-01

    Cystic renal neoplasms and renal epithelial stromal tumors are diagnostically challenging and represent some novel tumor entities. In this article, clinical and pathologic features of established and novel entities are discussed. Predominantly cystic renal tumors include cystic nephroma/mixed epithelial and stromal tumor, synovial sarcoma, and multilocular cystic renal cell carcinoma. These entities are own tumor entities of the 2004 WHO classification of renal tumors. Tubulocystic carcinoma and acquired cystic disease-associated renal cell carcinoma are neoplasms with an intrinsically cystic growth pattern. Both tumor types should be included in a future WHO classification as novel entities owing to their characteristic features. Cysts and clear cell renal cell carcinoma frequently coexist within the kidneys of patients with von Hippel-Lindau disease. Sporadic clear cell renal cell carcinomas often contain cysts, usually as a minor component. Some clear cell renal cell carcinomas have prominent cysts, and multilocular cystic renal cell carcinoma is composed almost exclusively of cysts. Recent molecular findings suggest that clear cell renal cancer may develop through cyst-dependent and cyst-independent molecular pathways.

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

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Michelini, S.; Urbanek, M.; Goldman, D.

    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 allelesmore » 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.« less

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

    PubMed

    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.

  10. Structural Basis for Modulation of Quality Control Fate in a Marginally Stable Protein.

    PubMed

    Brock, Kelly P; Abraham, Ayelet-chen; Amen, Triana; Kaganovich, Daniel; England, Jeremy L

    2015-07-07

    The human von Hippel-Lindau (VHL) tumor suppressor is a marginally stable protein previously used as a model substrate of eukaryotic refolding and degradation pathways. When expressed in the absence of its cofactors, VHL cannot fold and is quickly degraded by the quality control machinery of the cell. We combined computational methods with in vivo experiments to examine the basis of the misfolding propensity of VHL. By expressing a set of randomly mutated VHL sequences in yeast, we discovered a more stable mutant form. Subsequent modeling suggested the mutation had caused a conformational change affecting cofactor and chaperone interaction, and this hypothesis was then confirmed by additional knockout and overexpression experiments targeting a yeast cofactor homolog. These findings offer a detailed structural basis for the modulation of quality control fate in a model misfolded protein and highlight burial mode modeling as a rapid means to detect functionally important conformational changes in marginally stable globular domains. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    PubMed Central

    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

  12. Von Hippel-Lindau Disease: A Rare Familiar Multi-System Disorder and the Impact of the Clinical Nurse Specialist

    DTIC Science & Technology

    1993-01-01

    would undergo removal of both adrenal glands, the renal cell carcinomas, a cholecystectomy and a choledochoduodenostomy for biliary drainage . The...bleeding, renal failure, and pancreatitis. After recovery, a craniotomy would be done to remove the hemangioblastoma that had been bleeding. The...analgesia. After a three month convalescence, the patient had a craniotomy and was home within a week. The patient’s siblings have all had negative eye

  13. The clinical spectrum of phaeochromocytoma: analysis of 115 patients.

    PubMed

    Safwat, Ahmed S; Bissada, Nabil K; Seyam, Raouf M; Al Sobhi, Saif; Hanash, Kamal A

    2008-06-01

    To analyse the presentation, manifestations and outcome in consecutive patients with phaeochromocytoma, as this disease has a wide range of pathological and clinical expressions. The records of 115 patients with phaeochromocytoma were analysed retrospectively, recording the patients' age, sex, presenting symptoms and clinical signs, chemical, radiological and pathological findings and associated conditions. Of the 115 patients, 90 had adrenal tumours, 18 extra-adrenal and seven combined adrenal and extra-adrenal tumours. Ten patients had malignant and 105 had benign phaeochromocytoma. Eighty-six patients had sporadic and 29 had familial phaeochromocytoma, comprising eight with von Hippel-Lindau (VHL) disease, 17 with multiple endocrine neoplasia type II (MEN II) and four with von Recklinghausen disease. Two patients with sporadic phaeochromocytoma had Grave's disease. Ten patients (8.7%) had malignant phaeochromocytoma, of whom two had MEN II. A pregnant woman required prolonged intensive-care management before adrenalectomy and lost a fetus. Phaeochromocytoma is an interesting clinical entity with a wide spectrum of pathological and clinical manifestations. The diagnosis of phaeochromocytoma is confirmed by chemical methods, and located using imaging techniques, with computed tomography, magnetic resonance imaging and (131)I-meta-iodobenzyl guanidine radioisotope scanning being the most common. This series reflects the pathological and clinical spectrum of phaeochromocytoma. The presence of other manifestations of familial phaeochromocytoma influenced the presentation and prognosis of these patients.

  14. Mapping structural landmarks, ligand binding sites and missense mutations to the collagen IV heterotrimers predicts major functional domains, novel interactions and variation in phenotypes in inherited diseases affecting basement membranes

    PubMed Central

    Des Parkin, J.; San Antonio, James D.; Pedchenko, Vadim; Hudson, Billy; Jensen, Shane T.; Savige, Judy

    2016-01-01

    Collagen IV is the major protein found in basement membranes. It comprises 3 heterotrimers (α1α1α2, α3α4α5, and α5α5α6) that form distinct networks, and are responsible for membrane strength and integrity. We constructed linear maps of the collagen IV heterotrimers (‘interactomes’) that indicated major structural landmarks, known and predicted ligand-binding sites, and missense mutations, in order to identify functional and disease-associated domains, potential interactions between ligands, and genotype-phenotype relationships. The maps documented more than 30 known ligand-binding sites as well as motifs for integrins, heparin, von Willebrand factor (VWF), decorin and bone morphogenetic protein (BMP). They predicted functional domains for angiogenesis and haemostasis, and disease domains for autoimmunity, tumor growth and inhibition, infection and glycation. Cooperative ligand interactions were indicated by binding site proximity, for example, between integrins, matrix metalloproteinases and heparin. The maps indicated that mutations affecting major ligand-binding sites, for example for Von Hippel Lindau (VHL) protein in the α1 chain or integrins in the α5 chain, resulted in distinctive phenotypes (Hereditary Angiopathy, Nephropathy, Aneurysms and muscle Cramps (HANAC) syndrome, and early onset Alport syndrome respectively). These maps further our understanding of basement membrane biology and disease, and suggest novel membrane interactions, functions, and therapeutic targets. PMID:21280145

  15. Space Weaponization and US-China Relations

    DTIC Science & Technology

    2008-01-01

    and his JD degree from the New York University School of Law. Mr. Blazejewski would like to thank Frank von Hippel and R. Scott Kemp for their comments...Totem and Taboo,” 18. 69. Krepon, “Lost in Space,” 7. 70. One suggestion by Frank von Hippel would be to try to detect the laser beam by its scattering...more.” Pillsbury Report, 9. 15. Statement by Eric D. Hagt in “Chinese Military Modernization and Its Impact on the United States and the Asia

  16. Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy.

    PubMed

    Martínez-Sáez, Olga; Gajate Borau, Pablo; Alonso-Gordoa, Teresa; Molina-Cerrillo, Javier; Grande, Enrique

    2017-03-01

    The loss of the Von Hippel-Lindau tumor suppressor (VHL) is a key oncogenic event in the vast majority of patients with clear cell renal cell carcinoma (ccRCC). With the loss of the VHL protein (pVHL) function, the hypoxia inducible factor α (HIF-α) accumulates inside the tumor cell and dimerizes with HIF-β. The HIF-α/HIF-β complex transcriptionally activates hundreds of genes promoting the adaptation to hypoxia that is implicated in tumor development. There is growing evidence showing that HIF-2α subunit has a central role in ccRCC over HIF-1α. Thus, efforts have been made to specifically target this pathway. PT2385 and PT2399 are first-in-class, orally available, small molecule inhibitors of HIF-2 that selectively disrupt the heterodimerization of HIF-2α with HIF-1β. Preclinical and clinical data indicate that these new molecules are effective in blocking cancer cell growth, proliferation, and tumor angiogenesis characteristic in ccRCC. Treatment with HIF-2α specific antagonists, either alone or in combination with immunotherapy or other antiangiogenic agents have the potential to transform the therapeutic landscape in this tumor in the future. Herein, we summarize the molecular background behind the use of HIF-2α inhibitors in ccRCC and give an overview of the development of new agents in this setting. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Morphological clues to the appropriate recognition of hereditary renal neoplasms.

    PubMed

    Moch, Holger; Ohashi, Riuko; Gandhi, Jatin S; Amin, Mahul B

    2018-05-01

    An important emerging role of the surgical pathologist besides the traditional tasks of establishment of the diagnosis and documentation of prognostic and predictive factors, is to recognize the possibility of a hereditary condition in cases where the histology is suggestive for a familial cancer syndrome. In recent years, the knowledge regarding all of the above roles, including the role of recognition of familial cancer, has particularly expanded in renal neoplasms with the close scrutiny to morphology, molecular correlates and clinical features of the different sub-types of renal cell carcinoma. Awareness of these clinically distinctive sub-types and their associated histologic clues will prompt the pathologist for further immunohistochemical or molecular work up, to look for clinical information to support the suspected diagnosis of familial cancer, to alert managing physician/s to look for stigmata of history of familial cancer, which will permit triaging patients and their families for appropriate genetic counseling. This review provides a comprehensive review of the known sub-types of renal cell carcinoma that have a predilection to occur in the setting of hereditary disease; examples include renal cancers occurring in the background of von Hippel Lindau disease, hereditary leiomyomatosis and renal cell carcinoma syndrome, tuberous sclerosis, Birt Hogg Dube syndrome and succinate dehydrogenase deficiency. Herein we focus on diagnostic clues for renal tumors occurring in a non-pediatric setting that should prompt their correct recognition and reiterate the importance of the correct diagnosis. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Gene Discovery in Prostate Cancer: Functional Identification and Isolation of PAC-1, a Novel Tumor Suppressor Gene Within Chromosome 10p

    DTIC Science & Technology

    1999-09-01

    I.. Zbar. B.. androle for the VHL gene in the development of hyperplasia in a number Lerman. I. I. Identification of the son Hippel-Lindau disease...of heterozy- gosity of chromosome 3p markers in small-cell lung cancer. Nature (Lond.). 329: eleguns produced hyperplasia in all tissues (26...central fibrovascular core lined by cuboidal tumor cells. Tumor weights were determined (Fig. 2d). At the end of 47 days after cells were

  19. Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1α protein-protein interface.

    PubMed

    Van Molle, Inge; Thomann, Andreas; Buckley, Dennis L; So, Ernest C; Lang, Steffen; Crews, Craig M; Ciulli, Alessio

    2012-10-26

    Fragment screening is widely used to identify attractive starting points for drug design. However, its potential and limitations to assess the tractability of often challenging protein:protein interfaces have been underexplored. Here, we address this question by means of a systematic deconstruction of lead-like inhibitors of the pVHL:HIF-1α interaction into their component fragments. Using biophysical techniques commonly employed for screening, we could only detect binding of fragments that violate the Rule of Three, are more complex than those typically screened against classical druggable targets, and occupy two adjacent binding subsites at the interface rather than just one. Analyses based on ligand and group lipophilicity efficiency of anchored fragments were applied to dissect the individual subsites and probe for binding hot spots. The implications of our findings for targeting protein interfaces by fragment-based approaches are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Preimplantation genetic diagnosis for cancer predisposition.

    PubMed

    Rechitsky, Svetlana; Verlinsky, Oleg; Chistokhina, Anna; Sharapova, Tatyana; Ozen, Seckin; Masciangelo, Christina; Kuliev, Anver; Verlinsky, Yury

    2002-01-01

    Preimplantation genetic diagnosis (PGD) has recently been offered for couples with an inherited predisposition for late onset disorders. This paper presents the results of PGD for a group of couples at risk for producing children with cancer predisposition. Using a standard IVF procedure, oocytes or embryos were tested for different mutations predisposing to cancer, preselecting and transferring only mutation-free embryos back to the patients. The procedure was performed for patients with predisposition to familial adenomatous polyposis coli (FAP), Von Hippel-Lindau syndrome (VHL), retinoblastoma, Li-Fraumeni syndrome, determined by p53 tumour suppressor gene mutations, neurofibromatosis types I and II and familial posterior fossa brain tumour (hSNF5). Overall, 20 PGD cycles were performed for 10 couples, resulting in preselection and transfer of 40 mutation-free embryos, which resulted in five unaffected clinical pregnancies and four healthy children born by the present time. Despite the controversy of PGD use for late onset disorders, the data demonstrate the usefulness of this approach as the only acceptable option for at-risk couples to avoid the birth of children with an inherited predisposition to cancer, and to have a healthy child.

  1. Confounding of the association between radiation exposure from CT scans and risk of leukemia and brain tumors by cancer susceptibility syndromes.

    PubMed

    Meulepas, Johanna M; Ronckers, Cécile M; Merks, Johannes; Weijerman, Michel E; Lubin, Jay H; Hauptmann, Michael

    2016-12-01

    Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of pediatric CT scans. We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk. Since empirical evidence is lacking in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about patterns of CT scans among CSS patients. We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome and other CSS. Moreover, tuberous sclerosis complex, von Hippel-Lindau disease, neurofibromatosis type 1 and other CSS do not meaningfully confound RRs for brain tumors. Empirical data on the use of CT scans among CSS patients is urgently needed. Our assessment indicates that associations with radiation exposure from pediatric CT scans and leukemia or brain tumors reported in previous studies are unlikely to be substantially confounded by unmeasured CSS.

  2. Childhood polycythemias/erythrocytoses: classification, diagnosis, clinical presentation, and treatment.

    PubMed

    Cario, H

    2005-03-01

    Polycythemias or erythrocytoses in childhood and adolescence are very rare. Systematic data on the clinical presentation and laboratory evaluations as well as on treatment regimens are sparse. The diagnostic program in absolute erythrocytosis includes extensive clinical, hematological, biochemical, and molecular biological examinations which should be applied following a stepwise algorithm. Absolute erythrocytoses are usually subdivided into primary and secondary forms. Primary erythrocytosis is a condition in which the erythropoietic compartment is expanding independently of extrinsic influences or by responding inadequately to them. Primary erythrocytoses include primary familial and congenital polycythemia (PFCP) due to mutations of the erythropoietin (Epo) receptor gene and the myeloproliferative disorder polycythemia vera. Secondary erythrocytoses are driven by hormonal factors (predominantly by Epo) extrinsic to the erythroid compartment. The increased Epo secretion may represent either a physiologic response to tissue hypoxia, an abnormal autonomous Epo production, or a dysregulation of the oxygen-dependent Epo synthesis. Congenital secondary erythrocytoses are caused, e.g., by hemoglobin variants with increased oxygen affinity, by 2,3-bisphosphoglycerate deficiency, or by mutations in the von Hippel-Lindau gene associated with a disturbed oxygen-dependent regulation of Epo synthesis.

  3. Establishment of a large panel of patient-derived preclinical models of human renal cell carcinoma.

    PubMed

    Lang, Hervé; Béraud, Claire; Bethry, Audrey; Danilin, Sabrina; Lindner, Véronique; Coquard, Catherine; Rothhut, Sylvie; Massfelder, Thierry

    2016-09-13

    The objective of the present work was to establish a large panel of preclinical models of human renal cell carcinoma (RCC) directly from patients, faithfully reproducing the biological features of the original tumor. RCC tissues (all stages/subtypes) were collected for 8 years from 336 patients undergoing surgery, xenografted subcutaneously in nude mice, and serially passaged into new mice up to 13 passages. Tissue samples from the primary tumor and tumors grown in mice through passages were analyzed for biological tissue stability by histopathology, mRNA profiling, von Hippel-Lindau gene sequencing, STR fingerprinting, growth characteristics and response to current therapies. Metastatic models were also established by orthotopic implantation and analyzed by imagery. We established a large panel of 30 RCC models (passage > 3, 8.9% success rate). High tumor take rate was associated with high stage and grade. Histopathologic, molecular and genetic characteristics were preserved between original tumors and case-matched xenografts. The models reproduced the sensitivity to targeted therapies observed in the clinic. Overall, these models constitute an invaluable tool for the clinical design of efficient therapies, the identification of predictive biomarkers and translational research.

  4. Mutation analysis of HIF prolyl hydroxylases (PHD/EGLN) in individuals with features of phaeochromocytoma and renal cell carcinoma susceptibility.

    PubMed

    Astuti, Dewi; Ricketts, Christopher J; Chowdhury, Rasheduzzaman; McDonough, Michael A; Gentle, Dean; Kirby, Gail; Schlisio, Susanne; Kenchappa, Rajappa S; Carter, Bruce D; Kaelin, William G; Ratcliffe, Peter J; Schofield, Christopher J; Latif, Farida; Maher, Eamonn R

    2011-02-01

    Germline mutations in the von Hippel-Lindau disease (VHL) and succinate dehydrogenase subunit B (SDHB) genes can cause inherited phaeochromocytoma and/or renal cell carcinoma (RCC). Dysregulation of the hypoxia-inducible factor (HIF) transcription factors has been linked to VHL and SDHB-related RCC; both HIF dysregulation and disordered function of a prolyl hydroxylase domain isoform 3 (PHD3/EGLN3)-related pathway of neuronal apoptosis have been linked to the development of phaeochromocytoma. The 2-oxoglutarate-dependent prolyl hydroxylase enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) have a key role in regulating the stability of HIF-α subunits (and hence expression of the HIF-α transcription factors). A germline PHD2 mutation has been reported in association with congenital erythrocytosis and recurrent extra-adrenal phaeochromocytoma. We undertook mutation analysis of PHD1, PHD2 and PHD3 in two cohorts of patients with features of inherited phaeochromocytoma (n=82) and inherited RCC (n=64) and no evidence of germline mutations in known susceptibility genes. No confirmed pathogenic mutations were detected suggesting that mutations in these genes are not a frequent cause of inherited phaeochromocytoma or RCC.

  5. Adrenal haemangioblastoma presenting as phaeochromocytoma: a rare manifestation of extraneural hemangioblastoma.

    PubMed

    Deb, Prabal; Pal, Seerat; Dutta, Vibha; Srivastava, Anand; Bhargava, Akshay; Yadav, Krishan Kumar

    2012-09-01

    Adrenal haemangioblastoma presenting clinically as pheochromocytoma is a rare manifestation of extraneural haemangioblastoma. We present an unusual case of von Hippel-Lindau (VHL) disease that had adrenal and cerebellar haemangioblastoma with multiple renal cysts, and a review of the literature. Unlike the usual manifestations of secondary polycythemia or increased intracranial pressure and hydrocephalus due to cerebellar lesion, this 36-year-old male presented with hypertension. Investigations revealed right suprarenal mass with raised urinary catecholamines and serum vanillylmandelic acid (VMA) levels, apparently confirming the clinical diagnosis of phaeochromocytoma. Histopathology of the biopsy specimen showed features of haemangioblastoma, which was confirmed by immunohistochemistry using antibodies to neuron specific enolase and aquaporin-1. Based on this, the patient was screened for possible features of VHL, which revealed cerebellar haemangioblastoma and multiple renal cysts with angiomatous lesion. Postoperative follow-up showed normal levels of catecholamines without any symptoms of phaeochromocytoma. Adrenal haemangioblastoma is a rare entity with only four cases reported in the literature. Surgical removal is the treatment of choice. However, screening for other possible features of VHL, even in the absence of clinical features, is essential to exclude other potential lesions.

  6. Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion.

    PubMed

    Sudarshan, Sunil; Shanmugasundaram, Karthigayan; Naylor, Susan L; Lin, Shu; Livi, Carolina B; O'Neill, Christine F; Parekh, Dipen J; Yeh, I-Tien; Sun, Lu-Zhe; Block, Karen

    2011-01-01

    Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer.

  7. Pseudohypoxia induced by miR-126 deactivation promotes migration and therapeutic resistance in renal cell carcinoma.

    PubMed

    Liu, Weijun; Chen, Hanxiang; Wong, Nathan; Haynes, Wesley; Baker, Callie M; Wang, Xiaowei

    2017-05-28

    Pseudohypoxia plays a central role in the progression and therapeutic resistance of clear cell renal cell carcinoma (ccRCC); however, the underlying mechanisms are poorly understood. MicroRNA miR-126 has decreased expression in metastatic or relapsed ccRCC as compared to primary tumors, but the mechanisms by which miR-126 is implicated in RCC remain unknown. Through RNA-seq profiling to evaluate the impact of overexpression or CRISPR knockout of miR-126, we have identified SERPINE1 as a miR-126-5p target regulating cell motility, and SLC7A5 as a miR-126-3p target regulating the mTOR/HIF pathway. Specifically, miR-126 inhibits HIFα protein expression independent of von Hippel-Lindau tumor suppressor (VHL). On the other hand, deactivation of miR-126 induces a pseudohypoxia state due to increased HIFα expression, which further enhances therapeutic resistance and cell motility mediated by SLC7A5 and SERPINE1, respectively. Finally, the clinical relevance of miR-126 modulated gene regulation in ccRCC has been confirmed with profiling data from The Cancer Genome Atlas. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy

    PubMed Central

    Wert, Katherine J; Mahajan, Vinit B; Zhang, Lijuan; Yan, Yuanqing; Li, Yao; Tosi, Joaquin; Wei Hsu, Chun; Nagasaki, Takayuki; Janisch, Kerstin M; Grant, Maria B; Mahajan, MaryAnn; Bassuk, Alexander G; Tsang, Stephen H

    2016-01-01

    Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders. PMID:27195131

  9. Simultaneous targeted activation of Notch1 and Vhl-disruption in the kidney proximal epithelial tubular cells in mice

    PubMed Central

    Johansson, Elinn; Rönö, Birgitte; Johansson, Martin; Lindgren, David; Möller, Christina; Axelson, Håkan; Smith, Emma M. K.

    2016-01-01

    Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene. Histological examination of the kidneys of the conditional mice demonstrate the existence of nests of dysplastic cells with a clear cytoplasm as a consequence of lipid accumulation, thus displaying a one important hallmark of human ccRCC. PMID:27491826

  10. The 2008 Lindau Nobel Laureate Meeting: Robert Huber, Chemistry 1988. Interview by Klaus J. Korak.

    PubMed

    Huber, Robert

    2008-11-25

    Robert Huber and his colleagues, Johann Deisenhofer and Hartmut Michel, elucidated the three-dimensional structure of the Rhodopseudomonas viridis photosynthetic reaction center. This membrane protein complex is a basic component of photosynthesis - a process fundamental to life on Earth - and for their work, Huber and his colleagues received the 1988 Nobel Prize in Chemistry. Because structural information is central to understanding virtually any biological process, Huber likens their discovery to "switching on the light" for scientists trying to understand photosynthesis. Huber marvels at the growth of structural biology since the time he entered the field, when crystallographers worked with hand-made instruments and primitive computers, and only "a handful" of crystallographers would meet annually in the Bavarian Alps. In the "explosion" of structural biology since his early days of research, Huber looks to the rising generation of scientists to solve the remaining mysteries in the field - such as the mechanisms that underlie protein folding. A strong proponent of science mentorship, Huber delights in meeting young researchers at the annual Nobel Laureate Meetings in Lindau, Germany. He hopes that among these young scientists is an "Einstein of biology" who, he says with a twinkle in his eye, "doesn't know it yet." The interview was conducted by JoVE co-founder Klaus J. Korak at the Lindau Nobel Laureate Meeting 2008 in Lindau, Germany.

  11. POTASSIUM BROMATE-INDUCED RAT CLEAR CELL RENAL TUMOR IS INDEPENDENT OF CODING REGION MUTATIONS IN THE VON HIPPEL- LINDAU GENE

    EPA Science Inventory

    Potassium bromate (KBr03) is a rat renal carcinogen and a major drinking water disinfection by-product from ozonization. While KBr03 is a human nephro- and neuro-toxicant, its carcinogenicity in humans is unknown. Clear cell renal tumors, the common form of human renal carcinomas...

  12. Targeting endogenous proteins for degradation through the affinity-directed protein missile system.

    PubMed

    Fulcher, Luke J; Hutchinson, Luke D; Macartney, Thomas J; Turnbull, Craig; Sapkota, Gopal P

    2017-05-01

    Targeted proteolysis of endogenous proteins is desirable as a research toolkit and in therapeutics. CRISPR/Cas9-mediated gene knockouts are irreversible and often not feasible for many genes. Similarly, RNA interference approaches necessitate prolonged treatments, can lead to incomplete knockdowns and are often associated with off-target effects. Targeted proteolysis can overcome these limitations. In this report, we describe an affinity-directed protein missile (AdPROM) system that harbours the von Hippel-Lindau (VHL) protein, the substrate receptor of the Cullin2 (CUL2) E3 ligase complex, tethered to polypeptide binders that selectively bind and recruit endogenous target proteins to the CUL2-E3 ligase complex for ubiquitination and proteasomal degradation. By using synthetic monobodies that selectively bind the protein tyrosine phosphatase SHP2 and a camelid-derived VHH nanobody that selectively binds the human ASC protein, we demonstrate highly efficient AdPROM-mediated degradation of endogenous SHP2 and ASC in human cell lines. We show that AdPROM-mediated loss of SHP2 in cells impacts SHP2 biology. This study demonstrates for the first time that small polypeptide binders that selectively recognize endogenous target proteins can be exploited for AdPROM-mediated destruction of the target proteins. © 2017 The Authors.

  13. Stable expression of HIF-1α in tubular epithelial cells promotes interstitial fibrosis

    PubMed Central

    Kimura, Kuniko; Iwano, Masayuki; Higgins, Debra F.; Yamaguchi, Yukinari; Nakatani, Kimihiko; Harada, Koji; Kubo, Atsushi; Akai, Yasuhiro; Rankin, Erinn B.; Neilson, Eric G.; Haase, Volker H.; Saito, Yoshihiko

    2008-01-01

    Chronic hypoxia accelerates renal fibrosis. The chief mediator of the hypoxic response is hypoxia-inducible factor 1 (HIF-1) and its oxygen-sensitive component HIF-1α. HIF-1 regulates a wide variety of genes, some of which are closely associated with tissue fibrosis. To determine the specific role of HIF-1 in renal fibrosis, we generated a knockout mouse in which tubular epithelial expression of von Hippel-Lindau tumor suppressor (VHL), which acts as a ubiquitin ligase to promote proteolysis of HIF-1α, was targeted. We investigated the effect of VHL deletion (i.e., stable expression of HIF-1α) histologically and used the anti-HIF-1α agent [3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole] (YC-1) to test whether inhibition of HIF-1α could represent a novel approach to treating renal fibrosis. The area of renal fibrosis was significantly increased in a 5/6 renal ablation model of VHL−/− mice and in all VHL−/− mice at least 60 wk of age. Injection of YC-1 inhibited the progression of renal fibrosis in unilateral ureteral obstruction model mice. In conclusion, HIF-1α appears to be a critical contributor to the progression of renal fibrosis and could be a useful target for its treatment. PMID:18667485

  14. Common regions of deletion in chromosome regions 3p12 and 3p14.2 in primary clear cell renal carcinomas.

    PubMed

    Lubinski, J; Hadaczek, P; Podolski, J; Toloczko, A; Sikorski, A; McCue, P; Druck, T; Huebner, K

    1994-07-15

    Nearly all clear cell renal cell carcinomas (RCCs) exhibit loss of alleles on the short arm of chromosome 3. Loss and mutation at the von Hippel-Lindau (VHL) gene at 3p25 probably occurs in most RCCs and, since the VHL gene was recently cloned, data on VHL involvement in RCCs is accumulating. However, the region 3p14-p12, a region that contains the familial RCC-associated t(3;8)(p14.2;q24) chromosome translocation and the small cell lung carcinoma-associated homozygous deletion at 3p13-12, has also been reported to exhibit allele loss in a large fraction of RCCs. In order to focus future studies on potential suppressor genes in the 3p14-p12 region, we have studied allele loss in 30 RCCs with 9 polymorphic simple sequence repeat markers spanning 3p21.1-p12. Partial losses in the 3p21-p12 region were observed, allowing determination of common regions of loss of heterozygosity overlap in 15 RCCs. Results suggested that most RCCs exhibit loss in a region which brackets the t(3;8) familial chromosome translocation at 3p14.2, and some show additional deletions within the U2020 small cell lung carcinoma deletion at 3p12.

  15. Deregulation of E2-EPF Ubiquitin Carrier Protein in Papillary Renal Cell Carcinoma

    PubMed Central

    Roos, Frederik C.; Evans, Andrew J.; Brenner, Walburgis; Wondergem, Bill; Klomp, Jeffery; Heir, Pardeep; Roche, Olga; Thomas, Christian; Schimmel, Heiko; Furge, Kyle A.; Teh, Bin T.; Thüroff, Joachim W.; Hampel, Christian; Ohh, Michael

    2011-01-01

    Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome-dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1α expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia-inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC. PMID:21281817

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

    PubMed

    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.

  17. An affinity-directed protein missile system for targeted proteolysis.

    PubMed

    Fulcher, Luke J; Macartney, Thomas; Bozatzi, Polyxeni; Hornberger, Annika; Rojas-Fernandez, Alejandro; Sapkota, Gopal P

    2016-10-01

    The von Hippel-Lindau (VHL) protein serves to recruit the hypoxia-inducible factor alpha (HIF1α) protein under normoxia to the CUL2 E3 ubiquitin ligase for its ubiquitylation and degradation through the proteasome. In this report, we modify VHL to engineer an affinity-directed protein missile (AdPROM) system to direct specific endogenous target proteins for proteolysis in mammalian cells. The proteolytic AdPROM construct harbours a cameloid anti-green fluorescence protein (aGFP) nanobody that is fused to VHL for either constitutive or tetracycline-inducible expression. For target proteins, we exploit CRISPR/Cas9 to rapidly generate human kidney HEK293 and U2OS osteosarcoma homozygous knock-in cells harbouring GFP tags at the VPS34 (vacuolar protein sorting 34) and protein associated with SMAD1 (PAWS1, aka FAM83G) loci, respectively. Using these cells, we demonstrate that the expression of the VHL-aGFP AdPROM system results in near-complete degradation of the endogenous GFP-VPS34 and PAWS1-GFP proteins through the proteasome. Additionally, we show that Tet-inducible destruction of GFP-VPS34 results in the degradation of its associated partner, UVRAG, and reduction in levels of cellular phosphatidylinositol 3-phosphate. © 2016 The Authors.

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

    PubMed Central

    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

  19. Single-cell genetic analysis validates cytopathological identification of circulating cancer cells in patients with clear cell renal cell carcinoma.

    PubMed

    Broncy, Lucile; Njima, Basma Ben; Méjean, Arnaud; Béroud, Christophe; Romdhane, Khaled Ben; Ilie, Marius; Hofman, Veronique; Muret, Jane; Hofman, Paul; Bouhamed, Habiba Chaabouni; Paterlini-Bréchot, And Patrizia

    2018-04-13

    Circulating Rare Cells (CRC) are non-haematological cells circulating in blood. They include Circulating Cancer Cells (CCC) and cells with uncertain malignant features (CRC-UMF) according to cytomorphology. Clear cell renal cell carcinomas frequently bear a mutated Von Hippel-Lindau (VHL) gene. To match blind genetic analysis of CRC and tumor samples with CRC cytopathological diagnosis. 29/30 patients harboured CRC (20 harboured CCC, 29 CRC-UMF) and 25/29 patients carried VHL mutations in their tumour. 205 single CRC (64 CCC, 141 CRC-UMF) provided genetic data. 57/57 CCC and 104/125 CRC-UMF from the 25 patients with VHL-mutated tumor carried the same VHL mutation detected in the tumor. Seven CCC and 16 CRC-UMF did not carry VHL mutations but were found in patients with wild-type VHL tumor tissue. All the CCC and 83,2% (104/125) of the CRC-UMF were found to carry the same VHL mutation identified in the corresponding tumorous tissue, validating cytopathological identification of CCC in patients with clear cell renal cell carcinoma. The blood of 30 patients with clear cell renal cell carcinoma was treated by ISET ® for CRC isolation, cytopathology and single-cell VHL mutations analysis, performed blindly and compared to VHL mutations of corresponding tumor tissues and leukocytes.

  20. Extraneuraxial Hemangioblastoma: Clinicopathologic Features and Review of the Literature.

    PubMed

    Bisceglia, Michele; Muscarella, Lucia A; Galliani, Carlos A; Zidar, Nina; Ben-Dor, David; Pasquinelli, Gianandrea; la Torre, Annamaria; Sparaneo, Angelo; Fanburg-Smith, Julie C; Lamovec, Janez; Michal, Michal; Bacchi, Carlos E

    2018-05-01

    Extraneuraxial hemangioblastoma occurs in nervous paraneuraxial structures, somatic tissues, and visceral organs, as part of von Hippel-Lindau disease (VHLD) or in sporadic cases. The VHL gene plausibly plays a key role in the initiation and tumorigenesis of both central nervous system and extraneuraxial hemangioblastoma, therefore, the underlying molecular and genetic mechanisms of the tumor growth are initially reviewed. The clinical criteria for the diagnosis of VHLD are summarized, with emphasis on the distinction of sporadic hemangioblastoma from the form fruste of VHLD (eg, hemangioblastoma-only VHLD). The world literature on the topic of extraneuraxial hemangioblastomas has been comprehensively reviewed with ∼200 cases reported to date: up to 140 paraneuraxial, mostly of proximal spinal nerve roots, and 65 peripheral, 15 of soft tissue, 6 peripheral nerve, 5 bone, and 39 of internal viscera, including 26 renal and 13 nonrenal. A handful of possible yet uncertain cases from older literature are not included in this review. The clinicopathologic features of extraneuraxial hemangioblastoma are selectively presented by anatomic site of origin, and the differential diagnosis is emphasized in these subsets. Reference is made also to 10 of the authors' personal cases of extraneuraxial hemangioblastomas, which include 4 paraneuraxial and 6 peripheral (2 soft tissue hemangioblastoma and 4 renal).

  1. Neoplasms of the Neuroendocrine Pancreas: An Update in the Classification, Definition, and Molecular Genetic Advances.

    PubMed

    Guilmette, Julie M; Nosé, Vania

    2018-06-14

    This review focuses on discussing the main modifications of the recently published 2017 WHO Classification of Neoplasms of the Neuroendocrine Pancreas (panNEN). Recent updates separate pancreatic neuroendocrine tumors into 2 broad categories: well-differentiated pancreatic neuroendocrine tumors (panNET) and poorly differentiated pancreatic neuroendocrine carcinoma (panNEC), and incorporates a new subcategory of "well-differentiated high-grade NET (G3)" to the well-differentiated NET category. This new classification algorithm aims to improve the prediction of clinical outcomes and survival and help clinicians select better therapeutic strategies for patient care and management. In addition, these neuroendocrine neoplasms are capable of producing large quantity of hormones leading to clinical hormone hypersecretion syndromes. These functioning tumors include, insulinomas, glucagonomas, somatostatinomas, gastrinomas, VIPomas, serotonin-producing tumors, and ACTH-producing tumors. Although most panNENs arise as sporadic diseases, a subset of these heterogeneous tumors present as parts on inherited genetic syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1, tuberous sclerosis, and glucagon cell hyperplasia and neoplasia syndromes. Characteristic clinical and morphologic findings for certain functioning and syndromic panNENs should alert both pathologists and clinicians as appropriate patient management and possible genetic counseling may be necessary.

  2. Wernher von Braun

    NASA Image and Video Library

    1965-04-13

    Walt Disney toured the West Test Area during his visit to the Marshall Space Flight Center on April 13, 1965. The three in center foreground are Karl Heimburg, Director, Test Division; Dr. von Braun, Director, MSFC; and Walt Disney. The Dynamic Test Stand with the S-1C stage being installed is in the background.

  3. PubMed Central

    Zanoletti, E.; Borsetto, D.; Opocher, G.; Mazzoni, A.; Martini, A.

    2017-01-01

    SUMMARY 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. PMID:29165437

  4. MANAGEMENT OF ENDOCRINE DISEASE: Outcome of adrenal sparing surgery in heritable pheochromocytoma.

    PubMed

    Castinetti, F; Taieb, D; Henry, J F; Walz, M; Guerin, C; Brue, T; Conte-Devolx, B; Neumann, H P H; Sebag, F

    2016-01-01

    The management of hereditary pheochromocytoma has drastically evolved in the last 20 years. Bilateral pheochromocytoma does not increase mortality in MEN2 or von Hippel-Lindau (VHL) mutation carriers who are followed regularly, but these mutations induce major morbidities if total bilateral adrenalectomy is performed. Cortical sparing adrenal surgery may be proposed to avoid definitive adrenal insufficiency. The surgical goal is to leave sufficient cortical tissue to avoid glucocorticoid replacement therapy. This approach was achieved by the progressive experience of minimally invasive surgery via the transperitoneal or retroperitoneal route. Cortical sparing adrenal surgery exhibits <5% significant recurrence after 10 years of follow-up and normal glucocorticoid function in more than 50% of the cases. Therefore, cortical sparing adrenal surgery should be systematically considered in the management of all patients with MEN2 or VHL hereditary pheochromocytoma. Hereditary pheochromocytoma is a rare disease, and a randomized trial comparing cortical sparing vs classical adrenalectomy is probably not possible. This lack of data most likely explains why cortical sparing surgery has not been adopted in most expert centers that perform at least 20 procedures per year for the treatment of this disease. This review examined recent data to provide insight into the technique, its indications, and the results and subsequent follow-up in the management of patients with hereditary pheochromocytoma with a special emphasis on MEN2. © 2016 European Society of Endocrinology.

  5. Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma

    PubMed Central

    Mehdi, Ali; Riazalhosseini, Yasser

    2017-01-01

    Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC. PMID:28812986

  6. Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma.

    PubMed

    Mehdi, Ali; Riazalhosseini, Yasser

    2017-08-16

    Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau ( VHL ) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1 , SETD2 and BAP1 , are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC.

  7. A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma.

    PubMed

    Wallace, Eli M; Rizzi, James P; Han, Guangzhou; Wehn, Paul M; Cao, Zhaodan; Du, Xinlin; Cheng, Tzuling; Czerwinski, Robert M; Dixon, Darryl D; Goggin, Barry S; Grina, Jonas A; Halfmann, Megan M; Maddie, Melissa A; Olive, Sarah R; Schlachter, Stephen T; Tan, Huiling; Wang, Bin; Wang, Keshi; Xie, Shanhai; Xu, Rui; Yang, Hanbiao; Josey, John A

    2016-09-15

    More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR. ©2016 American Association for Cancer Research.

  8. Targeting HIF2 in Clear Cell Renal Cell Carcinoma.

    PubMed

    Cho, Hyejin; Kaelin, William G

    2016-01-01

    Inactivation of the von Hippel-Lindau tumor-suppressor protein (pVHL) is the signature "truncal" event in clear cell renal cell carcinoma, which is the most common form of kidney cancer. pVHL is part of a ubiquitin ligase the targets the α subunit of the hypoxia-inducible factor (HIF) transcription factor for destruction when oxygen is available. Preclinical studies strongly suggest that deregulation of HIF, and particularly HIF2, drives pVHL-defective renal carcinogenesis. Although HIF2α was classically considered undruggable, structural and chemical work by Rick Bruick and Kevin Gardner at University of Texas Southwestern laid the foundation for the development of small molecule direct HIF2α antagonists (PT2385 and the related tool compound PT2399) by Peloton Therapeutics that block the dimerization of HIF2α with its partner protein ARNT1. These compounds inhibit clear cell renal cell carcinoma growth in preclinical models, and PT2385 has now entered the clinic. Nonetheless, the availability of such compounds, together with clustered regularly interspaced short palindromic repeat (CRISPR)-based gene editing approaches, has revealed a previously unappreciated heterogeneity among clear cell renal carcinomas and patient-derived xenografts with respect to HIF2 dependence, suggesting that predictive biomarkers will be needed to optimize the use of such agents in the clinic. © 2016 Cho and Kaelin; Published by Cold Spring Harbor Laboratory Press.

  9. Deregulation of E2-EPF ubiquitin carrier protein in papillary renal cell carcinoma.

    PubMed

    Roos, Frederik C; Evans, Andrew J; Brenner, Walburgis; Wondergem, Bill; Klomp, Jeffery; Heir, Pardeep; Roche, Olga; Thomas, Christian; Schimmel, Heiko; Furge, Kyle A; Teh, Bin T; Thüroff, Joachim W; Hampel, Christian; Ohh, Michael

    2011-02-01

    Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome-dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1α expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia-inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  10. Epigenetic silencing of Na,K-ATPase β1 subunit gene ATP1B1 by methylation in clear cell renal cell carcinoma

    PubMed Central

    Selvakumar, Ponniah; Owens, Tori A; David, Justin M; Petrelli, Nicholas J; Christensen, Brock C; Lakshmikuttyamma, Ashakumary; Rajasekaran, Ayyappan K

    2014-01-01

    The Na,K-ATPase or sodium pump carries out the coupled extrusion of Na+ and uptake of K+ across the plasma membranes of cells of most higher eukaryotes. We have shown earlier that Na,K-ATPase-β1 (NaK-β) protein levels are highly reduced in poorly differentiated kidney carcinoma cells in culture and in patients' tumor samples. The mechanism(s) regulating the expression of NaK-β in tumor tissues has yet to be explored. We hypothesized that DNA methylation plays a role in silencing the NaK-β gene (ATP1B1) expression in kidney cancers. In this study, to the best of our knowledge we provide the first evidence that ATP1B1 is epigenetically silenced by promoter methylation in both renal cell carcinoma (RCC) patients’ tissues and cell lines. We also show that knockdown of the von Hippel-Lindau (VHL) tumor suppressor gene in RCC cell lines results in enhanced ATP1B1 promoter AT hypermethylation, which is accompanied by reduced expression of NaK-β. Furthermore, treatment with 5-Aza-2′-deoxycytidine rescued the expression of ATP1B1 mRNA as well as NaK-β protein in these cells. These data demonstrate that promoter hypermethylation is associated with reduced NaK-β expression, which might contribute to RCC initiation and/or disease progression. PMID:24452105

  11. Epigenetic silencing of Na,K-ATPase β 1 subunit gene ATP1B1 by methylation in clear cell renal cell carcinoma.

    PubMed

    Selvakumar, Ponniah; Owens, Tori A; David, Justin M; Petrelli, Nicholas J; Christensen, Brock C; Lakshmikuttyamma, Ashakumary; Rajasekaran, Ayyappan K

    2014-04-01

    The Na,K-ATPase or sodium pump carries out the coupled extrusion of Na(+) and uptake of K(+) across the plasma membranes of cells of most higher eukaryotes. We have shown earlier that Na,K-ATPase-β 1 (NaK-β) protein levels are highly reduced in poorly differentiated kidney carcinoma cells in culture and in patients' tumor samples. The mechanism(s) regulating the expression of NaK-β in tumor tissues has yet to be explored. We hypothesized that DNA methylation plays a role in silencing the NaK-β gene (ATP1B1) expression in kidney cancers. In this study, to the best of our knowledge we provide the first evidence that ATP1B1 is epigenetically silenced by promoter methylation in both renal cell carcinoma (RCC) patients' tissues and cell lines. We also show that knockdown of the von Hippel-Lindau (VHL) tumor suppressor gene in RCC cell lines results in enhanced ATP1B1 promoter AT hypermethylation, which is accompanied by reduced expression of NaK-β. Furthermore, treatment with 5-Aza-2'-deoxycytidine rescued the expression of ATP1B1 mRNA as well as NaK-β protein in these cells. These data demonstrate that promoter hypermethylation is associated with reduced NaK-β expression, which might contribute to RCC initiation and/or disease progression.

  12. Adenomatous tumors of the middle ear and temporal bone: clinical, morphological and tumor biological characteristics of challenging neoplastic lesions.

    PubMed

    Duderstadt, M; Förster, Christine; Welkoborsky, H-J; Ostertag, H

    2012-03-01

    Adenomatous tumors of the middle ear and temporal bone are rare tumors. In this retrospective study, we examined nine patients who underwent surgery for an adenomatous tumor of the middle ear, mastoid cavity or eustachian tube. In seven patients, a middle ear adenoma (MEA) and in two patients an aggressive papillary tumor (APT) was diagnosed. We report the clinical, radiologic, morphologic, immunohistochemical and DNA image cytometrical characteristics that can help to correctly classify these tumors. Therapy consisted of surgical excision of the tumors in eight cases. In one elderly patient, only a large biopsy was taken, because this patient suffered from cardial and kidney disorders and was not suitable for an extended surgical approach. This patient received stereotactic radiotherapy. Seven patients underwent planned second look operation. Recurrences occurred in three patients (one with APT, two with MEA), whereas in two of these cases rather a residual tumor due to initial incomplete tumor resection occurred. By image analysis, DNA cytometry MEA were considered benign, whereas the appearance of aneuploid tumor cells in APT confirmed these tumors as low grade malignant lesions. The proliferation rates were equally low in both entities. APT and MEA are tumor entities which can only be correctly classified by a synopsis of histopathology, immunohistochemistry and DNA image cytometry. The recommended therapy is the complete tumor excision. In cases of APT, von Hippel-Lindau syndrome has to be excluded.

  13. Defense and Arms Control Studies Program, Annual Report 1991-1992

    DTIC Science & Technology

    1992-01-01

    Targets?" April 22 - John Friedman Lead Engineer, The MITRE Corporation, "FiberOptics" April 29 - Frank Von Hippel Director, Center for Energy and...1991). Eric J. Labs, "Do Weak States Bandwagon?" Security Studies (Spring 1992). George Lewis and Theodore Postol, "SLCMs - Ignored, Then Stored...Jervis, Schelling, Waltz, Blainey, von Clausewitz, Brodie, Allison, Steinbruner, and Huntington. Students write a seminar pa- per in which theoretical

  14. The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma

    PubMed Central

    Dadone, Bérengère; Durand, Matthieu; Borchiellini, Delphine; Amiel, Jean; Pouyssegur, Jacques; Rioux-Leclercq, Nathalie; Pages, Gilles; Burel-Vandenbos, Fanny; Mazure, Nathalie M.

    2018-01-01

    Background Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. Methods ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. Results A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. Conclusions This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets. PMID:29481555

  15. Meta-analysis of Clear Cell Renal Cell Carcinoma Gene Expression Defines a Variant Subgroup and Identifies Gender Influences on Tumor Biology

    PubMed Central

    Brannon, A. Rose; Haake, Scott M.; Hacker, Kathryn E.; Pruthi, Raj S.; Wallen, Eric M.; Nielsen, Matthew E.; Rathmell, W. Kimryn

    2011-01-01

    Background Clear cell renal cell carcinoma (ccRCC) displays molecular and histologic heterogeneity. Previously described subsets of this disease, ccA and ccB, were defined based on multigene expression profiles, but it is unclear whether these subgroupings reflect the full spectrum of disease or how these molecular subtypes relate to histologic descriptions or gender. Objective Determine whether additional subtypes of ccRCC exist and whether these subtypes are related to von Hippel-Lindau (VHL) inactivation, hypoxia-inducible factor (HIF) 1 and 2 expression, tumor histology, or gender. Design, setting, and participants Six large, publicly available ccRCC gene expression databases were identified that cumulatively provided data for 480 tumors for meta-analysis via meta-array compilation. Measurements Unsupervised consensus clustering was performed on the meta-arrays. Tumors were examined for the relationship of multigene-defined consensus subtypes and expression signatures of VHL mutation and HIF status, tumor histology, and gender. Results and limitations Two dominant subsets of ccRCC were observed. However, a minor third cluster was revealed that correlated strongly with a wild type (WT) VHL expression profile and indications of variant histologies. When variant histologies were removed, ccA tumors naturally divided by gender. This technique is limited by the potential for persistent batch effect, tumor sampling bias, and restrictions of annotated information. Conclusions The ccA and ccB subsets of ccRCC are robust in meta-analysis among histologically conventional ccRCC tumors. A third group of tumors was identified that may represent a new variant of ccRCC. Within definitively clear cell tumors, gender may delineate tumors in such a way that it could have implications regarding current treatments and future drug development. PMID:22030119

  16. Wernher von Braun

    NASA Image and Video Library

    1960-01-01

    In this photo, Director of the US Army Ballistic Missile Agency (ABMA) Development Operations Division, Dr. Wernher von Braun, is standing before a display of Army missiles celebrating ABMA's Fourth Open House. The missiles in the background include (left to right) a satellite on a Juno II shroud with a Nike Ajax pointing left in front of a Jupiter missile. The Lacrosse is in front of the Juno II. The Nike Hercules points skyward in front of the Juno II and the Redstone.

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

    PubMed

    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).

  18. VHL deletion impairs mammary alveologenesis but is not sufficient for mammary tumorigenesis.

    PubMed

    Seagroves, Tiffany N; Peacock, Danielle L; Liao, Debbie; Schwab, Luciana P; Krueger, Robin; Handorf, Charles R; Haase, Volker H; Johnson, Randall S

    2010-05-01

    Overexpression of hypoxia inducible factor-1 (HIF-1)alpha, which is common in most solid tumors, correlates with poor prognosis and high metastatic risk in breast cancer patients. Because HIF-1alpha protein stability is tightly controlled by the tumor suppressor von Hippel-Lindau (VHL), deletion of VHL results in constitutive HIF-1alpha expression. To determine whether VHL plays a role in normal mammary gland development, and if HIF-1alpha overexpression is sufficient to initiate breast cancer, Vhl was conditionally deleted in the mammary epithelium using the Cre/loxP system. During first pregnancy, loss of Vhl resulted in decreased mammary epithelial cell proliferation and impaired alveolar differentiation; despite these phenotypes, lactation was sufficient to support pup growth. In contrast, in multiparous dams, Vhl(-/-) mammary glands exhibited a progressive loss of alveolar epithelium, culminating in lactation failure. Deletion of Vhl in the epithelium also impacted the mammary stroma, as there was increased microvessel density accompanied by hemorrhage and increased immune cell infiltration. However, deletion of Vhl was not sufficient to induce mammary tumorigenesis in dams bred continuously for up to 24 months of age. Moreover, co-deletion of Hif1a could not rescue the Vhl(-/-)-dependent phenotype as dams were unable to successfully lactate during the first lactation. These results suggest that additional VHL-regulated genes besides HIF1A function to maintain the proliferative and regenerative potential of the breast epithelium.

  19. The role of the cilium in hereditary tumor predisposition syndromes

    PubMed Central

    Klasson, Timothy D.; Giles, Rachel H.

    2014-01-01

    The primary cilium is a highly conserved cell organelle that is closely connected to processes involved in cell patterning and replication. Amongst their many functions, cilia act as “signal towers” through which cell-cell signaling cascades pass. Dysfunction of cilia or the myriad processes that are connected with cilium function can lead to disease. Due to the sheer number of cellular processes that at some point involve the primary cilium, the effects of misregulation are highly heterogeneous between different cell populations. However, because of the importance of primary cilia in the development, growth, patterning and orientation of cells and tissues, a common thread has emerged in which defective cilia can lead to disorganization, which can contribute to the growth of neoplasms, including cancer and pre-cancerous phenotypes. Because cilia are so vital for signaling during cell replication and the cell fate decisions that are important in childhood growth, symptoms often arise early in life. Here we review recent work connecting misregulation of the primary cilium with tumor formation in a variety of tissues in the developing body, with a particular focus on the syndromes in which classic tumor genes are mutated, including von Hippel-Lindau disease (OMIM 193300), adenomatous polyposis coli (OMIM 175100), tuberous sclerosis (OMIM 191100) and Birt-Hogg-Dubé syndrome (OMIM 135150). Timely diagnosis of these syndromes is essential for entry into appropriate screening protocols, which have been shown to effectively prolong life expectancy in these cohorts of patients. PMID:27625869

  20. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Choi, Jieun; Koh, Eunjin; Lee, Yu Shin

    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 growthmore » 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.« less

  1. State-of-the-science: An update on renal cell carcinoma

    PubMed Central

    Jonasch, Eric; Futreal, Andrew; Davis, Ian; Bailey, Sean; Kim, William Y.; Brugarolas, James; Giaccia, Amato; Kurban, Ghada; Pause, Armin; Frydman, Judith; Zurita, Amado; Rini, Brian I.; Sharma, Pam; Atkins, Michael; Walker, Cheryl; Rathmell, W. Kimryn

    2012-01-01

    Renal cell carcinomas (RCC) are emerging as a complex set of diseases with major socioeconomic impact and a continued rise in incidence throughout the world. As the field of urologic oncology faces these trends, several major genomic and mechanistic discoveries have altered our core understanding of this multitude of cancers, including several new rare subtypes of renal cancers. This review will examine these new findings, and place them in the context of the well-established association of clear cell RCC (ccRCC) with mutations in the von Hippel-Lindau (VHL) gene and resultant aberrant hypoxia inducible factor (HIF) signaling. The impact of novel ccRCC-associated genetic lesions on chromatin remodeling and epigenetic regulation is explored. The effects of VHL mutation on primary ciliary function, extracellular matrix homeostasis, and tumor metabolism are discussed. VHL proteostasis is reviewed, with the goal of harnessing the proteostatic machinery to refunctionalize mutant VHL. Translational efforts using molecular tools to understand discriminating features of ccRCC tumors and develop improved prognostic and predictive algorithms are presented and new therapeutics arising from the earliest molecular discoveries in ccRCC are summarized. By creating an integrated review of the key genomic and molecular biological disease characteristics of ccRCC and placing these data in the context of the evolving therapeutic landscape, we intend to facilitate interaction between basic, translational and clinical researchers involved in the treatment of this devastating disease, and accelerate progress towards its ultimate eradication. PMID:22638109

  2. Autophagy mediates HIF2α degradation and suppresses renal tumorigenesis

    PubMed Central

    Liu, Xian-De; Yao, Jun; Tripathi, Durga Nand; Ding, Zhiyong; Xu, Yi; Sun, Mianen; Zhang, Jiangwei; Bai, Shanshan; German, Peter; Hoang, Anh; Zhou, Lijun; Jonasch, Darius; Zhang, Xuesong; Conti, Claudio J.; Efstathiou, Eleni; Tannir, Nizar M; Eissa, N. Tony; Mills, Gordon B.; Walker, Cheryl Lyn; Jonasch, Eric

    2014-01-01

    Autophagy is a conserved process involved in lysosomal degradation of protein aggregates and damaged organelles. The role of autophagy in cancer is a topic of intense debate, and the underlying mechanism is still not clear. The hypoxia inducible factor 2α (HIF2α), an oncogenic transcription factor implicated in renal tumorigenesis, is known to be degraded by the ubiquitin-proteasome system (UPS). Here we report that HIF2α is in part constitutively degraded by autophagy. HIF2α interacts with autophagy-lysosome system components. Inhibition of autophagy increases HIF2α, while induction of autophagy decreases HIF2α. The E3 ligase von Hippel Lindau (VHL) and autophagy receptor protein p62 are required for autophagic degradation of HIF2α. There is a compensatory interaction between the UPS and autophagy in HIF2α degradation. Autophagy inactivation redirects HIF2α to proteasomal degradation, while proteasome inhibition induces autophagy and increases the HIF2α-p62 interaction. Importantly, clear cell renal cell carcinoma (ccRCC) is frequently associated with mono-allelic loss and/or mutation of autophagy related gene ATG7, and low expression level of autophagy genes correlates with ccRCC progression. The protein levels of ATG7 and beclin 1 are also reduced in ccRCC tumors. This study indicates that autophagy plays an anticancer role in ccRCC tumorigenesis, and suggests that constitutive autophagic degradation of HIF2α is a novel tumor suppression mechanism. PMID:24998849

  3. Analysis of the hypoxia-sensing pathway in Drosophila melanogaster

    PubMed Central

    Arquier, Nathalie; Vigne, Paul; Duplan, Eric; Hsu, Tien; Therond, Pascal P.; Frelin, Christian; D'Angelo, Gisela

    2005-01-01

    The mechanism by which hypoxia induces gene transcription involves the inhibition of HIF-1α (hypoxia-inducible factor-1 α subunit) PHD (prolyl hydroxylase) activity, which prevents the VHL (von Hippel-Lindau)-dependent targeting of HIF-1α to the ubiquitin/proteasome pathway. HIF-1α thus accumulates and promotes gene transcription. In the present study, first we provide direct biochemical evidence for the presence of a conserved hypoxic signalling pathway in Drosophila melanogaster. An assay for 2-oxoglutarate-dependent dioxygenases was developed using Drosophila embryonic and larval homogenates as a source of enzyme. Drosophila PHD has a low substrate specificity and hydroxylates key proline residues in the ODD (oxygen-dependent degradation) domains of human HIF-1α and Similar, the Drosophila homologue of HIF-1α. The enzyme promotes human and Drosophila [35S]VHL binding to GST (glutathione S-transferase)–ODD-domain fusion protein. Hydroxylation is enhanced by proteasomal inhibitors and was ascertained using an anti-hydroxyproline antibody. Secondly, by using transgenic flies expressing a fusion protein that combined an ODD domain and the green fluorescent protein (ODD–GFP), we analysed the hypoxic cascade in different embryonic and larval tissues. Hypoxic accumulation of the reporter protein was observed in the whole tracheal tree, but not in the ectoderm. Hypoxic stabilization of ODD–GFP in the ectoderm was restored by inducing VHL expression in these cells. These results show that Drosophila tissues exhibit different sensitivities to hypoxia. PMID:16176182

  4. MicroRNA-566 activates EGFR signaling and its inhibition sensitizes glioblastoma cells to nimotuzumab.

    PubMed

    Zhang, Kai-Liang; Zhou, Xuan; Han, Lei; Chen, Lu-Yue; Chen, Ling-Chao; Shi, Zhen-Dong; Yang, Ming; Ren, Yu; Yang, Jing-Xuan; Frank, Thomas S; Zhang, Chuan-Bao; Zhang, Jun-Xia; Pu, Pei-Yu; Zhang, Jian-Ning; Jiang, Tao; Wagner, Eric J; Li, Min; Kang, Chun-Sheng

    2014-03-20

    Epidermal growth factor receptor (EGFR) is amplified in 40% of human glioblastomas. However, most glioblastoma patients respond poorly to anti-EGFR therapy. MicroRNAs can function as either oncogenes or tumor suppressor genes, and have been shown to play an important role in cancer cell proliferation, invasion and apoptosis. Whether microRNAs can impact the therapeutic effects of EGFR inhibitors in glioblastoma is unknown. miR-566 expression levels were detected in glioma cell lines, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate VHL as a direct target gene of miR-566. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm whether miR-566 inhibition could sensitize anti-EGFR therapy. In this study, we demonstrated that miR-566 is up-regulated in human glioma cell lines and inhibition of miR-566 decreased the activity of the EGFR pathway. Lentiviral mediated inhibition of miR-566 in glioblastoma cell lines significantly inhibited cell proliferation and invasion and led to cell cycle arrest in the G0/G1 phase. In addition, we identified von Hippel-Lindau (VHL) as a novel functional target of miR-566. VHL regulates the formation of the β-catenin/hypoxia-inducible factors-1α complex under miR-566 regulation. miR-566 activated EGFR signaling and its inhibition sensitized glioblastoma cells to anti-EGFR therapy.

  5. Premalignant lesions in the kidney.

    PubMed

    Kirkali, Z; Yorukoglu, K

    2001-12-07

    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.

  6. (1)H NMR metabolomics analysis of renal cell carcinoma cells: Effect of VHL inactivation on metabolism.

    PubMed

    Cuperlovic-Culf, Miroslava; Cormier, Kevin; Touaibia, Mohamed; Reyjal, Julie; Robichaud, Sarah; Belbraouet, Mehdi; Turcotte, Sandra

    2016-05-15

    Von Hippel-Lindau (VHL) is an onco-suppressor involved in oxygen and energy-dependent promotion of protein ubiquitination and proteosomal degradation. Loss of function mutations of VHL (VHL-cells) result in organ specific cancers with the best studied example in renal cell carcinomas. VHL has a well-established role in deactivation of hypoxia-inducible factor (HIF-1) and in regulation of PI3K/AKT/mTOR activity. Cell culture metabolomics analysis was utilized to determined effect of VHL and HIF-1α or HIF-2α on metabolism of renal cell carcinomas (RCC). RCC cells were stably transfected with VHL or shRNA designed to silence HIF-1α or HIF-2α genes. Obtained metabolic data was analysed qualitatively, searching for overall effects on metabolism as well as quantitatively, using methods developed in our group in order to determine specific metabolic changes. Analysis of the effect of VHL and HIF silencing on cellular metabolic footprints and fingerprints provided information about the metabolic pathways affected by VHL through HIF function as well as independently of HIF. Through correlation network analysis as well as statistical analysis of significant metabolic changes we have determined effects of VHL and HIF on energy production, amino acid metabolism, choline metabolism as well as cell regulation and signaling. VHL was shown to influence cellular metabolism through its effect on HIF proteins as well as by affecting activity of other factors. © 2015 UICC.

  7. Kruppel-like factor 2 inhibits hypoxia-inducible factor 1alpha expression and function in the endothelium.

    PubMed

    Kawanami, Daiji; Mahabeleshwar, Ganapati H; Lin, Zhiyong; Atkins, G Brandon; Hamik, Anne; Haldar, Saptarsi M; Maemura, Koji; Lamanna, Joseph C; Jain, Mukesh K

    2009-07-31

    Hypoxia-inducible factor 1 (HIF-1) is a central regulator of the hypoxic response in many cell types. In endothelial cells, HIF-1 induces the expression of key proangiogenic factors to promote angiogenesis. Recent studies have identified Kruppel-like factor 2 (KLF2) as a potent inhibitor of angiogenesis. However, the role of KLF2 in regulating HIF-1 expression and function has not been evaluated. KLF2 expression was induced acutely by hypoxia in endothelial cells. Adenoviral overexpression of KLF2 inhibited hypoxia-induced expression of HIF-1alpha and its target genes such as interleukin 8, angiopoietin-2, and vascular endothelial growth factor in endothelial cells. Conversely, knockdown of KLF2 increased expression of HIF-1alpha and its targets. Furthermore, KLF2 inhibited hypoxia-induced endothelial tube formation, whereas endothelial cells from mice with haploinsufficiency of KLF2 showed increased tube formation in response to hypoxia. Consistent with this ex vivo observation, KLF2 heterozygous mice showed increased microvessel density in the brain. Mechanistically, KLF2 promoted HIF-1alpha degradation in a von Hippel-Lindau protein-independent but proteasome-dependent manner. Finally, KLF2 disrupted the interaction between HIF-1alpha and its chaperone Hsp90, suggesting that KLF2 promotes degradation of HIF-1alpha by affecting its folding and maturation. These observations identify KLF2 as a novel inhibitor of HIF-1alpha expression and function. Therefore, KLF2 may be a target for modulating the angiogenic response in disease states.

  8. Reproductive disturbances in multiple neuroendocrine tumor syndromes.

    PubMed

    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.

  9. The use of intraoperative near-infrared indocyanine green videoangiography in the microscopic resection of hemangioblastomas.

    PubMed

    Tamura, Yoji; Hirota, Yuki; Miyata, Shiro; Yamada, Yoshitaka; Tucker, Adam; Kuroiwa, Toshihiko

    2012-08-01

    The authors assessed the usefulness of intraoperative near-infrared indocyanine green videoangiography (ICG-VA) in the microscopic resection of hemangioblastomas. From January 2009 to February 2012, nine consecutive patients (seven men, two women) who underwent surgery for hemangioblastomas using intraoperative ICG-VA were included in this study. Surgery was performed on four cystic cerebellar lesions with mural nodules, two solid tumors (one in the cerebellar hemisphere and one in the medulla oblongata), one spinal tumor and multiple tumors in two patients with von Hippel-Lindau disease. Of the nine patients, three were treated for recurrent tumor. The ICG-induced fluorescence images of hemangioblastomas with variable presentation were evaluated. All tumors could be completely removed en bloc. Blood flow in the tumor and tumor-related vessels at the brain surface were clearly detected by ICG-VA in all cases, except one recurrent tumor where postoperative adhesive scar tissue obstructed ICG-induced fluorescence resulting in poor delineation of the blood flow patterns and tumor margins. ICG-VA was also helpful for detecting the multiple small mural nodules within the cyst or the tumors buried under thin gliotic neural tissue despite reduced fluorescence. Intraoperative ICG-VA is a safe and easy modality for confirming the vascular flow patterns in hemangioblastomas. In addition, ICG-VA provided useful information for intracystic small lesions or lesions concealed under thin brain tissue in order to accomplish total resection of these tumors.

  10. Detection of Special Nuclear Material with High Purity Germanium (HPGe) and Mercuric Iodide (HgI2) Gamma Detectors

    DTIC Science & Technology

    2003-03-01

    to Achieve and Verify Deep Reductions in the Nuclear Arsenals. Ed. F. von Hippel and R.Z. Sagdeev. New York: Gordon and Breach Science Publishers... 1996 p . 1253-60. 21. Shleien, Bernard, Lester Slaback, and Brian Birky, Handbook of Health Physics and Radiological Health, 3rd Edition. Williams...70 13. Pu- 240 key gammas

  11. Wernher von Braun

    NASA Image and Video Library

    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.

  12. Wernher von Braun

    NASA Image and Video Library

    1977-06-16

    Dr. Wernher von Braun served as Marshall Space Flight Center's first director from July 1, 1960 until January 27, 1970, when he was appointed NASA Deputy Associate Administrator for Planning. Following World War II, Dr. von Braun and his German colleagues arrived in the United States under Project Paper Clip to continue their rocket development work. In 1950, von Braun and his rocket team were transferred from Ft. Bliss, Texas to Huntsville, Alabama to work for the Army's rocket program at Redstone Arsenal and later, NASA's Marshall Space Flight Center. Under von Braun's leadership, Marshall developed the Saturn V launch vehicle which took Apollo astronauts to the moon. Dr. von Braun died in Alexandria, Va., on June 16, 1977, seven years after his NASA appointment. This photo was taken at the site where he was laid to rest.

  13. Wernher von Braun

    NASA Image and Video Library

    1960-01-01

    Dr. Wernher von Braun served as Marshall Space Flight Center's first director from July 1, 1960 until January 27, 1970, when he was appointed NASA Deputy Associate Administrator for Plarning. Following World War II, Dr. von Braun and his German colleagues arrived in the United States under Project Paperclip to continue their rocket development work. In 1950, von Braun and his rocket team were transferred from Ft. Bliss, Texas to Huntsville, Alabama to work for the Army's rocket program at Redstone Arsenal and later, NASA's Marshall Space Flight Center. Under von Braun's leadership, Marshall developed the Saturn V launch vehicle which took Apollo astronauts to the moon.

  14. Isolation and antiproliferative activity of chemical constituents from Asystasia buettneri Lindau.

    PubMed

    Hamid, Abdulmumeen A; Aiyelaagbe, Olapeju O; Negi, Arvind S; Luqman, Suaib; Kaneez, Fatima

    2017-08-03

    N-hexane and methanol extracts of Asystasia buettneri Lindau aerial parts exhibited antiproliferative activity on leukaemia blood carcinoma, K-562. Hexadecane (1), 1,3-propan-2-ol (9Z,12'Z,15″Z)-bis(doeicos-9,12,15-trienoate) (2), hydrocarbon, 2,3,3,10,23-pentamethyl tetraeicos-10,13,16-trien-1-ol (3), hexadecanoic acid (4) and taraxerol (5) were isolated from n-hexane extract; stigmasterol (6) and (Z)-9-octadecenoic acid (7) were isolated from ethyl acetate extract; while unsaturated hydrocarbons, octadecene (8), 8-methyl tetradec-6-ene (9) and 19-methyl eicos-1-ene (10), fatty acids, (Z)-5-hexadecenoic acid (11), 11,22-dimethyl ethyltrieicos-11-enoate (12) and taraxasterol (13) were isolated from methanol extract of the plant. Compounds 4, 5, 7, 11, 12 and 13 exhibited antiproliferative activity against K-562, while compounds 5, 6, 7 and 9 revealed antiproliferative activity by inhibiting hepatic liver (WRL68) cell lines.

  15. Pregnancy and delivery in women with von Willebrand's disease and different von Willebrand factor mutations.

    PubMed

    Castaman, Giancarlo; Tosetto, Alberto; Rodeghiero, Francesco

    2010-06-01

    Pregnancy in von Willebrand's disease may carry a significant risk of bleeding. Information on changes in factor VIII and von Willebrand factor and pregnancy outcome in relation to von Willebrand factor gene mutations are very scanty. We examined biological response to desmopressin, changes in factor VIII and von Willebrand factor and pregnancy outcome in a cohort of 23 women with von Willebrand's disease characterized at molecular level and prospectively followed during 2000-2007. Thirty-one pregnancies occurred during the study period. Remarkably, similar changes of factor VIII and von Willebrand factor were observed after desmopressin and during pregnancy in nine women with R854Q, R1374H, V1665E, V1822G and C2362F mutations. Women with von Willebrand's disease and R1205H and C1130F mutations (17 pregnancies in 12 women) had only a slight increase of factor VIII and von Willebrand factor during pregnancy while their response to desmopressin was marked but short-lived. For these women, two to three desmopressin administrations within the first 48 hours were sufficient to successfully manage vaginal delivery. Two women with recessive von Willebrand's disease due to compound heterozygosity for different gene mutations had a spontaneous, major increase in factor VIII while von Willebrand factor remained severely reduced. Desmopressin increased factor VIII and was clinically useful in the first case, while a factor VIII/von Willebrand factor concentrate was required in the second patient not responsive to the compound. Factor VIII/von Willebrand factor concentrate was also required for two women with type 2 A von Willebrand's disease with V1665E mutations who had no von Willebrand factor activity change during pregnancy. In one of them, delayed bleeding occurred 15 days later requiring treatment with Factor VIII/von Willebrand factor concentrate. No miscarriages or stillbirths occurred. Close follow-up and detailed guidelines for the management of parturition have

  16. Compromised JMJD6 histone demethylase activity impacts on VHL gene repression in preeclampsia.

    PubMed

    Alahari, Sruthi; Post, Martin; Rolfo, Alessandro; Weksberg, Rosanna; Caniggia, Isabella

    2018-01-24

    The von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5-7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive. We examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia. Placentae were obtained from early-onset (E-PE: n=56; <34 weeks of gestation) and late onset preeclampsia (L-PE: n=19; ≥ 34 weeks of gestation). Placentae from healthy normotensive age-matched preterm and term pregnancies (PTC: n=43; TC: n=23) were included as controls. We measured the activity of Jumonji domain containing protein 6 (JMJD6), a Fe2+ and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL. JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592 treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592-treated mice. Our study uncovers novel epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia. Copyright © 2018 Endocrine Society

  17. Confounding of the Association between Radiation Exposure from CT Scans and Risk of Leukemia and Brain Tumors by Cancer Susceptibility Syndromes.

    PubMed

    Meulepas, Johanna M; Ronckers, Cécile M; Merks, Johannes; Weijerman, Michel E; Lubin, Jay H; Hauptmann, Michael

    2016-01-01

    Recent studies linking radiation exposure from pediatric computed tomography (CT) to increased risks of leukemia and brain tumors lacked data to control for cancer susceptibility syndromes (CSS). These syndromes might be confounders because they are associated with an increased cancer risk and may increase the likelihood of CT scans performed in children. We identify CSS predisposing to leukemia and brain tumors through a systematic literature search and summarize prevalence and risk estimates. Because there is virtually no empirical evidence in published literature on patterns of CT use for most types of CSS, we estimate confounding bias of relative risks (RR) for categories of radiation exposure based on expert opinion about the current and previous patterns of CT scans among CSS patients. We estimate that radiation-related RRs for leukemia are not meaningfully confounded by Down syndrome, Noonan syndrome, or other CSS. In contrast, RRs for brain tumors may be overestimated due to confounding by tuberous sclerosis complex (TSC) while von Hippel-Lindau disease, neurofibromatosis type 1, or other CSS do not meaningfully confound. Empirical data on the use of CT scans among CSS patients are urgently needed. Our assessment indicates that associations with leukemia reported in previous studies are unlikely to be substantially confounded by unmeasured CSS, whereas brain tumor risks might have been overestimated due to confounding by TSC. Future studies should identify TSC patients in order to avoid overestimation of brain tumor risks due to radiation exposure from CT scans. ©2015 American Association for Cancer Research.

  18. Posterior Retroperitoneoscopic Resection of Extra-adrenal Paraganglioma Located in the Aorto-caval Space.

    PubMed

    Kang, Sang-Wook; Kandil, Emad; Kim, Min Jhi; Kim, Kwang Soon; Lee, Cho Rok; Jeong, Jong Ju; Nam, Kee-Hyun; Chung, Woong Youn; Park, Cheong Soo

    2018-04-01

    The posterior retroperitoneoscopic adrenalec tomy has several advantages compared with the transperitoneal approach such as a shorter and more direct route to the target organ, no breach of the intraperitoneal space, and no required retraction of the adjacent organs. It also is a safe procedure with a short learning curve.1 - 5 This report presents a challenging case of an extra-adrenal paraganglioma located in the aorto-caval space and managed using the retroperitoneal approach. A 39-year-old man was placed in the prone jackknife position, and three incisions were made in the right posterior abdominal wall for placement of the laparoscopic ports. The retroperitoneal space was entered with diathermy and blunt finger dissection, and retropneumoperitoneum was achieved with carbon dioxide insufflation pressure up to 18 mmHg. After identification of the right kidney and vessels, the tumor was meticulously dissected and excised with an energy device. The specimen was removed using a laparoscopic specimen retrieval bag, and the port sites were closed in layers. The operative time was 130 min, and the total blood loss was 30 ml. The tumor was diagnosed as a moderately differentiated extra-adrenal paraganglioma. The Von Hippel-Lindau gene mutation was detected using next-generation sequencing. The posterior retroperitoneoscopic approach is a safe, feasible, and effective method for excising an extra-adrenal paraganglioma even in the aorto-caval space. The authors suggest that this procedure is a useful surgical option for treatment of an aorto-caval paraganglioma for selected patients and by experienced surgeons.

  19. Transferrin receptor 1 upregulation in primary tumor and downregulation in benign kidney is associated with progression and mortality in renal cell carcinoma patients

    PubMed Central

    Greene, Christopher J.; Attwood, Kristopher; Sharma, Nitika J.; Gross, Kenneth W.; Smith, Gary J.; Xu, Bo; Kauffman, Eric C.

    2017-01-01

    The central dysregulated pathway of clear cell (cc) renal cell carcinoma (RCC), the von Hippel Lindau/hypoxia inducible factor-α axis, is a key regulator of intracellular iron levels, however the role of iron uptake in human RCC tumorigenesis and progression remains unknown. We conducted a thorough, large-scale investigation of the expression and prognostic significance of the primary iron uptake protein, transferrin receptor 1 (TfR1/CD71/TFRC), in RCC patients. TfR1 immunohistochemistry was performed in over 1500 cores from 574 renal cell tumor patient tissues (primary tumors, matched benign kidneys, metastases) and non-neoplastic tissues from 36 different body sites. TfR1 levels in RCC tumors, particularly ccRCC, were significantly associated with adverse clinical prognostic features (anemia, lower body mass index, smoking), worse tumor pathology (size, stage, grade, multifocality, sarcomatoid dedifferentiation) and worse survival outcomes, including after adjustments for tumor pathology. Highest TfR1 tissue levels in the non-gravid body were detected in benign renal tubule epithelium. Opposite to TfR1 changes in the primary tumor, TfR1 levels in benign kidney dropped during tumor progression and were inversely associated with worse survival outcomes, independent of tumor pathology. Quantitative measurement of TfR1 subcellular localization in cell lines demonstrated mixed cytoplasmic and membranous expression with increased TfR1 in clusters in ccRCC versus benign renal cell lines. Results of this study support an important role for TfR1 in RCC progression and identify TfR1 as a novel RCC biomarker and therapeutic target. PMID:29291011

  20. SUPPRESSION OF HIF-1α TRANSCRIPTIONAL ACTIVITY BY THE HIF PROLYL HYDROXYLASE EGLN1*

    PubMed Central

    To, Kenneth K. W.; Huang, L. Eric

    2005-01-01

    The cellular response to hypoxia is, at least in part, mediated by the transcriptional regulation of hypoxia-responsive genes involved in balancing the intracellular ATP production and consumption. Recent evidence suggests that the transcription factor, HIF-1α, functions as a master regulator of oxygen homeostasis by controlling a broad range of cellular events in hypoxia. In normoxia, HIF-1α is targeted for destruction via prolyl hydroxylation, an oxygen-dependent modification that signals for recognition by the E3 ubiquitin ligase complex containing the von Hippel-Lindau tumor suppressor (VHL). Three HIF prolyl hydroxylases (EGLN1, EGLN2, and EGLN3) have been identified in mammals, among which, EGLN1 and EGLN3, are hypoxia-inducible at their mRNA levels in a HIF-1α-dependent manner. In this study, we demonstrate that apart from promoting HIF-1α proteolysis in normoxia, EGLN1 specifically represses HIF-1α transcriptional activity in hypoxia. Ectopic expression of EGLN1 inhibited HIF-1α transcriptional activity without altering its protein levels in a VHL-deficient cell line, indicating a discrete activity of EGLN1 in transcriptional repression. Conversely, silencing of EGLN1 expression augmented HIF-1α transcriptional activity and its target gene expression in hypoxia. Hence, we propose that the accumulated EGLN1 in hypoxia acts as a negative-feedback mechanism to modulate HIF-1α target gene expression. Our finding also provides new insight into the pharmacological manipulation of the HIF prolyl hydroxylase for ischemic diseases. PMID:16157596

  1. The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation.

    PubMed

    Lovell, M; Lott, S T; Wong, P; El-Naggar, A; Tucker, S; Killary, A M

    1999-05-01

    Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity have been observed at high frequency in the nonpapillary form of sporadic renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) gene has been identified as a tumor suppressor gene for RCC at 3p25, and functional studies as well as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor genes for sporadic RCC. We have previously functionally defined a novel genetic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, distinct from the VHL gene, that mediates tumor suppression and rapid cell death of RCC cells in vivo. We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC. Results document the functional involvement of NRC-1 in not only different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillary RCC, a less frequent histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting a role for NRC-1 as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC-1.

  2. Clinical and Molecular Features of Renal and Pheochromocytoma/Paraganglioma Tumor Association Syndrome (RAPTAS): Case Series and Literature Review.

    PubMed

    Casey, Ruth T; Warren, Anne Y; Martin, Jose Ezequiel; Challis, Benjamin G; Rattenberry, Eleanor; Whitworth, James; Andrews, Katrina A; Roberts, Thomas; Clark, Graeme R; West, Hannah; Smith, Philip S; Docquier, France M; Rodger, Fay; Murray, Vicki; Simpson, Helen L; Wallis, Yvonne; Giger, Olivier; Tran, Maxine; Tomkins, Susan; Stewart, Grant D; Park, Soo-Mi; Woodward, Emma R; Maher, Eamonn R

    2017-11-01

    The co-occurrence of pheochromocytoma (PC) and renal tumors was linked to the inherited familial cancer syndrome von Hippel-Lindau (VHL) disease more than six decades ago. Subsequently, other shared genetic causes of predisposition to renal tumors and to PC, paraganglioma (PGL), or head and neck paraganglioma (HNPGL) have been described, but case series of non-VHL-related cases of renal tumor and pheochromocytoma/paraganglioma tumor association syndrome (RAPTAS) are rare. To determine the clinical and molecular features of non-VHL RAPTAS by literature review and characterization of a case series. A review of the literature was performed and a retrospective study of referrals for investigation of genetic causes of RAPTAS. Literature review revealed evidence of an association, in addition to VHL disease, between germline mutations in SDHB, SDHC, SDHD, TMEM127, and MAX genes and RAPTAS [defined here as the co-occurrence of tumors from both classes (PC/PGL/HNPGL and renal tumors) in the same individual or in first-degree relatives]. In both the literature review and our case series of 22 probands with non-VHL RAPTAS, SDHB mutations were the most frequent cause of non-VHL RAPTAS. A genetic cause was identified in 36.3% (8/22) of kindreds. Renal tumors and PC/PGL/HNPGL tumors share common molecular features and their co-occurrence in an individual or family should prompt genetic investigations. We report a case of MAX-associated renal cell carcinoma and confirm the role of TMEM127 mutations with renal cell carcinoma predisposition. Copyright © 2017 Endocrine Society

  3. Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells

    PubMed Central

    Nguyen, Thao; Hatfield, Stephen M.; Ohta, Akio; Sitkovsky, Michail V.

    2017-01-01

    Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF. In addition, hypoxia downregulated antigen presenting proteins like TAP 1/2 and LMP7 that are known to have a dominant role in surface display of peptide-MHC complexes. Corroborating oxygen-dependent regulation of MHC antigen presentation, hyperoxia (60% oxygen) transcriptionally upregulated MHC expression and increased levels of TAP2, LMP2 and 7. In conclusion, this study reveals a novel mechanism by which intra-tumoral hypoxia and HIF can potentiate immune escape. It also suggests the use of hyperoxia to improve tumor cell-based cancer vaccines and for mining novel immune epitopes. Furthermore, this study highlights the advantage of 3D cell cultures in reproducing hypoxia-dependent changes observed in the TME. PMID:29155844

  4. Wernher von Braun

    NASA Image and Video Library

    1970-02-24

    In 1970 Marshall Space Flight Center (MSFC) Director Dr. Wernher von Braun (right) was reassigned to NASA Headquarters to serve as Deputy Associate Administrator for Plarning. Prior to his transfer, Dr. von Braun was honored for his career in Huntsville, Alabama, with the celebration of "Wernher von Braun Day." Among those participating were Alabama Governor Albert Brewer (left) and Alabama Senator John Sparkman (center). (Courtesy of Huntsville/Madison County Public library)

  5. The Army Digital Terrain Catalog II (ADTC)

    DTIC Science & Technology

    2006-06-01

    Engineering (Eds.). Readings for Systems Engineering & Engineering Management. Mason, OH: Thomson Customer Publishing, 2004, p. 2. [3] E. von Hippel ...responsive, deployable, agile, versatile, lethal, survivable, and sustainable force. --Former Army Chief of Staff General Eric Shinseki and former...to advance the tenets of Army Transformation. As former Army Chief of Staff General Eric Shinseki and former Army Secretary Thomas White have stated

  6. Wernher von Braun

    NASA Image and Video Library

    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.

  7. Flying Blind: The Rise, Fall, and Possible Resurrection of Science Policy Advice in the United States

    DTIC Science & Technology

    2004-12-01

    Guillemin * Herbert A. Hauptman * Dudley R. Herschbach * Roald Hoffmann John P. Holdren * David H. Hubel * Jerome Karle Carl Kaysen * H. Gobind Khorana...Townes Frank von Hippel Robert A. Weinberg Myron Wegman * Steven Weinberg * Torsten N. Wiesel Alfred Yankauer Herbert F. York * Nobel Laureate Tara...Anderson * Kenneth J. Arrow * Julius Axelrod * David Baltimore * Baruj Benacerraf * Paul Berg * Hans A. Bethe * J. Michael Bishop * Nicolaas Bloembergen

  8. Dr. Wernher von Braun

    NASA Technical Reports Server (NTRS)

    2004-01-01

    Dr. von Braun is looking out from a 10th floor window of building 4200 at the Marshall Space Flight Center (MSFC). He was the first Center Director and served as the Director from July 1960 through February 1970. Following World War II, Dr. von Braun and his German colleagues arrived in the United States under the Project Paperclip (American acquisition of German rocket experts) to continue their rocket development work. In 1950, von Braun and his German Rocket Team (also called the Peenemuende Team) were transferred from Ft. Bliss, Texas to Huntsville, Alabama to work for the Army's rocket program at Redstone Arsenal and later, NASA's Marshall Space Flight Center (MSFC). Under Dr. von Braun's leadership, MSFC developed the Saturn V launch vehicle, which placed the first men, two American astronauts, on the Moon. Wernher von Braun's life was dedicated to expanding man's knowledge through the exploration of space.

  9. Wernher von Braun

    NASA Image and Video Library

    1959-01-01

    Five of the seven original astronauts are seen with Dr. von Braun inspecting the Mercury-Redstone hardware in the Fabrication Laboratory of Army Ballistic Missile Agency (ABMA) in 1959. Left to right: Astronauts Walter Schirra, Alan Shepard, John Glenn, Scott Carpenter, Gordon Cooper, and Dr. von Braun.

  10. Investigation of a Passive, Temporal, Neutron Monitoring System that Functions within the Confines of Start I

    DTIC Science & Technology

    2003-03-01

    was appreciated and their expertise was invaluable. I would also like to thank laboratory technician, Mr. Eric Taylor, whose assistance, skill...Sagdeev, “Detecting Nuclear Warheads,” in Reversing the Arms Race: How to Achieve and Verify Deep Reductions in the Nuclear Arsenals. Ed. F. von ... Hippel and R.Z. Sagdeev. New York: Gordon and Breach Science Publishers, 1990 7) Brigman, Charles J. Introduction To The Physics of Nuclear Weapon

  11. 6-Mercaptopurine, an activator of Nur77, enhances transcriptional activity of HIF-1alpha resulting in new vessel formation.

    PubMed

    Yoo, Y-G; Na, T-Y; Yang, W-K; Kim, H-J; Lee, I-K; Kong, G; Chung, J-H; Lee, M-O

    2007-05-31

    Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis. Previously, we reported that the orphan nuclear receptor Nur77 functions in stabilizing HIF-1alpha. Here, we demonstrate that 6-mercaptopurine (6-MP), an activator of the NR4A family members, enhances transcriptional activity of HIF-1. 6-MP enhanced the protein-level of HIF-1alpha as well as vascular endothelial growth factor (VEGF) in a dose- and time-dependent manner. The induction of HIF-1alpha was abolished by the transfection of either a dominant-negative Nur77 mutant or si-Nur77, indicating a critical role of Nur77 in the 6-MP action. The HIF-1alpha protein level remained up to 60 min in the presence of 6-MP when de novo protein synthesis was blocked by cycloheximide, suggesting that 6-MP induces stabilization of the HIF-1alpha protein. The fact that 6-MP decreased the association of HIF-1alpha with von Hippel-Lindau protein and the acetylation of HIF-1alpha, may explain how 6-MP induced stability of HIF-1alpha. Further, 6-MP induced the transactivation function of HIF-1alpha by recruiting co-activator cyclic-AMP-response-element-binding protein. Finally, 6-MP enhanced the expression of HIF-1alpha and VEGF, and the formation of capillary tubes in human umbilical vascular endothelial cells. Together, our results provide a new insight for 6-MP action in the stabilization of HIF-1alpha and imply a potential application of 6-MP in hypoxia-associated human vascular diseases.

  12. Expression of lactate/H⁺ symporters MCT1 and MCT4 and their chaperone CD147 predicts tumor progression in clear cell renal cell carcinoma: immunohistochemical and The Cancer Genome Atlas data analyses.

    PubMed

    Kim, Younghye; Choi, Jung-Woo; Lee, Ju-Han; Kim, Young-Sik

    2015-01-01

    Clear cell renal cell carcinomas (ccRCCs) have inactivation of the von Hippel-Lindau protein, leading to the accumulation of hypoxia-inducible factor-α (HIF-α). HIF-1α induces aerobic glycolysis, the Warburg effect, whereas HIF-2α functions as an oncoprotein. Lactate transport through monocarboxylate transporters (MCTs) and the chaperone CD147 is essential for high glycolytic cancer cell survival. To elucidate the clinical significance of MCT1, MCT4, and CD147 expression, we investigated their expressions by immunohistochemistry in ccRCC specimens and validated the results by an open-access The Cancer Genome Atlas data analysis. Overexpression of MCT1, MCT4, and CD147 was observed in 49.4% (89/180), 39.4% (71/180), and 79.4% (143/180) of ccRCC patients, respectively. High MCT1 expression was associated with older age (P = .017), larger tumor size (P = .015), and advanced TNM stage (P = .012). However, MCT4 overexpression was not related to any variables. CD147 overexpression correlated with high grade (P = .005), tumor necrosis (P = .016), and larger tumor size (P = .038). In univariate analysis, high expression of MCT1 (P < .001), MCT4 (P = .016), and CD147 (P = .02) was linked to short progression-free survival. In multivariate analysis, high MCT1 expression was associated with worse progression-free survival (P = .001). In conclusion, high expression of MCT1 and CD147 is associated with poor prognostic factors. Overexpression of MCT1, MCT4, and CD147 predicts tumor progression. Reversing the Warburg effect by targeting the lactate transporters may be a useful strategy to prevent ccRCC progression. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. A case of pheochromocytoma with negative MIBG scintigraphy, PET-CT and genetic tests (VHL included) and a rare case of post-operative erectile dysfunction.

    PubMed

    Defeudis, Giuseppe; Fioriti, Elvira; Palermo, Andrea; Tuccinardi, Dario; Minucci, Angelo; Capoluongo, Ettore; Pozzilli, Paolo; Manfrini, Silvia

    2018-06-02

    Pheochromocytoma (Ph) is a rare catecholamine-secreting neuroendocrine tumour that arises from the chromaffin cells of the adrenal medulla. Ph usually presents with symptoms including paroxysmal headache, sweating, palpitations, and hypertension. During a computed tomography (CT) scan in a normotensive 49-year-old man, an incidentaloma of 4.5 cm was detected. Hypercortisolism was excluded after the dexamethasone suppression test, levels of DHEAS all falling within the normal range. After a 24-h urine collection, normal urinary metanephrines and a 4-fold higher level compared to the normal range of urinary normetanephrines were observed. Cortisoluria levels were within the normal range. Multiple endocrine neoplasia type 2 (MEN 2) was also excluded. Before the adrenalectomy, 123 I meta-iodobenzylguanidine scintigraphy (MIBG) and 18F-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG PET)/CT were performed and were both negative. Histological examination confirmed the laboratory diagnosis of Ph. Genetic screening to evaluate the SDHB, SDHD, RET, CDKN1B, and VHL genes was requested in order to test for Von Hippel Lindau disease, but unexpectedly all of these were negative. On follow-up after surgery, the patient presented normal urinary catecholamines. However, after Ph removal, he reported frequent episodes of erectile dysfunction (ED) despite non-use of any antihypertensive medications and in the absence of any other precipitating factors, such as hormonal imbalance. This is a case report in which, in a normotensive patient with Ph, both MIBG and FDG PET-CT were negative, as were also genetic exams, including VHL, this underlining the difficulties in diagnosing this condition; furthermore, a rare case of ED occurred after surgery.

  14. Microsurgical Resection of Spinal Cord Hemangioblastoma: 2-Dimensional Operative Video.

    PubMed

    Pojskic, Mirza; Arnautovic, Kenan I

    2018-05-18

    This video demonstrates microsurgical resection of spinal cord hemangioblastoma. Hemangioblastomas are rare, benign, highly vascularized tumors classified as grade I according to World Health Organization classification systems. About 3% of all intramedullary tumors are hemangioblastomas.1,2 Spinal cord hemangioblastomas are either sporadic3,4 or manifestations of von Hippel-Lindau (VHL) disease in 20% to 45% of patients.5,6 A 30-year-old male presented with sudden onset urinary incontinence. Magnetic resonance imaging showed contrast enhancing intramedullary tumor with adjacent cyst in T11, and syringomyelia extending to C1. Surgical resection followed rules that apply to resection of arteriovascular malformations: coagulation of arterial feeders precedes the coagulation of the draining vein, which is preserved until the end of surgery.2,4,5,7,8 First, posterior midline myelotomy was performed and the tumor cyst was drained in order to develop a dissection plane. Following this, we continuously separated dorsal nerve roots from the tumor nodule using microsurgical technique. The key step in tumor resection is devascularization of the tumor, achievable in 2 ways.2,7,9-13 The circumferential detachment of the normal pia from the tumor pia is crucial in developing a plane of dissection. The coagulation and division of arterial feeders while preserving the drainage vein further devascularizes the tumor. Once the tumor mural nodule was detached from the spinal cord, the drainage vein was coagulated last and the tumor was removed. The patient fully recovered from his incontinence and was neurologically intact. Screening for VHL disease was negative. Written consent was obtained directly from the patient.

  15. Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation

    PubMed Central

    Peri, Suraj; Caretti, Elena; Tricarico, Rossella; Devarajan, Karthik; Cheung, Mitchell; Sementino, Eleonora; Menges, Craig W.; Nicolas, Emmanuelle; Vanderveer, Lisa A.; Howard, Sharon; Conrad, Peggy; Crowell, James A.; Campbell, Kerry S.; Ross, Eric A.; Godwin, Andrew K.; Yeung, Anthony T.; Clapper, Margie L.; Uzzo, Robert G.; Henske, Elizabeth P.; Ricketts, Christopher J.; Vocke, Cathy D.; Linehan, W. Marston; Testa, Joseph R.; Bellacosa, Alfonso; Kopelovich, Levy; Knudson, Alfred G.

    2017-01-01

    Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal one-hit cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the Warburg effect. Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NF?B and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention. PMID:27682873

  16. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-α-prolyl-4-hydroxylases

    PubMed Central

    2004-01-01

    An important regulator involved in oxygen-dependent gene expression is the transcription factor HIF (hypoxia-inducible factor), which is composed of an oxygen-sensitive α-subunit (HIF-1α or HIF-2α) and a constitutively expressed β-subunit. In normoxia, HIF-1α is destabilized by post-translational hydroxylation of Pro-564 and Pro-402 by a family of oxygen-sensitive dioxygenases. The three HIF-modifying human enzymes have been termed prolyl hydroxylase domain containing proteins (PHD1, PHD2 and PHD3). Prolyl hydroxylation leads to pVHL (von-Hippel-Lindau protein)-dependent ubiquitination and rapid proteasomal degradation of HIF-1α. In the present study, we report that human PHD2 and PHD3 are induced by hypoxia in primary and transformed cell lines. In the human osteosarcoma cell line, U2OS, selective suppression of HIF-1α expression by RNA interference resulted in a complete loss of hypoxic induction of PHD2 and PHD3. Induction of PHD2 by hypoxia was lost in pVHL-deficient RCC4 cells. These results suggest that hypoxic induction of PHD2 and PHD3 is critically dependent on HIF-α. Using a VHL capture assay, we demonstrate that HIF-α prolyl-4-hydroxylase capacity of cytoplasmic and nuclear protein extracts was enhanced by prolonged exposure to hypoxia. Degradation of HIF-1α after reoxygenation was accelerated, which demonstrates functional relevance of the present results. We propose a direct, negative regulatory mechanism, which limits accumulation of HIF-1α in hypoxia and leads to accelerated degradation on reoxygenation after long-term hypoxia. PMID:15104534

  17. Early surgical treatment of retinal hemangioblastomas.

    PubMed

    van Overdam, Koen A; Missotten, Tom; Kilic, Emine; Spielberg, Leigh H

    2017-02-01

    To evaluate the clinical course after early surgical treatment with excision of retinal hemangioblastomas (RHs) before development of major complications. Interventional case series of four eyes (four patients) with a peripheral RH that had not yet been treated by laser or cryotherapy prior to surgery. All eyes underwent 23-gauge vitrectomy with lesion excision. One patient underwent ligation of the feeder vessel prior to lesion excision. Best-corrected visual acuity and clinical course were assessed during a follow-up period of at least 4 years. Four patients (mean age 27.3 years; range 19-32) were included, of whom two had von Hippel-Lindau syndrome. Visual acuity improved in three patients (mean 4.8 lines; range 3-10) and remained stable at 0.0 logMAR in one patient. There were no intraoperative complications. Postoperative complications included transient mild vitreous haemorrhage (n = 2), and local epiretinal membrane formation at the excision location (n = 1). At 4 years postoperatively, there were no long-term complications. There was one case of a new lesion, which was effectively treated with laser. Vitrectomy with RH excision seems to be an effective approach for larger RHs and could be considered an early treatment option in selected cases. Postoperative complications were limited in scope of this case series. Important points to consider during vitrectomy are effective closure of feeder and draining vessels as well as complete removal of posterior hyaloid and epiretinal membranes in order to avoid postoperative vitreous haemorrhage and proliferative vitreoretinopathy. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  18. Egr-1 and serum response factor are involved in growth factors- and serum-mediated induction of E2-EPF UCP expression that regulates the VHL-HIF pathway.

    PubMed

    Lim, Jung Hwa; Jung, Cho-Rok; Lee, Chan-Hee; Im, Dong-Soo

    2008-11-01

    E2-EPF ubiquitin carrier protein (UCP) has been shown to be highly expressed in common human cancers and target von Hippel-Lindau (VHL) for proteosomal degradation in cells, thereby stabilizing hypoxia-inducible factor (HIF)-1alpha. Here, we investigated cellular factors that regulate the expression of UCP gene. Promoter deletion assay identified binding sites for early growth response-1 (Egr-1) and serum response factor (SRF) in the UCP promoter. Hepatocyte or epidermal growth factor (EGF), or phorbol 12-myristate 13-acetate induced UCP expression following early induction of Egr-1 expression in HeLa cells. Serum increased mRNA and protein levels of SRF and UCP in the cell. By electrophoretic mobility shift and chromatin immunoprecipitation assays, sequence-specific DNA-binding of Egr-1 and SRF to the UCP promoter was detected in nuclear extracts from HeLa cells treated with EGF and serum, respectively. Overexpression of Egr-1 or SRF increased UCP expression. RNA interference-mediated depletion of endogenous Egr-1 or SRF impaired EGF- or serum-mediated induction of UCP expression, which was required for cancer cell proliferation. Systemic delivery of EGF into mice also increased UCP expression following early induction of Egr-1 expression in mouse liver. The induced UCP expression by the growth factors or serum increased HIF-1alpha protein level under non-hypoxic conditions, suggesting that the Egr-1/SRF-UCP-VHL pathway is in part responsible for the increased HIF-1alpha protein level in vitro and in vivo. Thus, growth factors and serum induce expression of Egr-1 and SRF, respectively, which in turn induces UCP expression that positively regulates cancer cell growth.

  19. The HILDA Complex Coordinates a Conditional Switch in the 3′-Untranslated Region of the VEGFA mRNA

    PubMed Central

    Yao, Peng; Potdar, Alka A.; Ray, Partho Sarothi; Eswarappa, Sandeepa M.; Flagg, Andrew C.; Willard, Belinda; Fox, Paul L.

    2013-01-01

    Cell regulatory circuits integrate diverse, and sometimes conflicting, environmental cues to generate appropriate, condition-dependent responses. Here, we elucidate the components and mechanisms driving a protein-directed RNA switch in the 3′UTR of vascular endothelial growth factor (VEGF)-A. We describe a novel HILDA (hypoxia-inducible hnRNP L–DRBP76–hnRNP A2/B1) complex that coordinates a three-element RNA switch, enabling VEGFA mRNA translation during combined hypoxia and inflammation. In addition to binding the CA-rich element (CARE), heterogeneous nuclear ribonucleoprotein (hnRNP) L regulates switch assembly and function. hnRNP L undergoes two previously unrecognized, condition-dependent posttranslational modifications: IFN-γ induces prolyl hydroxylation and von Hippel-Lindau (VHL)-mediated proteasomal degradation, whereas hypoxia stimulates hnRNP L phosphorylation at Tyr359, inducing binding to hnRNP A2/B1, which stabilizes the protein. Also, phospho-hnRNP L recruits DRBP76 (double-stranded RNA binding protein 76) to the 3′UTR, where it binds an adjacent AU-rich stem-loop (AUSL) element, “flipping” the RNA switch by disrupting the GAIT (interferon-gamma-activated inhibitor of translation) element, preventing GAIT complex binding, and driving robust VEGFA mRNA translation. The signal-dependent, HILDA complex coordinates the function of a trio of neighboring RNA elements, thereby regulating translation of VEGFA and potentially other mRNA targets. The VEGFA RNA switch might function to ensure appropriate angiogenesis and tissue oxygenation during conflicting signals from combined inflammation and hypoxia. We propose the VEGFA RNA switch as an archetype for signal-activated, protein-directed, multi-element RNA switches that regulate posttranscriptional gene expression in complex environments. PMID:23976881

  20. Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome.

    PubMed

    Därr, Roland; Nambuba, Joan; Del Rivero, Jaydira; Janssen, Ingo; Merino, Maria; Todorovic, Milena; Balint, Bela; Jochmanova, Ivana; Prchal, Josef T; Lechan, Ronald M; Tischler, Arthur S; Popovic, Vera; Miljic, Dragana; Adams, Karen T; Prall, F Ryan; Ling, Alexander; Golomb, Meredith R; Ferguson, Michael; Nilubol, Naris; Chen, Clara C; Chew, Emily; Taïeb, David; Stratakis, Constantine A; Fojo, Tito; Yang, Chunzhang; Kebebew, Electron; Zhuang, Zhengping; Pacak, Karel

    2016-12-01

    Worldwide, the syndromes of paraganglioma (PGL), somatostatinoma (SOM) and early childhood polycythemia are described in only a few patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A). This study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings into perspective these experiences with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11-46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8-38) and SOMs at 29 years (range 22-38). PGLs were multiple, recurrent and metastatic in 100, 100 and 29% of all cases, and SOMs in 40, 40 and 60%, respectively. All PGLs were primarily norepinephrine-producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [ 18 F]-fluorodihydroxyphenylalanine ([ 18 F]-FDOPA). Therefore, [ 18 F]-FDOPA PET/CT, not [ 68 Ga]-(DOTA)-[Tyr3]-octreotate ([ 68 Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges. © 2016 Society for Endocrinology.

  1. Polycythemia and paraganglioma with a novel somatic HIF2A mutation in a male.

    PubMed

    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.

  2. Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T).

    PubMed

    Alosi, Daniela; Bisgaard, Marie Luise; Hemmingsen, Sophie Nowak; Krogh, Lotte Nylandsted; Mikkelsen, Hanne Birte; Binderup, Marie Louise Mølgaard

    2017-02-01

    Evaluation of the pathogenicity of a gene variant of unknown significance (VUS) is crucial for molecular diagnosis and genetic counseling, but can be challenging. This is especially so in phenotypically variable diseases, such as von Hippel-Lindau disease (vHL). vHL is caused by germline mutations in the VHL gene, which predispose to the development of multiple tumors such as central nervous system hemangioblastomas and renal cell carcinoma (RCC). We propose a method for the evaluation of VUS pathogenicity through our experience with the VHL missense mutation c.241C>T (p.P81S). 1) Clinical evaluation of known variant carriers: We evaluated a family of five VHL p.P81S carriers, as well as the clinical characteristics of all the p.P81S carriers reported in the literature; 2) Evaluation of tumor tissue via genetic analysis, histology, and immunohistochemistry (IHC); 3) Assessment of the variant's impact on protein structure and function, using multiple databases, in silico algorithms, and reports of functional studies. Only one family member had clinical signs of vHL with early-onset RCC. IHC analysis showed no VHL protein expressed in the tumor, consistent with biallelic VHL inactivation. The majority of in silico algorithms reported p.P81S as possibly pathogenic in relation to vHL or RCC, but there were discrepancies. Functional studies suggest that p.P81S impairs the VHL protein's function. The VHL p.P81S mutation is most likely a low-penetrant pathogenic variant predisposing to RCC development. We suggest the above-mentioned method for VUS evaluation with use of different methods, especially a variety of in silico methods and tumor tissue analysis.

  3. Titanisierung von Implantatoberflächen

    NASA Astrophysics Data System (ADS)

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

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

  4. Wernher von Braun

    NASA Image and Video Library

    1968-01-22

    Dr. Wernher Von Braun, stands in front of a Saturn IB Launch Vehicle at Kennedy Space Center (KSC). Dr. Von Braun was Marshall's first Center Director (1960-1970). Under his leadership Marshall was responsible for the development of the Saturn rockets, the Skylab project and getting the United States into Space and landing on the moon with the Apollo missions.

  5. Beyond victimhood. The struggle of Munich anatomist Titus von Lanz during National Socialism.

    PubMed

    Schütz, Mathias; Waschke, Jens; Marckmann, Georg; Steger, Florian

    2015-09-01

    The article analyzes the life and career of the anatomist Titus von Lanz (1897-1967) of Munich focusing on the period of National Socialism (NS). Von Lanz lost his position as an associate professor at the Anatomical Institute of Munich University because of his marriage to a "half-Jewish" woman in 1938. In contrast to most of his colleagues affected by National Socialist measures, von Lanz had opportunities to save his career and made extensive use of them. His story is that of a complicated struggle for the continuation of his work, involving a wide range of supporters from prestigious physicians to high-ranking National Socialist officials as well as the alienation of his colleagues at the Munich department of anatomy. The article tries to clarify these developments through the presentation of his social background, his supporters, his enemies, the research he conducted during NS and von Lanz' own remembrance of these developments from the post-war period. It aims at laying out a critical appreciation of his motives and actions, thereby contributing to the understanding of individual behavior of anatomists under NS. Copyright © 2015 Elsevier GmbH. All rights reserved.

  6. Wernher von Braun

    NASA Image and Video Library

    1970-02-24

    Dr. von Braun was honored with a series of farewell events and ceremonies prior to his reassignment to NASA Headquarters in Washington, D.C. Alabama Governor Brewer greets Dr. von Braun following his speech at the front of the Madison County Courthouse in Huntsville, Alabama on February 24, 1970. Behind are Madison County Commissioner James Record, Huntsville Mayor Joe Davis, and U.S. Senator Sparkman.

  7. Wernher von Braun

    NASA Image and Video Library

    1969-07-24

    Apollo 11 splashdown celebration in Huntsville, Alabama, on July 24, 1969. Huntsville Alabama is the home of the Marshall Space Flight Center which developed the Saturn vehicles under the direction of Dr. von Braun. The photo shows Dr. von Braun speaking to the crowd at the Madison County Courthouse as Mayor Joe Davis, Madison County Commissioner James Record and City Council President Ken Johnson look on.

  8. Wernher von Braun

    NASA Image and Video Library

    1969-07-24

    Dr. von Braun is carried aloft on the shoulders of Huntsville city officials during the Apollo 11 celebration in Huntsville, Alabama, on July 24, 1969. Huntsville, Alabama is the home of the Marshall Space Flight Center which developed the Saturn vehicles under the direction of Dr. von Braun. The Apollo 11 lifted off in July and made the first marned lunar landing on the Moon.

  9. Free Space Analysis of the Scattered Electromagnetic Fields as a Dipole Approaches a Leaky Coaxial Cable.

    DTIC Science & Technology

    1981-12-01

    Transactions on Antennas and Propagation, Vol AP-4: 288-93 (July 1956). 16. Von Hippel , Arthur R. Dielectric Materials and Applications. New York: John Wiley...KA=1,10 AT-KA/10.0-0.05 P-11-ATAN (ANT/CD! ST I EOIST-SORT(A%T92.0,COIST#*Z.0) M(-SQ2T(dETAI*,2Z.0-dFTA*#2.0) ARC ISHO*EDIST CALL MODBES(ARG1,KL) ERIC

  10. Diagnosis and management of von Willebrand's syndrome.

    PubMed

    Rick, M E

    1994-05-01

    von Willebrand's disease is the most common of the inherited bleeding disorders. It is caused by quantitative and/or qualitative abnormalities of von Willebrand factor, and it usually presents with bleeding from mucosal surfaces. The diagnosis is confirmed by measuring von Willebrand factor activity and antigen levels, factor VIII activity, and performing a multimer analysis of von Willebrand factor. Treatment may require plasma-derived concentrates, but can often be accomplished with DDAVP, a vasopressin analogue that causes transient release of von Willebrand factor from body storage sites.

  11. A double commutant theorem for Murray–von Neumann algebras

    PubMed Central

    Liu, Zhe

    2012-01-01

    Murray–von Neumann algebras are algebras of operators affiliated with finite von Neumann algebras. In this article, we study commutativity and affiliation of self-adjoint operators (possibly unbounded). We show that a maximal abelian self-adjoint subalgebra of the Murray–von Neumann algebra associated with a finite von Neumann algebra is the Murray–von Neumann algebra , where is a maximal abelian self-adjoint subalgebra of and, in addition, is . We also prove that the Murray–von Neumann algebra with the center of is the center of the Murray–von Neumann algebra . Von Neumann’s celebrated double commutant theorem characterizes von Neumann algebras as those for which , where , the commutant of , is the set of bounded operators on the Hilbert space that commute with all operators in . At the end of this article, we present a double commutant theorem for Murray–von Neumann algebras. PMID:22543165

  12. Wernher von Braun

    NASA Image and Video Library

    1964-03-24

    Marshall Space Flight Center Director Dr. Wernher von Braun presents Lady Bird Johnson with an inscribed hard hat during the First Lady's March 24, 1964 visit. While at the Marshall Center, Mrs. Johnson addressed Center employees, toured facilities and witnessed test firings of a Saturn I first stage and an F-1 engine. Dr. von Braun is wearing a Texas hat presented to him months earlier by Lyndon Johnson during a visit to the Johnson ranch in Texas.

  13. Wernher von Braun

    NASA Image and Video Library

    1958-01-31

    Jet Propulsion Laboratory Director Dr. James Pickering, Dr. James van Allen of the State University of Iowa, and Army Ballistic missionile Agency Technical Director Dr. Wernher von Braun triumphantly display a model of the Explorer I, America's first satellite, shortly after the satellite's launch on January 31, 1958. The Jet Propulsion Laboratory packed and tested the payload, a radiation detection experiment designed by Dr. van Allen. Dr. von Braun's rocket team at Redstone Arsenal in Huntsville, Alabama, developed the Juno I launch vehicle, a modified Jupiter-C.

  14. Liquid Biopsy zur Überwachung von Melanompatienten.

    PubMed

    Gaiser, Maria Rita; von Bubnoff, Nikolas; Gebhardt, Christoffer; Utikal, Jochen Sven

    2018-04-01

    In den letzten sechs Jahren wurden verschiedene innovative systemische Therapien zur Behandlung des metastasierten malignen Melanoms (MM) entwickelt. Die konventionelle Chemotherapie wurde durch neuartige Primärtherapien abgelöst, darunter systemische Immuntherapien (Anti-CTLA4- und Anti-PD1-Antikörper; Zulassung von Anti-PDL1-Antikörpern erwartet) und Therapien, die gegen bestimmte Mutationen gerichtet sind (BRAF, NRAS und c-KIT). Daher stehen die behandelnden Ärzte neuen Herausforderungen gegenüber, beispielsweise der Stratifizierung von Patienten für geeignete Behandlungen und der Überwachung von Langzeit-Respondern auf Progression. Folglich werden zuverlässige Methoden zur Überwachung von Krankheitsprogression oder Behandlungsresistenz benötigt. Lokalisierte und fortgeschrittene Krebserkrankungen können zur Bildung zirkulierender Tumorzellen und Tumor-DNA (ctDNA) führen, die sich in Proben von peripherem Blut nachweisen und quantifizieren lassen (Liquid Biopsy). Im Fall von Melanompatienten können die Ergebnisse von Liquid Biopsy als neuartige prädiktive Biomarker bei therapeutischen Entscheidungen hilfreich sein, insbesondere im Zusammenhang mit mutationsbasierten zielgerichteten Therapien. Die Herausforderungen bei der Anwendung der Liquid Biopsy beinhalten strikte Kriterien für den Phänotyp der zirkulierenden MM-Zellen oder ihrer Fragmente und die Instabilität von ctDNA im Blut. In diesem Übersichtsartikel diskutieren wir die Beschränkungen der Liquid Biopsy hinsichtlich ihrer Anwendung in der Routinediagnostik. © 2018 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  15. p.Arg82Leu von Hippel-Lindau (VHL) Gene Mutation among Three Members of a Family with Familial Bilateral Pheochromocytoma in India: Molecular Analysis and In Silico Characterization

    PubMed Central

    John, Anulekha Mary; C, George Priya Doss; Ebenazer, Andrew; Seshadri, Mandalam Subramaniam; Nair, Aravindan; Rajaratnam, Simon; Pai, Rekha

    2013-01-01

    Various missense mutations in the VHL gene have been reported among patients with familial bilateral pheochromocytoma. However, the p.Arg82Leu mutation in the VHL gene described here among patients with familial bilateral pheochromocytoma, has never been reported previously in a germline configuration. Interestingly, long-term follow-up of these patients indicated that the mutation might have had little impact on the normal function of the VHL gene, since all of them have remained asymptomatic. We further attempted to correlate this information with the results obtained by in silico analysis of this mutation using SIFT, PhD-SNP SVM profile, MutPred, PolyPhen2, and SNPs&GO prediction tools. To gain, new mechanistic insight into the structural effect, we mapped the mutation on to 3D structure (PDB ID 1LM8). Further, we analyzed the structural level changes in time scale level with respect to native and mutant protein complexes by using 12 ns molecular dynamics simulation method. Though these methods predict the mutation to have a pathogenic potential, it remains to be seen if these patients will eventually develop symptomatic disease. PMID:23626751

  16. Dr. von Braun Briefing Walt Disney

    NASA Technical Reports Server (NTRS)

    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.

  17. Wernher von Braun

    NASA Image and Video Library

    1970-06-27

    This photograph was taken after Dr. von Braun moved from his post as Director of the Marshall Space Flight Center (MSFC) to Deputy Associate Administrator for Planning at NASA Headquarters. On June 27, 1970, he visited the MSFC again during the center’s 10th anniversary to look at a mockup of the spacecraft that would later be known as Skylab. With von Braun are (left to right): Herman K. Weidner, director of Science and Engineering at MSFC, and James R. Thompson of the center’s Astrionics Laboratory.

  18. Hypoxia inducible factor 1 links fast-patterned muscle activity and fast muscle phenotype in rats.

    PubMed

    Lunde, Ida G; Anton, Siobhan L; Bruusgaard, Jo C; Rana, Zaheer A; Ellefsen, Stian; Gundersen, Kristian

    2011-03-15

    Exercise influences muscle phenotype by the specific pattern of action potentials delivered to the muscle, triggering intracellular signalling pathways. PO2 can be reduced by an order of magnitude in working muscle. In humans, carriers of a hyperactive polymorphism of the transcription factor hypoxia inducible factor 1α (HIF-1α) have 50% more fast fibres, and this polymorphism is prevalent among strength athletes. We have investigated the putative role of HIF-1α in mediating activity changes in muscle.When rat muscles were stimulated with short high frequency bursts of action potentials known to induce a fast muscle phenotype, HIF-1α increased by about 80%. In contrast, a pattern consisting of long low frequency trains known to make fast muscles slow reduced the HIF-1α level of the fast extensor digitorum longus (EDL) muscle by 44%. Nuclear protein extracts from normal EDL contained 2.3-fold more HIF-1α and 4-fold more HIF-1β than the slow soleus muscle, while von-Hippel-Lindau protein was 4.8-fold higher in slow muscles. mRNA displayed a reciprocal pattern; thus FIH-1 mRNA was almost 2-fold higher in fast muscle, while the HIF-1α level was half, and consequently protein/mRNA ratio for HIF-1α was more than 4-fold higher in the fast muscle, suggesting that HIF-1α is strongly suppressed post-transcriptionally in slow muscles.When HIF-1α was overexpressed for 14 days after somatic gene transfer in adult rats, a slow-to-fast transformation was observed, encompassing an increase in fibre cross sectional area, oxidative enzyme activity and myosin heavy chain. The latter was shown to be regulated at the mRNA level in C2C12 myotubes.

  19. Automated noninvasive classification of renal cancer on multiphase CT

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Linguraru, Marius George; Wang, Shijun; Shah, Furhawn

    2011-10-15

    Purpose: To explore the added value of the shape of renal lesions for classifying renal neoplasms. To investigate the potential of computer-aided analysis of contrast-enhanced computed-tomography (CT) to quantify and classify renal lesions. Methods: A computer-aided clinical tool based on adaptive level sets was employed to analyze 125 renal lesions from contrast-enhanced abdominal CT studies of 43 patients. There were 47 cysts and 78 neoplasms: 22 Von Hippel-Lindau (VHL), 16 Birt-Hogg-Dube (BHD), 19 hereditary papillary renal carcinomas (HPRC), and 21 hereditary leiomyomatosis and renal cell cancers (HLRCC). The technique quantified the three-dimensional size and enhancement of lesions. Intrapatient and interphasemore » registration facilitated the study of lesion serial enhancement. The histograms of curvature-related features were used to classify the lesion types. The areas under the curve (AUC) were calculated for receiver operating characteristic curves. Results: Tumors were robustly segmented with 0.80 overlap (0.98 correlation) between manual and semi-automated quantifications. The method further identified morphological discrepancies between the types of lesions. The classification based on lesion appearance, enhancement and morphology between cysts and cancers showed AUC = 0.98; for BHD + VHL (solid cancers) vs. HPRC + HLRCC AUC = 0.99; for VHL vs. BHD AUC = 0.82; and for HPRC vs. HLRCC AUC = 0.84. All semi-automated classifications were statistically significant (p < 0.05) and superior to the analyses based solely on serial enhancement. Conclusions: The computer-aided clinical tool allowed the accurate quantification of cystic, solid, and mixed renal tumors. Cancer types were classified into four categories using their shape and enhancement. Comprehensive imaging biomarkers of renal neoplasms on abdominal CT may facilitate their noninvasive classification, guide clinical management, and monitor responses to drugs or interventions.« less

  20. New strategy for renal fibrosis: Targeting Smad3 proteins for ubiquitination and degradation.

    PubMed

    Wang, Xin; Feng, Shaozhen; Fan, Jinjin; Li, Xiaoyan; Wen, Qiong; Luo, Ning

    2016-09-15

    Smad3 is a critical signaling protein in renal fibrosis. Proteolysis targeting chimeric molecules (PROTACs) are small molecules designed to degrade target proteins via ubiquitination. They have three components: (1) a recognition motif for E3 ligase; (2) a linker; and (3) a ligand for the target protein. We aimed to design a new PROTAC to prevent renal fibrosis by targeting Smad3 proteins and using hydroxylated pentapeptide of hypoxia-inducible factor-1α as the recognition motif for von Hippel-Lindau (VHL) ubiquitin ligase (E3). Computer-aided drug design was used to find a specific ligand targeting Smad3. Surface plasmon resonance (SPR) was used to verify and optimize screening results. Synthesized PROTAC was validated by two-stage mass spectrometry. The PROTAC's specificity for VHL (E3 ligase) was proved with two human renal carcinoma cell lines, 786-0 (VHL(-)) and ACHN (VHL(+)), and its anti-fibrosis effect was tested in renal fibrosis cell models. Thirteen small molecular compounds (SMCs) were obtained from the Enamine library using GLIDE molecular docking program. SPR results showed that #8 SMC (EN300-72284) combined best with Smad3 (KD=4.547×10(-5)M). Mass spectrometry showed that synthesized PROTAC had the correct peptide molecular weights. Western blot showed Smad3 was degraded by PROTAC with whole-cell lysate of ACHN but not 786-0. Degradation, but not ubiquitination, of Smad3 was inhibited by proteasome inhibitor MG132. The upregulation of fibronectin and Collagen I induced by TGF-β1 in both renal fibroblast and mesangial cells were inhibited by PROTAC. The new PROTAC might prevent renal fibrosis by targeting Smad3 for ubiquitination and degradation. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. DNA hypermethylation profiles in squamous cell carcinoma of the vulva.

    PubMed

    Stephen, Josena K; Chen, Kang Mei; Raitanen, Misa; Grénman, Seija; Worsham, Maria J

    2009-01-01

    Gene silencing through promoter hypermethylation is a growing concept in the development of human cancers. In this study, we examined the contribution of aberrant methylation of promoter regions in methylation-prone tumor suppressors to the pathogenesis of vulvar cancer. Thirteen cell lines from 12 patients with squamous cell carcinoma of the vulva were evaluated for aberrant methylation status and gene copy number alterations, concomitantly, using the methylation-specific multiplex ligation-dependent probe amplification assay. Of the 22 tumor suppressor genes examined, aberrant methylation was observed for 9 genes: tumor protein p73 (TP73), fragile histidine triad (FHIT), von Hippel-Lindau (VHL), adenomatosis polyposis coli (APC), estrogen receptor 1 (ESR1), cyclin-dependent kinase inhibitor 2B (CDKN2B), death-associated protein kinase 1 (DAPK1), glutathione S-transferase pi (GSTP1), and immunoglobin superfamily, member 4 (IGSF4). The most frequently methylated genes included TP73 in 9 of 13 cell lines, and IGSF4, DAPK1, and FHIT in 3 of 13 cell lines. Methylation-specific polymerase chain reaction was performed for TP73 and FHIT to confirm aberrant methylation by methylation-specific multiplex ligation-dependent probe amplification. In the context of gene copy number and methylation status, both copies of the TP73 gene were hypermethylated. Loss or decreased mRNA expression of TP73 and IGSF4 by reverse transcription polymerase chain reaction confirmed aberrant methylation. Frequent genetic alterations of loss and gain of gene copy number included gain of GSTP1 and multiple endocrine neoplasia type 1 (MEN1), and loss of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) and IGSF4 in over 50% of the squamous cell carcinoma of the vulva cell lines. These findings underscore the contribution of both genetic and epigenetic events to the underlying pathogenesis of squamous cell carcinoma of the vulva.

  2. PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient's overall survival.

    PubMed

    Högner, Anica; Krause, Hans; Jandrig, Burkhard; Kasim, Mumtaz; Fuller, Tom Florian; Schostak, Martin; Erbersdobler, Andreas; Patzak, Andreas; Kilic, Ergin

    2018-03-01

    To identify the clinicopathological association of PBRM1 (Polybromo-1 gene) and VHL (von Hippel-Lindau gene) expression at mRNA and protein levels in clear cell renal cell carcinoma (ccRCC) and its role in tumor progression. Immunohistochemical analysis, Western blotting and qPCR analysis of PBRM1 and VHL were performed on fresh-frozen ccRCC and adjacent normal tissue obtained from 70 patients who underwent radical nephrectomy. In addition, a tissue microarray (TMA) from specimens of 326 ccRCC patients was used to evaluate the effect of loss of PBRM1 and VHL immunohistological expression on clinicopathological features as well as patient survival. In frozen tissue, PBRM1 and VHL mRNA were significantly down-regulated in most ccRCC tumors (77.6%/80.6%). Simultaneous weak PBRM1 and VHL protein expression was observed in 21.4% of frozen tumors. In the TMA samples, weak PBRM1 and VHL immunohistochemical staining was observed in 60.4% of the cases and was correlated (P<0.001). The association of PBRM1 and VHL immunohistochemical expression with clinicopathological parameters depicts a variable picture: predominantly weak PBRM1 and VHL expression were significantly associated with higher Fuhrman grade (P = 0.012 and 0.024, respectively) but only weak VHL expression was associated with a higher pT stage (P = 0.023). PBRM1 expression did not affect the overall survival, whereas weak VHL expression was associated with decreased patient overall survival (P = 0.013). Our data suggest that reduced expression of PBRM1 and VHL is correlated with an increased tumor aggressiveness. Low VHL expression was identified as a risk factor for worse patient overall survival, independently from PBRM1 expression pattern. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. The pVHL172 isoform is not a tumor suppressor and up-regulates a subset of pro-tumorigenic genes including TGFB1 and MMP13

    PubMed Central

    Hascoet, Pauline; Chesnel, Franck; Jouan, Florence; Goff, Cathy Le; Couturier, Anne; Darrigrand, Eric; Mahe, Fabrice; Rioux-Leclercq, Nathalie; Goff, Xavier Le; Arlot-Bonnemains, Yannick

    2017-01-01

    The von Hippel-Lindau (VHL) tumor suppressor gene is often deleted or mutated in ccRCC (clear cell renal cell carcinoma) producing a non-functional protein. The gene encodes two mRNA, and three protein isoforms (pVHL213, pVHL160 and pVHL172). The pVHL protein is part of an E3 ligase complex involved in the ubiquitination and proteasomal degradation of different proteins, particularly hypoxia inducible factors (HIF) that drive the transcription of genes involved in the regulation of cell proliferation, angiogenesis or extracellular matrix remodelling. Other non-canonical (HIF-independent) pVHL functions have been described. A recent work reported the expression of the uncharacterized protein isoform pVHL172 which is translated from the variant 2 by alternative splicing of the exon 2. This splice variant is sometimes enriched in the ccRCCs and the protein has been identified in the respective samples of ccRCCs and different renal cell lines. Functional studies on pVHL have only concerned the pVHL213 and pVHL160 isoforms, but no function was assigned to pVHL172. Here we show that pVHL172 stable expression in renal cancer cells does not regulate the level of HIF, exacerbates tumorigenicity when 786-O-pVHL172 cells were xenografted in mice. The pVHL172-induced tumors developed a sarcomatoid phenotype. Moreover, pVHL172 expression was shown to up regulate a subset of pro-tumorigenic genes including TGFB1, MMP1 and MMP13. In summary we identified that pVHL172 is not a tumor suppressor. Furthermore our findings suggest an antagonistic function of this pVHL isoform in the HIF-independent aggressiveness of renal tumors compared to pVHL213. PMID:29100286

  4. Knowledge of genetic testing for hereditary kidney cancer in Canada is lacking: The results of the Canadian national hereditary kidney cancer needs assessment survey

    PubMed Central

    Violette, Philippe D.; Kamel-Reid, Suzanne; Graham, Gail E.; Reaume, M. Neil; Jewett, Michael A.; Care, Melanie; Basiuk, Joan; Pautler, Stephen E.

    2014-01-01

    Introducton: Treatment of hereditary renal cell carcinoma (HRCC) requires a multidisciplinary approach that may involve medical oncologists, geneticists, genetic counsellors, and urologists. The objective of our survey was to obtain current and representative information about the use and perceived importance of genetic testing for HRCC in Canada. Methods: A self-administered web-based survey was provided to Canadian medical oncologists, geneticists, genetic counsellors, and urologists in collaboration with their respective associations. The survey was created through an iterative process in consultation with the Kidney Cancer Research Network of Canada and contained both quantitative and qualitative components. The survey was designed to be exploratory and results were compared across regions. Results: The overall response was low (6.6%). Of the respondents, 42%, 33%, 19%, 5% were genetic counsellors, urologists, medical oncologists and medical geneticists, respectively. Of the respondents, 62.7% described their practice as academic, and 37.3% described it as non-academic. Non-academic respondents tended to refer for genetic counselling less frequently than academic (48.6% vs. 67.2%). Most respondents believed that genetic testing for HRCC was available (82.8%), although 47.7% did not know which tests were available. This observation was consistent across provinces. Testing for Von Hippel-Lindau syndrome was given the highest priority among respondents. Limited provider knowledge, clinical guidelines, institutional funding, access, and poor coordination between disciplines were cited as barriers to testing. Interpretation: There is a need to increase provider knowledge of genetic testing for HRCC. These findings support the development of practice guidelines and national strategies to improve coordination of specialists and access to genetics services. Limitations of the present study include low survey response which did not allow for inferential analysis by

  5. Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta.

    PubMed

    Alahari, Sruthi; Post, Martin; Caniggia, Isabella

    2015-08-01

    Persistent low oxygen is implicated in the pathogenesis of placental-associated pathologies such as preeclampsia, a serious disorder of pregnancy. Emerging evidence implicates a novel family of Jumonji C catalytic domain proteins as mediators of hypoxic gene expression. Here, we investigated the regulatory relationship between Jumonji C domain containing protein 6 (JMJD6) and hypoxia-inducible factor (HIF)1A in the human placenta at physiological and pathological conditions. JMJD6 expression inversely correlated with changes in oxygen tension during early placental development, ie, high at 7-9 weeks when-partial pressure of O2 is low and declining afterwards when-partial pressure of O2 increases. Moreover, JMJD6 protein was significantly elevated in early-onset preeclamptic placentae, localizing to the syncytiotrophoblast layer and syncytial knots. Exposure of primary isolated trophoblast cells, human villous explants, and JEG3 choriocarcinoma cells to low oxygen (3%) and sodium nitroprusside (inducer of oxidative stress) also resulted in elevated JMJD6 levels, which was abrogated by HIF1A knockdown. In normoxia, knockdown of JMJD6 in JEG3 cells stabilized HIF1A with a concomitant decrease in von Hippel-Lindau (VHL) tumor suppressor protein, a negative regulator of HIF1A stability. In contrast, overexpression of JMJD6 enhanced VHL expression and destabilized HIF1A. JMJD6 regulation of VHL stability did not involve the ubiquitin-proteasome system but likely occurred through lysyl hydroxylation and small ubiquitin-like modifier 1-dependent small ubiquitin-like modifierylation. In summary, our data signify a novel role for JMJD6 as an oxygen sensor in the human placenta, and alterations in the JMJD6-VHL-HIF1A feedback loop may indirectly contribute to elevated HIF1A found in preeclampsia.

  6. Phaeochromocytoma: state-of-the-art.

    PubMed

    Donckier, J E; Michel, L

    2010-01-01

    Phaeochromocytomas are catecholamine-secreting tumours that arise from chromaffin cells of the adrenal medulla and extra-adrenal sites. Extra-adrenal phaeochromocytomas are called paragangliomas. A diagnosis of phaeochromocytoma is suspected by typical paroxysmal symptoms, unusual or refractory hypertension, discovery of an adrenal incidentaloma or a family history of phaeochromocytoma or paraganglioma, possibly associated with other genetic syndromes (multiple endocrine neoplasia type 2 A or B, neurofibromatosis type 1 and von Hippel-Lindau disease). It can be confirmed by measurements of urinary or plasma fractionated catecholamines and metanephrines. The best diagnostic performances are achieved by metanephrines. Twenty-four hour urine fractionated metanephrines are still recommended as a screening test but some experts prefer plasma measurements in high-risk patients. Increased serum chromogranin-A levels, combined with high catecholamine or metanephrine in a patient with normal renal function is also a tool, virtually diagnostic of phaeochromocytoma. Recent studies have suggested that 25% of patients with phaeochromocytoma have germline mutations of several genes (NF1, VHL, SDHD, SDHB and RET). Thus, genetic testing should be carried out according to an algorithm of risk factors and specific characteristics. Once a biochemical diagnosis of phaeochromocytoma is made, a CT scan or MRI of the abdomen and pelvis should be performed first. If these investigations remain negative, the chest and neck should be explored. After anatomical imaging, functional imaging by 123I-MIBG should be considered. If the MIBG scan is negative, other imaging modalities have recently proven to be useful (PET, Octreoscan). After localization, the treatment of phaeochromocytoma is a surgical resection, which may be laparoscopic. Preoperative preparation with alpha- and beta-adrenergic blockade and/or calcium channel blockers associated with volume expansion is essential. Malignant

  7. New HIF2α inhibitors: potential implications as therapeutics for advanced pheochromocytomas and paragangliomas.

    PubMed

    Toledo, Rodrigo Almeida

    2017-09-01

    Two recent independent studies published in Nature show robust responses of clear cell renal cell carcinoma (ccRCC) cell lines, preclinical ccRCC xenograft models and, remarkably, a patient with progressive ccRCC despite receiving multiple lines of treatment, to the long-awaited, recently developed inhibitors of hypoxia-inducible factor 2-alpha (HIF2α). This commentary published in Endocrine-Related Cancer is based on the recognition of similar molecular drivers in ccRCC and the endocrine neoplasias pheochromocytomas and paragangliomas (PPGLs), ultimately leading to stabilization of HIFs. HIF-stabilizing mutations have been detected in the von Hippel-Lindau (VHL) gene, as well as in other genes, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH) and transcription elongation factor B subunit 1 (TCEB1), as well as the gene that encodes HIF2α itself: EPAS1 HIF2α Importantly, the recent discovery of EPAS1 mutations in PPGLs and the results of comprehensive in vitro and in vivo studies revealing their oncogenic roles characterized a hitherto unknown direct mechanism of HIF2α activation in human cancer. The now available therapeutic opportunity to successfully inhibit HIF2α pharmacologically with PT2385 and PT2399 will certainly spearhead a series of investigations in several types of cancers, including patients with SDHB -related metastatic PPGL for whom limited therapeutic options are currently available. Future studies will determine the efficacy of these promising drugs against the hotspot EPAS1 mutations affecting HIF2α amino acids 529-532 (in PPGLs) and amino acids 533-540 (in erythrocytosis type 4), as well as against HIF2α protein activated by VHL , SDHx and FH mutations in PPGL-derived chromatin cells. © 2017 Society for Endocrinology.

  8. E2-EPF UCP Possesses E3 Ubiquitin Ligase Activity via Its Cysteine 118 Residue.

    PubMed

    Lim, Jung Hwa; Shin, Hee Won; Chung, Kyung-Sook; Kim, Nam-Soon; Kim, Ju Hee; Jung, Hong-Ryul; Im, Dong-Soo; Jung, Cho-Rok

    Here, we show that E2-EPF ubiquitin carrier protein (UCP) elongated E3-independent polyubiquitin chains on the lysine residues of von Hippel-Lindau protein (pVHL) and its own lysine residues both in vitro and in vivo. The initiation of the ubiquitin reaction depended on not only Lys11 linkage but also the Lys6, Lys48 and Lys63 residues of ubiquitin, which were involved in polyubiquitin chain formation on UCP itself. UCP self-association occurred through the UBC domain, which also contributed to the interaction with pVHL. The polyubiquitin chains appeared on the N-terminus of UCP in vivo, which indicated that the N-terminus of UCP contains target lysines for polyubiquitination. The Lys76 residue of UCP was the most critical site for auto-ubiquitination, whereas the polyubiquitin chain formation on pVHL occurred on all three of its lysines (Lys159, Lys171 and Lys196). A UCP mutant in which Cys118 was changed to alanine (UCPC118A) did not form a polyubiquitin chain but did strongly accumulate mono- and di-ubiquitin via auto-ubiquitination. Polyubiquitin chain formation required the coordination of Cys95 and Cys118 between two interacting molecules. The mechanism of the polyubiquitin chain reaction of UCP may involve the transfer of ubiquitin from Cys95 to Cys118 by trans-thiolation, with polyubiquitin chains forming at Cys118 by reversible thioester bonding. The polyubiquitin chains are then moved to the lysine residues of the substrate by irreversible isopeptide bonding. During the elongation of the ubiquitin chain, an active Cys118 residue is required in both parts of UCP, namely, the catalytic enzyme and the substrate. In conclusion, UCP possesses not only E2 ubiquitin conjugating enzyme activity but also E3 ubiquitin ligase activity, and Cys118 is critical for polyubiquitin chain formation.

  9. E2-EPF UCP Possesses E3 Ubiquitin Ligase Activity via Its Cysteine 118 Residue

    PubMed Central

    Lim, Jung Hwa; Shin, Hee Won; Chung, Kyung-Sook; Kim, Nam-Soon; Kim, Ju Hee; Jung, Hong-Ryul; Im, Dong-Soo; Jung, Cho-Rok

    2016-01-01

    Here, we show that E2-EPF ubiquitin carrier protein (UCP) elongated E3-independent polyubiquitin chains on the lysine residues of von Hippel-Lindau protein (pVHL) and its own lysine residues both in vitro and in vivo. The initiation of the ubiquitin reaction depended on not only Lys11 linkage but also the Lys6, Lys48 and Lys63 residues of ubiquitin, which were involved in polyubiquitin chain formation on UCP itself. UCP self-association occurred through the UBC domain, which also contributed to the interaction with pVHL. The polyubiquitin chains appeared on the N-terminus of UCP in vivo, which indicated that the N-terminus of UCP contains target lysines for polyubiquitination. The Lys76 residue of UCP was the most critical site for auto-ubiquitination, whereas the polyubiquitin chain formation on pVHL occurred on all three of its lysines (Lys159, Lys171 and Lys196). A UCP mutant in which Cys118 was changed to alanine (UCPC118A) did not form a polyubiquitin chain but did strongly accumulate mono- and di-ubiquitin via auto-ubiquitination. Polyubiquitin chain formation required the coordination of Cys95 and Cys118 between two interacting molecules. The mechanism of the polyubiquitin chain reaction of UCP may involve the transfer of ubiquitin from Cys95 to Cys118 by trans-thiolation, with polyubiquitin chains forming at Cys118 by reversible thioester bonding. The polyubiquitin chains are then moved to the lysine residues of the substrate by irreversible isopeptide bonding. During the elongation of the ubiquitin chain, an active Cys118 residue is required in both parts of UCP, namely, the catalytic enzyme and the substrate. In conclusion, UCP possesses not only E2 ubiquitin conjugating enzyme activity but also E3 ubiquitin ligase activity, and Cys118 is critical for polyubiquitin chain formation. PMID:27685940

  10. The two glycolytic markers GLUT1 and MCT1 correlate with tumor grade and survival in clear-cell renal cell carcinoma.

    PubMed

    Ambrosetti, Damien; Dufies, Maeva; Dadone, Bérengère; Durand, Matthieu; Borchiellini, Delphine; Amiel, Jean; Pouyssegur, Jacques; Rioux-Leclercq, Nathalie; Pages, Gilles; Burel-Vandenbos, Fanny; Mazure, Nathalie M

    2018-01-01

    Clear-cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. Although ccRCC is characterized by common recurrent genetic abnormalities, including inactivation of the von Hippel-Lindau (vhl) tumor suppressor gene resulting in stabilization of hypoxia-inducible factors (HIFs), the tumor aggressiveness and outcome of ccRCC is variable. New biomarkers are thus required to improve ccRCC diagnosis, prognosis and therapeutic options. This work aims to investigate the expression of HIF and proteins involved in metabolism and pH regulation. Their correlation to histoprognostic parameters and survival was analyzed. ccRCC of 45 patients were analyzed. HIF-1α, HIF-2α, HAF, GLUT1, MCT1, MCT4, CAIX and CAXII expression was assessed by immunohistochemistry in a semi-quantitative and qualitative manner. The GLUT1, MCT1, MCT4, CAIX and CAXII mRNA levels were analyzed in an independent cohort of 43 patients. A significant correlation was observed between increased GLUT1, MCT1, CAXII protein expression and a high Fuhrman grade in ccRCC patients. Moreover, while HIF-1α, HIF-2α and HAF expression was heterogenous within tumors, we observed and confirmed that HIF-2α co-localized with HAF. We confirmed, in an independent cohort, that GLUT1, MCT1 and CAXII mRNA levels correlated with the Fuhrman grade. Moreover, we demonstrated that the high mRNA level of both MCT1 and GLUT1 correlated with poor prognosis. This study demonstrates for the first time a link between the aggressiveness of high- Fuhrman grade ccRCC and metabolic reprogramming. It also confirms the role of HIF-2α and HAF in tumor invasiveness. Finally, these results demonstrate that MCT1 and GLUT1 are strong prognostic markers and promising therapeutic targets.

  11. Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation.

    PubMed

    Fu, Chenglai; Tyagi, Richa; Chin, Alfred C; Rojas, Tomas; Li, Ruo-Jing; Guha, Prasun; Bernstein, Isaac A; Rao, Feng; Xu, Risheng; Cha, Jiyoung Y; Xu, Jing; Snowman, Adele M; Semenza, Gregg L; Snyder, Solomon H

    2018-02-02

    Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. We have investigated the role of IPMK in regulating angiogenesis. Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α. © 2017 American Heart Association, Inc.

  12. The value of "liver windows" settings in the detection of small renal cell carcinomas on unenhanced computed tomography.

    PubMed

    Sahi, Kamal; Jackson, Stuart; Wiebe, Edward; Armstrong, Gavin; Winters, Sean; Moore, Ronald; Low, Gavin

    2014-02-01

    To assess if "liver window" settings improve the conspicuity of small renal cell carcinomas (RCC). Patients were analysed from our institution's pathology-confirmed RCC database that included the following: (1) stage T1a RCCs, (2) an unenhanced computed tomography (CT) abdomen performed ≤ 6 months before histologic diagnosis, and (3) age ≥ 17 years. Patients with multiple tumours, prior nephrectomy, von Hippel-Lindau disease, and polycystic kidney disease were excluded. The unenhanced CT was analysed, and the tumour locations were confirmed by using corresponding contrast-enhanced CT or magnetic resonance imaging studies. Representative single-slice axial, coronal, and sagittal unenhanced CT images were acquired in "soft tissue windows" (width, 400 Hounsfield unit (HU); level, 40 HU) and liver windows (width, 150 HU; level, 88 HU). In addition, single-slice axial, coronal, and sagittal unenhanced CT images of nontumourous renal tissue (obtained from the same cases) were acquired in soft tissue windows and liver windows. These data sets were randomized, unpaired, and were presented independently to 3 blinded radiologists for analysis. The presence or absence of suspicious findings for tumour was scored on a 5-point confidence scale. Eighty-three of 415 patients met the study criteria. Receiver operating characteristics (ROC) analysis, t test analysis, and kappa analysis were used. ROC analysis showed statistically superior diagnostic performance for liver windows compared with soft tissue windows (area under the curve of 0.923 vs 0.879; P = .0002). Kappa statistics showed "good" vs "moderate" agreement between readers for liver windows compared with soft tissue windows. Use of liver windows settings improves the detection of small RCCs on the unenhanced CT. Copyright © 2014 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.

  13. The functional interplay between the HIF pathway and the ubiquitin system - more than a one-way road.

    PubMed

    Günter, Julia; Ruiz-Serrano, Amalia; Pickel, Christina; Wenger, Roland H; Scholz, Carsten C

    2017-07-15

    The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue functions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalyzed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage. The best-studied function is the targeting of proteins for proteasomal degradation. The activity of E3 ligases is antagonized by proteins called deubiquitinases (or deubiquitinating enzymes), which negatively regulate ubiquitin chains. This is performed in most cases by the catalytic removal of these chains from the targeted protein. The HIF pathway is regulated in an oxygen-dependent manner by oxygen-sensing hydroxylases. Covalent modification of HIFα subunits leads to the recruitment of an E3 ligase complex via the von Hippel-Lindau (VHL) protein and the subsequent polyubiquitination and proteasomal degradation of HIFα subunits, demonstrating the regulation of the HIF pathway by the ubiquitin system. This unidirectional effect of an E3 ligase on the HIF pathway is the best-studied example for the interplay between these two important cellular processes. However, additional regulatory mechanisms of the HIF pathway through the ubiquitin system are emerging and, more recently, also the reciprocal regulation of the ubiquitin system through components of the HIF pathway. Understanding these mechanisms and their relevance for the activity of each other is of major importance for the comprehensive elucidation of the oxygen-dependent regulation of cellular processes. This review describes the current knowledge of the functional bidirectional interplay between the HIF pathway and the ubiquitin system on the protein level. Copyright © 2017

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

    PubMed Central

    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

  15. Novel insights into the polycythemia-paraganglioma-somatostatinoma syndrome

    PubMed Central

    Därr, Roland; Nambuba, Joan; Del Rivero, Jaydira; Janssen, Ingo; Merino, Maria; Todorovic, Milena; Balint, Bela; Jochmanova, Ivana; Prchal, Josef T.; Lechan, Ronald M.; Tischler, Arthur S.; Popovic, Vera; Miljic, Dragana; Adams, Karen T.; Prall, F. Ryan; Ling, Alexander; Golomb, Meredith R.; Ferguson, Michael; Nilubol, Naris; Chen, Clara C.; Chew, Emily; Taïeb, David; Stratakis, Constantine A.; Fojo, Tito; Yang, Chunzhang; Kebebew, Electron; Zhuang, Zhengping; Pacak, Karel

    2016-01-01

    The syndrome of paraganglioma (PGL), somatostatinoma (SOM), and early childhood polycythemia in patients with somatic mutations in the hypoxia-inducible factor 2 alpha (HIF2A) gene is described in only a few patients worldwide. The present study provides detailed information about the clinical aspects and course of 7 patients with this syndrome and brings these experiences into perspective with the pertinent literature. Six females and one male presented at a median age of 28 years (range 11–46). Two were found to have HIF2A somatic mosaicism. No relatives were affected. All patients were diagnosed with secondary polycythemia before age 8 and before PGL/SOM developed. PGLs were found at a median age of 17 years (range 8–38) and SOMs at 29 years (range 22–38). PGLs were multiple, recurrent, and metastatic in 100%, 100%, and 29% of all cases, and SOMs in 40%, 40%, and 60%, respectively. All PGLs were primarily norepinephrine producing. All patients had abnormal ophthalmologic findings and those with SOMs had gallbladder disease. Computed tomography (CT) and magnetic resonance imaging revealed cystic lesions at multiple sites and hemangiomas in 4 patients (57%), previously thought to be pathognomonic for von Hippel-Lindau disease. The most accurate radiopharmaceutical to detect PGL appeared to be [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA). Therefore, [18F]-FDOPA PET/CT, not [68Ga]-(DOTA)-[Tyr3]-octreotate ([68Ga]-DOTATATE) PET/CT is recommended for tumor localization and aftercare in this syndrome. The long-term prognosis of the syndrome is unknown. However, to date no deaths occurred after 6 years follow-up. Physicians should be aware of this unique syndrome and its diagnostic and therapeutic challenges. PMID:27679736

  16. Verbesserung der Symmetrie von Hirnaufnahmen entlang der Sagittalebene

    NASA Astrophysics Data System (ADS)

    Ens, Konstantin; Wenzel, Fabian; Fischer, Bernd

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

  17. Structure-Guided Design of Peptides as Tools to Probe the Protein-Protein Interaction between Cullin-2 and Elongin BC Substrate Adaptor in Cullin RING E3 Ubiquitin Ligases.

    PubMed

    Cardote, Teresa A F; Ciulli, Alessio

    2017-09-21

    Cullin RING E3 ubiquitin ligases (CRLs) are large dynamic multi-subunit complexes that control the fate of many proteins in cells. CRLs are attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. Herein we describe a structure-guided biophysical approach to probe the protein-protein interaction (PPI) between the Cullin-2 scaffold protein and the adaptor subunits Elongin BC within the context of the von Hippel-Lindau complex (CRL2 VHL ) using peptides. Two peptides were shown to bind at the targeted binding site on Elongin C, named the "EloC site", with micromolar dissociation constants, providing a starting point for future optimization. Our results suggest ligandability of the EloC binding site to short linear peptides, unveiling the opportunity and challenges to develop small molecules that have the potential to target selectively the Cul2-adaptor PPI within CRLs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. A note on derivations of Murray–von Neumann algebras

    PubMed Central

    Kadison, Richard V.; Liu, Zhe

    2014-01-01

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

  19. A note on derivations of Murray-von Neumann algebras.

    PubMed

    Kadison, Richard V; Liu, Zhe

    2014-02-11

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

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

    PubMed

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

    2018-03-01

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

  1. Report on von Willebrand Disease in Malaysia

    PubMed Central

    Periayah, Mercy Halleluyah; Halim, Ahmad Sukari; Saad, Arman Zaharil Mat; Yaacob, Nik Soriani; Karim, Faraizah Abdul

    2016-01-01

    BACKGROUND: Von Willebrand disease (vWD) is an inherited hemostatic disorder that affects the hemostasis pathway. The worldwide prevalence of vWD is estimated to be 1% of the general population but only 0.002% in Malaysia. AIM: Our present paper has been written to disclose the statistical counts on the number of vWD cases reported from 2011 to 2013. MATERIAL AND METHODS: This article is based on sociodemographic data, diagnoses and laboratory findings of vWD in Malaysia. A total of 92 patients were reported to have vWD in Malaysia from 2011 to 2013. RESULTS: Sociodemographic-analysis revealed that 60% were females, 63% were of the Malay ethnicity, 41.3% were in the 19-44 year old age group and 15.2% were from Sabah, with the East region having the highest registered number of vWD cases. In Malaysia, most patients are predominately affected by vWD type 1 (77.2%). Factor 8, von Willebrand factor: Antigen and vWF: Collagen-Binding was the strongest determinants in the laboratory profiles of vWD. CONCLUSION: This report has been done with great interest to provide an immense contribution from Malaysia, by revealing the statistical counts on vWD from 2011-2013. PMID:27275342

  2. Dr. von Braun In Front of a Display of Missiles

    NASA Technical Reports Server (NTRS)

    1960-01-01

    In this photo, Director of the US Army Ballistic Missile Agency (ABMA) Development Operations Division, Dr. Wernher von Braun, is standing before a display of Army missiles celebrating ABMA's Fourth Open House. The missiles in the background include (left to right) a satellite on a Juno II shroud with a Nike Ajax pointing left in front of a Jupiter missile. The Lacrosse is in front of the Juno II. The Nike Hercules points skyward in front of the Juno II and the Redstone.

  3. Strategic Studies Quarterly: An Air Force-Sponsored Strategic Forum for Military, Government, and Academic Professionals. Volume 2, Number 1

    DTIC Science & Technology

    2008-03-01

    School of, la. \\ Ir . Blazejewski would like to thank Frank von Hippel and R. Scott Kemp for their comments on an earlier version of t is article. S< 5...example, - homas E Homer-Dixon, "Environmental Scarcities and Violent Conflict: Evidence from Cases," International Security 19, no. 1 (Summer 1994): 5...of AFRICOM. .3. Michael Clough, Free At Last? US Po/ity toward Africa and the h-nd oe’the Cold W" Ir (NcX York: Council on Foreign Relations Press

  4. Clarifying the link between von Neumann and thermodynamic entropies

    NASA Astrophysics Data System (ADS)

    Deville, Alain; Deville, Yannick

    2013-01-01

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

  5. An MRI Von Economo - Koskinas atlas.

    PubMed

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

    2018-04-15

    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.

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

    PubMed

    Schmidt, G; Holubar, K

    1990-01-01

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

  7. von Willebrand's disease antigen II. A new plasma and platelet antigen deficient in severe von Willebrand's disease.

    PubMed Central

    Montgomery, R R; Zimmerman, T S

    1978-01-01

    Factor VIII-related antigen (VIIIag) is deficient in plasma and platelets of patients with severe von Willebrand's disease. This study reports a second von Willebrand's disease antigen (vWagII), distinct from VIIIag, that is also deficient in the platelets and plasma of patients with severe von Willebrand's disease. VIIIag and vWagII are separable by molecular exclusion chromatography, sucrose density gradient ultracentrifugation, and crossed immunoelectrophoresis. They show reactions of immunologic nonidentity with each other, and thus, do not share a precursor-product relationship. vWagII is released from normal platelets during blood clotting, accounting for a fourfold higher concentration of vWagII in serum over plasma. Images PMID:307007

  8. Wernher von Braun

    NASA Image and Video Library

    1962-12-20

    Dr. von Braun, Major General Francis McMorrow, and Alabama Governor, John Patterson (far left) participated in the ground breaking ceremony for the University of Alabama Research Institute in Huntsville, December 20, 1962.

  9. Wernher von Braun

    NASA Image and Video Library

    1965-11-05

    In this photograph, Marshall Space Flight Center Director, Dr. Wernher von Braun, presents a Co-Inventor’s award to MSFC employee Martin Hall of the Mechanical Engineering Laboratory during the NASA Anniversary ceremony.

  10. Dr. Wernher Von Braun Memorial Dinner

    NASA Image and Video Library

    2017-10-26

    The annual Dr. Wernher Von Braun Memorial Dinner was held at the U.S. Space and Rocket Center's Davidson Center on October 26, 2017 with Keynote speaker General John Hyten, Commander of U.S. Strategic Command. Emcee was Mark Larson of Mark Larson Media Services, Inc. Dr. Wernher Von Braun Memorial Scholarships were presented to 8 college students by the National Space Club. Educator of the Year was awarded to Tammy Thorpe; Community Service award was presented to Huntsville, Al. Mayor Tommy Battle. The Communications Award was presented to retired astronaut Dr. Mike Massimino. The Distinguished Science Award was presented to Dr. Martin Weisskopf. The Astronautics Engineer Award was presented to Douglas R. Cooke. The Dr. Wernher Von Braun Space Flight Trophy was presented to Robert Lightfoot.

  11. Wernher von Braun

    NASA Image and Video Library

    1967-08-28

    Marshall Space Flight Center’s (MSFC) director, Dr. Wernher von Braun (right), inspects a component of a laser experiment being conducted in MSFC’s Space Sciences Laboratory during a tour on August 28, 1967.

  12. Wernher von Braun

    NASA Image and Video Library

    1962-09-11

    Marshall Space Flight Center Director Dr. Wernher von Braun explains a detail from a Saturn IB mockup and engine to President John F. Kennedy, Vice President Lyndon Johnson and other guests, September 11, 1962.

  13. Bewertung von Fahrzeuggeräuschen

    NASA Astrophysics Data System (ADS)

    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).

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

    NASA Astrophysics Data System (ADS)

    Schneider, Ivo

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

  15. Wernher von Braun

    NASA Image and Video Library

    1962-01-01

    Dr. Wernher von Braun, Director of the Marshall Space Flight Center (MSFC), during his tour of the Space information Division of North American Aviation (NAA) in Downey, California, where the Saturn SII stage was developed.

  16. Wernher von Braun

    NASA Image and Video Library

    1964-10-14

    This photograph, dated October 14, 1964, was taken at the Marned Spacecraft Center, now the Johnson Space Center in Houston, Texas. Dr. von Braun is shown looking over consoles in the Manned Spaceflight Control Center.

  17. Regional Morphology Analysis Package (RMAP): Empirical Orthogonal Function Analysis, Background and Examples

    DTIC Science & Technology

    2007-10-01

    1984. Complex principal component analysis : Theory and examples. Journal of Climate and Applied Meteorology 23: 1660-1673. Hotelling, H. 1933...Sediments 99. ASCE: 2,566-2,581. Von Storch, H., and A. Navarra. 1995. Analysis of climate variability. Applications of statistical techniques. Berlin...ERDC TN-SWWRP-07-9 October 2007 Regional Morphology Empirical Analysis Package (RMAP): Orthogonal Function Analysis , Background and Examples by

  18. Wernher von Braun

    NASA Image and Video Library

    1959-03-03

    Dr. von Braun, Director of the Development Operations Divisons, and Dr. Debus, Director of the Missile Firing Laboratory; Army Ballistic Missile Agency (ABMA), in the blockhouse during the launch of the Pioneer IV, March 3, 1959.

  19. Wernher von Braun

    NASA Image and Video Library

    1960-11-03

    Marshall Space Flight Center’s (MSFC) Director, Dr. Wernher von Braun, is pictured here with Army Ballistic Missile Agency’s (ABMA) Commanding General, J.B. Medaris, before a display of Army missles at the ABMA test lab.

  20. Childhood Picture of Dr. von Braun

    NASA Technical Reports Server (NTRS)

    1912-01-01

    This is a childhood picture of Dr. von Braun (center) with his brothers. Dr. Wernher von Braun was born in Wirsitz, Germany, March 23, 1912. His childhood dreams of marned space flight were fulfilled when giant Saturn rockets, developed under his direction at NASA's Marshall Space Flight Center, boosted the manned Apollo spacecraft to the Moon. His life was dedicated to expanding man's knowledge through the exploration of space.

  1. Laboratory diagnosis of von Willebrand's disease.

    PubMed

    Rick, M E

    1994-12-01

    The diagnosis of von Willebrand's disease is becoming complex as more is understood about the disease. Clinical information and laboratory data are necessary for the diagnosis because of the overlap of normal and abnormal laboratory values. A complete evaluation including von Willebrand factor multimers, ristocetin-induced platelet aggregation, factor VIII activity level, and a template bleeding time is necessary to correctly classify the patient so that optimal treatment may be given.

  2. Wernher von Braun

    NASA Image and Video Library

    1959-01-01

    Marshall Space Flight Center Director Wernher von Braun presents General J.B. Medaris with a new golf bag. General Medaris, (left) was a Commander of the Army Ballistic Missile Agency (ABMA) in Redstone Arsenal, Alabama during 1955 to 1958.

  3. Dr. von Braun Tries Out the NBS

    NASA Technical Reports Server (NTRS)

    1967-01-01

    Marshall Space Flight Center (MSFC) Director, Dr. von Braun, is shown fitted with suit and diving equipment as he prepares for a tryout in the MSFC Neutral Buoyancy Simulator (NBS). Weighted to a neutrally buoyant condition, Dr. von Braun was able to perform tasks underwater which simulated weightless conditions found in space.

  4. Wernher von Braun

    NASA Image and Video Library

    1950-01-01

    Dr. von Braun stands beside a model of the upper stage (Earth-returnable stage) of the three-stage launch vehicle built for the series of the motion picture productions of space flight produced by Walt Disney in the mid-1950's.

  5. Wernher von Braun

    NASA Image and Video Library

    1959-01-01

    In this picture, Dr. Wernher von Braun, who was serving as Director of the Army Ballistic Missile Agency's (ABMA) Development Operations Division, is shown posed with his Mercedes 220SE automobile in front of Redstone Building 4488, which houses the ABMA.

  6. Von Neumann was not a Quantum Bayesian.

    PubMed

    Stacey, Blake C

    2016-05-28

    Wikipedia has claimed for over 3 years now that John von Neumann was the 'first quantum Bayesian'. In context, this reads as stating that von Neumann inaugurated QBism, the approach to quantum theory promoted by Fuchs, Mermin and Schack. This essay explores how such a claim is, historically speaking, unsupported. © 2016 The Author(s).

  7. Herstellung von Chitosan und einige Anwendungen

    NASA Astrophysics Data System (ADS)

    Struszczyk, Marcin Henryk

    2001-05-01

    1. Die Deacetylierung von crabshell - Chitosan führte gleichzeitig zu einem drastischen Abfall der mittleren viscosimetrischen Molmasse ( Mv), insbesondere wenn die Temperatur und die Konzentration an NaOH erhöht werden. Diese Parameter beeinflussten jedoch nicht den Grad der Deacetylierung (DD). Wichtig ist jedoch die Quelle des Ausgangsmaterials: Chitin aus Pandalus borealis ist ein guter Rohstoff für die Herstellung von Chitosan mit niedrigem DD und gleichzeitig hoher mittlerer Mv, während Krill-Chitin (Euphausia superba) ein gutes Ausgangsmaterial zur Herstellung von Chitosan mit hohem DD und niedrigem Mv ist. Chitosan, das aus Insekten (Calliphora erythrocephala), unter milden Bedingungen (Temperatur: 100°C, NaOH-Konzentration: 40 %, Zeit: 1-2h ) hergestellt wurde, hatte die gleichen Eigenschaften hinsichtlich DD und Mv wie das aus Krill hergestellte Chitosan. Der Bedarf an Zeit, Energie und NaOH ist für die Herstellung von Insekten-Chitosan geringer als für crabshell-Chitosan vergleichbare Resultaten für DD und Mv. 2. Chitosan wurde durch den Schimmelpilz Aspergillus fumigatus zu Chitooligomeren fermentiert. Die Ausbeute beträgt 25%. Die Chitooligomere wurden mit Hilfe von HPLC und MALDI-TOF-Massenspektrmetrie identifiziert. Die Fermentationsmischung fördert die Immunität von Pflanzen gegen Bakterien und Virusinfektion. Die Zunahme der Immunität schwankt jedoch je nach System Pflanze-Pathogen. Die Fermentation von Chitosan durch Aspergillus fumigatus könnte eine schnelle und billige Methode zur Herstellung von Chitooligomeren mit guter Reinheit und Ausbeute sein. Eine partiell aufgereinigte Fermentationsmischung dieser Art könnte in der Landwirtschaft als Pathogeninhibitor genutzt werden. Durch kontrollierte Fermentation, die Chitooligomere in definierter Zusammensetzung (d.h. definierter Verteilung des Depolymerisationsgrades) liefert, könnte man zu Mischungen kommen, die für die jeweilige Anwendung eine optimale Bioaktivität besitzen. 3

  8. Locally Compact Quantum Groups. A von Neumann Algebra Approach

    NASA Astrophysics Data System (ADS)

    Van Daele, Alfons

    2014-08-01

    In this paper, we give an alternative approach to the theory of locally compact quantum groups, as developed by Kustermans and Vaes. We start with a von Neumann algebra and a comultiplication on this von Neumann algebra. We assume that there exist faithful left and right Haar weights. Then we develop the theory within this von Neumann algebra setting. In [Math. Scand. 92 (2003), 68-92] locally compact quantum groups are also studied in the von Neumann algebraic context. This approach is independent of the original C^*-algebraic approach in the sense that the earlier results are not used. However, this paper is not really independent because for many proofs, the reader is referred to the original paper where the C^*-version is developed. In this paper, we give a completely self-contained approach. Moreover, at various points, we do things differently. We have a different treatment of the antipode. It is similar to the original treatment in [Ann. Sci. & #201;cole Norm. Sup. (4) 33 (2000), 837-934]. But together with the fact that we work in the von Neumann algebra framework, it allows us to use an idea from [Rev. Roumaine Math. Pures Appl. 21 (1976), 1411-1449] to obtain the uniqueness of the Haar weights in an early stage. We take advantage of this fact when deriving the other main results in the theory. We also give a slightly different approach to duality. Finally, we collect, in a systematic way, several important formulas. In an appendix, we indicate very briefly how the C^*-approach and the von Neumann algebra approach eventually yield the same objects. The passage from the von Neumann algebra setting to the C^*-algebra setting is more or less standard. For the other direction, we use a new method. It is based on the observation that the Haar weights on the C^*-algebra extend to weights on the double dual with central support and that all these supports are the same. Of course, we get the von Neumann algebra by cutting down the double dual with this unique

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

    NASA Technical Reports Server (NTRS)

    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.

  10. Color constancy: enhancing von Kries adaption via sensor transformations

    NASA Astrophysics Data System (ADS)

    Finlayson, Graham D.; Drew, Mark S.; Funt, Brian V.

    1993-09-01

    Von Kries adaptation has long been considered a reasonable vehicle for color constancy. Since the color constancy performance attainable via the von Kries rule strongly depends on the spectral response characteristics of the human cones, we consider the possibility of enhancing von Kries performance by constructing new `sensors' as linear combinations of the fixed cone sensitivity functions. We show that if surface reflectances are well-modeled by 3 basis functions and illuminants by 2 basis functions then there exists a set of new sensors for which von Kries adaptation can yield perfect color constancy. These new sensors can (like the cones) be described as long-, medium-, and short-wave sensitive; however, both the new long- and medium-wave sensors have sharpened sensitivities -- their support is more concentrated. The new short-wave sensor remains relatively unchanged. A similar sharpening of cone sensitivities has previously been observed in test and field spectral sensitivities measured for the human eye. We present simulation results demonstrating improved von Kries performance using the new sensors even when the restrictions on the illumination and reflectance are relaxed.

  11. Dr. von Braun With Management Team

    NASA Technical Reports Server (NTRS)

    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.

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

    NASA Technical Reports Server (NTRS)

    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.

  13. Alexander von Humboldt and the concept of animal electricity.

    PubMed

    Kettenmann, H

    1997-06-01

    More than two hundred years ago, Alexander von Humboldt helped to establish Galvani's view that muscle and nerve tissue are electrically excitable. His 1797 publication was a landmark for establishing the concept of animal electricity. Almost half a century later, von Humboldt became the mentor of the young du Bois-Reymond. With the help of von Humboldt's promotion, du Bois-Reymond demonstrated convincingly that animal tissue has the intrinsic capacity to generate electrical activity, and thus laid the ground for modern electrophysiology.

  14. Purification and characterization of a novel polysaccharide-peptide complex from Clinacanthus nutans Lindau leaves.

    PubMed

    Huang, Danmin; Li, Yunhong; Cui, Fengjie; Chen, Jun; Sun, Jiamin

    2016-02-10

    A novel polysaccharide-peptide complex CNP-1-2 with molecular weight of 9.17 × 10(4) Da was obtained from Clinacanthus nutans Lindau leaves by hot water extraction, ethanol precipitation, and purification with Superdex 200 and DEAE-Sepharose Fast Flow column chromatography. CNP-1-2 exhibited the highest growth inhibitory effect on human gastric cancer cells SGC-7901 with inhibition ratio of 92.34% and stimulated activation of macrophages with NO secretion level of 47.53 μmol/L among the polysaccharide fractions. CNP-1-2 comprised approximately 87.25% carbohydrate and 9.37% protein. Monosaccharide analysis suggested that CNP-1-2 was composed of L-rhamnose, l-arabinose, D-mannose, D-glucose and D-galactose with a molar ratio of 1.30:1.00:2.56:4.95:5.09. Methylation analysis, FT-IR, and (1)H NMR spectroscopy analysis revealed that CNP-1-2 might have a backbone consisting of 1,4-linked Glcp, 1,3-linked Glcp, 1,3-linked Manp, 1,4-linked Galp, 1,2,6-linked Galp and 1,2,6-linked Galp. Its side chain might be composed of 1-linked Araf, 1,6-linked Galp and 1-linked Rhap residues. AFM (atomic force micrograph) analysis revealed that CNP-1-2 had the molecular aggregation along with branched and entangled structure. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Dr. von Braun With German Rocket Experimenters

    NASA Technical Reports Server (NTRS)

    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.

  16. von Kármán swirling flow between a rotating and a stationary smooth disk: Experiment

    NASA Astrophysics Data System (ADS)

    Mukherjee, Aryesh; Steinberg, Victor

    2018-01-01

    Precise measurements of the torque in a von Kármán swirling flow between a rotating and a stationary smooth disk in three Newtonian fluids with different dynamic viscosities are reported. From these measurements the dependence of the normalized torque, called the friction coefficient, on Re is found to be of the form Cf=1.17 (±0.03 ) Re-0.46±0.003 where the scaling exponent and coefficient are close to that predicted theoretically for an infinite, unshrouded, and smooth rotating disk which follows from an exact similarity solution of the Navier-Stokes equations, obtained by von Kármán. An error analysis shows that deviations from the theory can be partially caused by background errors. Measurements of the azimuthal Vθ and axial velocity profiles along radial and axial directions reveal that the flow core rotates at Vθ/r Ω ≃0.22 (up to z ≈4 cm from the rotating disk and up to r0/R ≃0.25 in the radial direction) in spite of the small aspect ratio of the vessel. Thus the friction coefficient shows scaling close to that obtained from the von Kármán exact similarity solution, but the observed rotating core provides evidence of the Batchelor-like solution [Q. J. Mech. Appl. Math. 4, 29 (1951), 10.1093/qjmam/4.1.29] different from the von Kármán [Z. Angew. Math. Mech. 1, 233 (1921), 10.1002/zamm.19210010401] or Stewartson [Proc. Camb. Philos. Soc. 49, 333 (1953), 10.1017/S0305004100028437] one.

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

    NASA Astrophysics Data System (ADS)

    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.

  18. Wernher von Braun

    NASA Image and Video Library

    1964-10-14

    This photograph is dated October 14, 1964, and shows Dr. von Braun, left, during a tour of the NASA Marned Spacecraft Center, now the Johnson Space Center. He is with Dr. J.P. Kuettner, center, from the Marshall Space Flight Center, and Warren J. North from the Manned Spacecraft Center.

  19. Dr. von Braun with Seven Original Mercury Astronauts

    NASA Technical Reports Server (NTRS)

    1959-01-01

    In this photo, Dr. Wernher von Braun, Director of the U.S. Army Ballistic Missile Agency's (ABMA) Development Operations Division, is shown briefing the seven original Mercury astronauts in ABMA's Fabrication Laboratory. (Left to right) Guss Grissom, Walter Schirra, Alan Shepard, John Glenn, Scott Carpenter, Gordon Cooper, Donald Slayton, and Dr. von Braun.

  20. Role of Fractionated External Beam Radiotherapy in Hemangioblastoma of the Central Nervous System

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Koh, Eng-Siew; Nichol, Alan; Millar, Barbara-Ann

    2007-12-01

    Purpose: To assess the clinical outcomes and toxicity in patients receiving fractionated external beam radiotherapy (EBRT) for hemangioblastoma of the central nervous system, treated at two Canadian radiation oncology institutions. Methods and Materials: Between January 1980 and December 2004, the data of all patients receiving EBRT for central nervous system hemangioblastoma were retrospectively reviewed. The patient, tumor, and treatment characteristics were collected and overall survival, disease-free survival, and EBRT-related toxicities assessed. Results: A total of 18 cases, 5 associated with von Hippel-Lindau disease (VHL) and 13 sporadic (non-VHL), with a total 31 lesions, were documented. These were located in themore » cerebellum in 20 and spinal cord in 8 patients. EBRT was delivered for recurrence in 12, adjuvantly for residual disease in 4, and definitively in 2. The EBRT schedules ranged from 50.0 to 55.8 Gy in 1.8-2.0-Gy daily fractions (n = 17), typically with parallel-opposed fields to the cerebellar target volumes and direct posterior fields for spinal disease. At a median follow-up of 5.1 years (range, 0.1-14.5), the 5-year OS rate was 69% (95% confidence interval [CI], 50-96%), decreasing to 30% (95% CI, 10-87%) at 10 years. The disease-free survival rate at 5 and 10 years was 57% (95% CI, 37-87%) and 30% (95% CI, 11-83%), respectively. The outcomes differed according to VHL status. The 5-year OS rate was 100% for those with VHL compared with 55% (95% CI, 32-95%) for those with non-VHL disease (log-rank p = 0.003), and the 5-year disease-free survival rate was 80% (95% CI, 52-100%) with VHL compared with 48% (95% CI, 26-89%) without (log-rank p = 0.036). Conclusions: Fractionated EBRT has a role in the management of extensive intracranial and/or spinal cord disease, the adjuvant treatment of residual postoperative disease, and the treatment of recurrence. More favorable outcomes were reported for VHL-associated lesions than for sporadic cases.« less

  1. A Splice Variant of the Human Ion Channel TRPM2 Modulates Neuroblastoma Tumor Growth through Hypoxia-inducible Factor (HIF)-1/2α*

    PubMed Central

    Chen, Shu-jen; Hoffman, Nicholas E.; Shanmughapriya, Santhanam; Bao, Lei; Keefer, Kerry; Conrad, Kathleen; Merali, Salim; Takahashi, Yoshinori; Abraham, Thomas; Hirschler-Laszkiewicz, Iwona; Wang, JuFang; Zhang, Xue-Qian; Song, Jianliang; Barrero, Carlos; Shi, Yuguang; Kawasawa, Yuka Imamura; Bayerl, Michael; Sun, Tianyu; Barbour, Mustafa; Wang, Hong-Gang; Madesh, Muniswamy; Cheung, Joseph Y.; Miller, Barbara A.

    2014-01-01

    The calcium-permeable ion channel TRPM2 is highly expressed in a number of cancers. In neuroblastoma, full-length TRPM2 (TRPM2-L) protected cells from moderate oxidative stress through increased levels of forkhead box transcription factor 3a (FOXO3a) and superoxide dismutase 2. Cells expressing the dominant negative short isoform (TRPM2-S) had reduced FOXO3a and superoxide dismutase 2 levels, reduced calcium influx in response to oxidative stress, and enhanced reactive oxygen species, leading to decreased cell viability. Here, in xenografts generated with SH-SY5Y neuroblastoma cells stably expressing TRPM2 isoforms, growth of tumors expressing TRPM2-S was significantly reduced compared with tumors expressing TRPM2-L. Expression of hypoxia-inducible factor (HIF)-1/2α was significantly reduced in TRPM2-S-expressing tumor cells as was expression of target proteins regulated by HIF-1/2α including those involved in glycolysis (lactate dehydrogenase A and enolase 2), oxidant stress (FOXO3a), angiogenesis (VEGF), mitophagy and mitochondrial function (BNIP3 and NDUFA4L2), and mitochondrial electron transport chain activity (cytochrome oxidase 4.1/4.2 in complex IV). The reduction in HIF-1/2α was mediated through both significantly reduced HIF-1/2α mRNA levels and increased levels of von Hippel-Lindau E3 ligase in TRPM2-S-expressing cells. Inhibition of TRPM2-L by pretreatment with clotrimazole or expression of TRPM2-S significantly increased sensitivity of cells to doxorubicin. Reduced survival of TRPM2-S-expressing cells after doxorubicin treatment was rescued by gain of HIF-1 or -2α function. These data suggest that TRPM2 activity is important for tumor growth and for cell viability and survival following doxorubicin treatment and that interference with TRPM2-L function may be a novel approach to reduce tumor growth through modulation of HIF-1/2α, mitochondrial function, and mitophagy. PMID:25391657

  2. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility.

    PubMed

    Preston, R S; Philp, A; Claessens, T; Gijezen, L; Dydensborg, A B; Dunlop, E A; Harper, K T; Brinkhuizen, T; Menko, F H; Davies, D M; Land, S C; Pause, A; Baar, K; van Steensel, M A M; Tee, A R

    2011-03-10

    Under conditions of reduced tissue oxygenation, hypoxia-inducible factor (HIF) controls many processes, including angiogenesis and cellular metabolism, and also influences cell proliferation and survival decisions. HIF is centrally involved in tumour growth in inherited diseases that give rise to renal cell carcinoma (RCC), such as Von Hippel-Lindau syndrome and tuberous sclerosis complex. In this study, we examined whether HIF is involved in tumour formation of RCC in Birt-Hogg-Dubé syndrome. For this, we analysed a Birt-Hogg-Dubé patient-derived renal tumour cell line (UOK257) that is devoid of the Birt-Hogg-Dubé protein (BHD) and observed high levels of HIF activity. Knockdown of BHD expression also caused a threefold activation of HIF, which was not as a consequence of more HIF1α or HIF2α protein. Transcription of HIF target genes VEGF, BNIP3 and CCND1 was also increased. We found nuclear localization of HIF1α and increased expression of VEGF, BNIP3 and GLUT1 in a chromophobe carcinoma from a Birt-Hogg-Dubé patient. Our data also reveal that UOK257 cells have high lactate dehydrogenase, pyruvate kinase and 3-hydroxyacyl-CoA dehydrogenase activity. We observed increased expression of pyruvate dehydrogenase kinase 1 (a HIF gene target), which in turn leads to increased phosphorylation and inhibition of pyruvate dehydrogenase. Together with increased protein levels of GLUT1, our data reveal that UOK257 cells favour glycolytic rather than lipid metabolism (a cancer phenomenon termed the 'Warburg effect'). UOK257 cells also possessed a higher expression level of the L-lactate influx monocarboxylate transporter 1 and consequently utilized L-lactate as a metabolic fuel. As a result of their higher dependency on glycolysis, we were able to selectively inhibit the growth of these UOK257 cells by treatment with 2-deoxyglucose. This work suggests that targeting glycolytic metabolism may be used therapeutically to treat Birt-Hogg-Dubé-associated renal lesions.

  3. MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells*

    PubMed Central

    Das, Falguni; Dey, Nirmalya; Bera, Amit; Kasinath, Balakuntalam S.; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh

    2016-01-01

    Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3′UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3′UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. PMID:27226530

  4. Loss of neurofibromatosis type 1 (NF1) gene expression in pheochromocytomas from patients without NF1

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Geist, R.T.; Gutmann, D.H.; Moley, J.F.

    The neurofibromatosis type 1 (NF1) gene encodes a tumor suppressor protein, termed neurofibromin. Loss of NF1 gene expression has been reported in Schwann cell tumors (neurofibrosarcomas) from patients with NF1 as well as malignant and neuroblastomas from patients without NF1. Previously, we demonstrated the lack of neurofibromin expression in six pheochromocytomas from patients with NF1, suggesting that neurofibromin loss is associated with the progression to neoplasia in pheochromocytomas in these patients. The lack of NF1 gene expression in NF1 patient pheochromocytomas supports the notion that neurofibromin might be an essential regulator of cell growth in these cells. To determine whethermore » NF1 gene expression is similarly altered in pheochromocytomas from patients without NF1, twenty pheochromocytomas were examined for the presence of NF1 RNA by reverse-transcribed PCR (RT-PCR). Lack of NF1 gene expression was documented in four of these twenty tumors (20%) which corresponds to previously reported numbers for malignant melanomas and neuroblastomas in non-NF1 patients. Of these twenty pheochromocytomas, one of four sporadic tumors, one of ten tumors from patients with MEN2A, one of four tumors from patients with MEN2B, and one of two tumors from patients with von Hippel-Lindau syndrome demonstrated loss of NF1 gene expression. In all cases, the quality and quantity of tumor RNA was determined by RT-PCR amplification using primers which amplify cyclophilin RNA. We previously demonstrated that these tumors do not harbor activating mutations of the N-ras, K-ras or H-ras proto-oncogenes. These results suggest that loss of NF1 gene expression is frequently associated with the progression to neoplasia in tumors derived from adrenal medullary tissue in patients without clinical manifestations of neurofibromatosis and supports the notion that neurofibromin is a tumor suppressor gene product involved in the pathogenesis of a wide variety of tumor types.« less

  5. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis.

    PubMed

    van Nederveen, Francien H; Gaal, José; Favier, Judith; Korpershoek, Esther; Oldenburg, Rogier A; de Bruyn, Elly M C A; Sleddens, Hein F B M; Derkx, Pieter; Rivière, Julie; Dannenberg, Hilde; Petri, Bart-Jeroen; Komminoth, Paul; Pacak, Karel; Hop, Wim C J; Pollard, Patrick J; Mannelli, Massimo; Bayley, Jean-Pierre; Perren, Aurel; Niemann, Stephan; Verhofstad, Albert A; de Bruïne, Adriaan P; Maher, Eamonn R; Tissier, Frédérique; Méatchi, Tchao; Badoual, Cécile; Bertherat, Jérôme; Amar, Laurence; Alataki, Despoina; Van Marck, Eric; Ferrau, Francesco; François, Jerney; de Herder, Wouter W; Peeters, Mark-Paul F M Vrancken; van Linge, Anne; Lenders, Jacques W M; Gimenez-Roqueplo, Anne-Paule; de Krijger, Ronald R; Dinjens, Winand N M

    2009-08-01

    Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively. Phaeochromocytoma-paraganglioma syndrome can be diagnosed

  6. Efficient generation of patient-matched malignant and normal primary cell cultures from clear cell renal cell carcinoma patients: clinically relevant models for research and personalized medicine.

    PubMed

    Lobo, Nazleen C; Gedye, Craig; Apostoli, Anthony J; Brown, Kevin R; Paterson, Joshua; Stickle, Natalie; Robinette, Michael; Fleshner, Neil; Hamilton, Robert J; Kulkarni, Girish; Zlotta, Alexandre; Evans, Andrew; Finelli, Antonio; Moffat, Jason; Jewett, Michael A S; Ailles, Laurie

    2016-07-16

    Patients with clear cell renal cell carcinoma (ccRCC) have few therapeutic options, as ccRCC is unresponsive to chemotherapy and is highly resistant to radiation. Recently targeted therapies have extended progression-free survival, but responses are variable and no significant overall survival benefit has been achieved. Commercial ccRCC cell lines are often used as model systems to develop novel therapeutic approaches, but these do not accurately recapitulate primary ccRCC tumors at the genomic and transcriptional levels. Furthermore, ccRCC exhibits significant intertumor genetic heterogeneity, and the limited cell lines available fail to represent this aspect of ccRCC. Our objective was to generate accurate preclinical in vitro models of ccRCC using tumor tissues from ccRCC patients. ccRCC primary single cell suspensions were cultured in fetal bovine serum (FBS)-containing media or defined serum-free media. Established cultures were characterized by genomic verification of mutations present in the primary tumors, expression of renal epithelial markers, and transcriptional profiling. The apparent efficiency of primary cell culture establishment was high in both culture conditions, but genotyping revealed that the majority of cultures contained normal, not cancer cells. ccRCC characteristically shows biallelic loss of the von Hippel Lindau (VHL) gene, leading to accumulation of hypoxia-inducible factor (HIF) and expression of HIF target genes. Purification of cells based on expression of carbonic anhydrase IX (CA9), a cell surface HIF target, followed by culture in FBS enabled establishment of ccRCC cell cultures with an efficiency of >80 %. Culture in serum-free conditions selected for growth of normal renal proximal tubule epithelial cells. Transcriptional profiling of ccRCC and matched normal cell cultures identified up- and down-regulated networks in ccRCC and comparison to The Cancer Genome Atlas confirmed the clinical validity of our cell cultures. The

  7. Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2α Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma.

    PubMed

    Courtney, Kevin D; Infante, Jeffrey R; Lam, Elaine T; Figlin, Robert A; Rini, Brian I; Brugarolas, James; Zojwalla, Naseem J; Lowe, Ann M; Wang, Keshi; Wallace, Eli M; Josey, John A; Choueiri, Toni K

    2018-03-20

    Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2α (HIF-2α). PT2385 is a first-in-class HIF-2α antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for ≥ 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of patients with ccRCC.

  8. Metabolic Modulation of Clear-cell Renal Cell Carcinoma with Dichloroacetate, an Inhibitor of Pyruvate Dehydrogenase Kinase.

    PubMed

    Kinnaird, Adam; Dromparis, Peter; Saleme, Bruno; Gurtu, Vikram; Watson, Kristalee; Paulin, Roxane; Zervopoulos, Sotirios; Stenson, Trevor; Sutendra, Gopinath; Pink, Desmond B; Carmine-Simmen, Katia; Moore, Ronald; Lewis, John D; Michelakis, Evangelos D

    2016-04-01

    Clear-cell renal cell carcinoma (ccRCC) exhibits suppressed mitochondrial function and preferential use of glycolysis even in normoxia, promoting proliferation and suppressing apoptosis. ccRCC resistance to therapy is driven by constitutive hypoxia-inducible factor (HIF) expression due to genetic loss of von Hippel-Lindau factor. In addition to promoting angiogenesis, HIF suppresses mitochondrial function by inducing pyruvate dehydrogenase kinase (PDK), a gatekeeping enzyme for mitochondrial glucose oxidation. To reverse mitochondrial suppression of ccRCC using the PDK inhibitor dichloroacetate (DCA). Radical nephrectomy specimens from patients with ccRCC were assessed for PDK expression. The 786-O ccRCC line and two animal models (chicken in ovo and murine xenografts) were used for mechanistic studies. Mitochondrial function, proliferation, apoptosis, HIF transcriptional activity, angiogenesis, and tumor size were measured in vitro and in vivo. Independent-sample t-tests and analysis of variance were used for statistical analyses. PDK was elevated in 786-O cells and in ccRCC compared to normal kidney tissue from the same patient. DCA reactivated mitochondrial function (increased respiration, Krebs cycle metabolites such as α-ketoglutarate [cofactor of factor inhibiting HIF], and mitochondrial reactive oxygen species), increased p53 activity and apoptosis, and decreased proliferation in 786-O cells. DCA reduced HIF transcriptional activity in an FIH-dependent manner, inhibiting angiogenesis in vitro. DCA reduced tumor size and angiogenesis in vivo in both animal models. DCA can reverse the mitochondrial suppression of ccRCC and decrease HIF transcriptional activity, bypassing its constitutive expression. Its previous clinical use in humans makes it an attractive candidate for translation to ccRCC patients. We show that an energy-boosting drug decreases tumor growth and tumor blood vessels in animals carrying human kidney cancer cells. This generic drug has been

  9. Meta-Analysis Identifies NF-κB as a Therapeutic Target in Renal Cancer

    PubMed Central

    Peri, Suraj; Devarajan, Karthik; Yang, Dong-Hua; Knudson, Alfred G.; Balachandran, Siddharth

    2013-01-01

    Objective To determine the expression patterns of NF-κB regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes. Methods Meta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-κB regulators and targets to determine the nature and extent of NF-κB deregulation in ccRCC. Results A highly-disproportionate fraction (~40%; p < 0.001) of NF-κB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-κB activity in this cancer. A subset of these genes, comprising a key NF-κB regulator (IKBKB) and established mediators of the NF-κB cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an ‘interferon signature’ may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-κB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-κB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-κB activity, and the appearance of an interferon signature during ccRCC tumorigenesis. Conclusions These findings identify NF-κB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-κB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-κB targets for potential therapeutic intervention in this currently

  10. Functional Imaging Signature of Patients Presenting with Polycythemia/Paraganglioma Syndromes.

    PubMed

    Janssen, Ingo; Chen, Clara C; Zhuang, Zhenping; Millo, Corina M; Wolf, Katherine I; Ling, Alexander; Lin, Frank I; Adams, Karen T; Herscovitch, Peter; Feelders, Richard A; Fojo, Antonio T; Taieb, David; Kebebew, Electron; Pacak, Karel

    2017-08-01

    Pheochromocytoma/paraganglioma (PPGL) syndromes associated with polycythemia have previously been described in association with mutations in the von Hippel-Lindau gene. Recently, mutations in the prolyl hydroxylase gene ( PHD ) 1 and 2 and in the hypoxia-inducible factor 2 α ( HIF2A ) were also found to be associated with multiple and recurrent PPGL. Such patients also presented with PPGL and polycythemia, and later on, some presented with duodenal somatostatinoma. In additional patients presenting with PPGL and polycythemia, no further mutations have been discovered. Because the functional imaging signature of patients with PPGL-polycythemia syndromes is still unknown, and because these tumors (in most patients) are multiple, recurrent, and metastatic, the goal of our study was to assess the optimal imaging approach using 4 different PET radiopharmaceuticals and CT/MRI in these patients. Methods: Fourteen patients (10 women, 4 men) with confirmed PPGL and polycythemia prospectively underwent 68 Ga-DOTATATE (13 patients), 18 F-FDG (13 patients), 18 F-fluorodihydroxyphenylalanine ( 18 F-FDOPA) (14 patients), 18 F-fluorodopamine ( 18 F-FDA) (11 patients), and CT/MRI (14 patients). Detection rates of PPGL lesions were compared between all imaging studies and stratified between the underlying mutations. Results: 18 F-FDOPA and 18 F-FDA PET/CT showed similar combined lesion-based detection rates of 98.7% (95% confidence interval [CI], 92.7%-99.8%) and 98.3% (95% CI, 90.9%-99.7%), respectively. The detection rates for 68 Ga-DOTATATE (35.3%; 95% CI, 25.0%-47.2%), 18 F-FDG (42.3; 95% CI, 29.9%-55.8%), and CT/MRI (60.3%; 95% CI, 48.8%-70.7%) were significantly lower ( P < 0.01), irrespective of the mutation status. Conclusion: 18 F-FDOPA and 18 F-FDA are superior to 18 F-FDG, 68 Ga-DOTATATE, and CT/MRI and should be the radiopharmaceuticals of choice in this rare group of patients. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  11. Ein Konzept für den energieeffizienten Betrieb von Mobilfunknetzen

    NASA Astrophysics Data System (ADS)

    Bayer, N.; von Hugo, D.

    2015-11-01

    Der flächendeckende Betrieb mehrerer Mobilfunknetze unterschiedlicher Technologie in einem Land sorgt aufgrund der ständigen Bereithaltung von Übertragungskapazität für Dienste mit zunehmend höherem Datenvolumenbedarf für einen erheblichen Energieverbrauch. Das Forschungsförderungsprojekt ComGreen hat sich zur Aufgabe gesetzt, durch lastadaptiven Betrieb und intelligente dynamische Rekonfiguration des Funkzugangsnetzes zur Energieeinsparung beizutragen. Konzept, Herausforderungen, ausgewählte Ergebnisse von Simulationen und prototypischem Betrieb werden ebenso wie typische Erwartungswerte des künftigen Energieverbrauchs im Mobilfunkbereich vorgestellt. Sowohl Berechnungen als auch Messungen zeigen, dass durch kontext-basierte dynamische Rekonfiguration von zellularen Funknetzen Energieeinsparungen im Bereich von 25-40 % ermöglicht werden.

  12. Wernher von Braun

    NASA Image and Video Library

    1959-03-04

    Dr. Wernher von Braun, Director of the U.S. Army Ballistic Missile Agency's (ABMA) Development Operations Division, talks to Huntsville Mayor R. B. "Speck" Searcy, center, and Army Ordnance Missile Command (ARMC) Major General John B. Medaris, right, during "Moon Day" celebrations in downtown Huntsville, Alabama. (Courtesy of Huntsville/Madison County Public Library)

  13. Wernher von Braun

    NASA Image and Video Library

    1965-05-25

    In this photo, Dr. von Braun anxiously awaits the launch of the Saturn I vehicle (SA-8) in the Launch Complex Control Center at the Kennedy Space Center in Florida on May 25, 1965. The SA-8 mission made the first night launch and deployed the Pegasus II micro meteoroid detection satellite.

  14. Dr. von Braun with Original Mercury Astronauts

    NASA Technical Reports Server (NTRS)

    1959-01-01

    Dr. Wernher von Braun, Director of the Army Ballistic Missile Agency's (ABMA) Development Operations Division, poses with the original Mercury astronauts in ABMA's Fabrication Laboratory during a 1959 visit. Inspecting Mercury-Redstone hardware are from left to right, Alan Shepard, Donald Deke Slayton, Virgil Gus Grissom, von Braun, Gordon Cooper, Wally Schirra, John Glenn, and Scott Carpenter. Project Mercury officially began October 7, 1958 as the United States' first manned space program.

  15. Platelet-independent adhesion of calcium-loaded erythrocytes to von Willebrand factor

    PubMed Central

    Bierings, Ruben; Meems, Henriet; Mul, Frederik P. J.; Geerts, Dirk; Vlaar, Alexander P. J.; Voorberg, Jan; Hordijk, Peter L.

    2017-01-01

    Adhesion of erythrocytes to endothelial cells lining the vascular wall can cause vaso-occlusive events that impair blood flow which in turn may result in ischemia and tissue damage. Adhesion of erythrocytes to vascular endothelial cells has been described in multiple hemolytic disorders, especially in sickle cell disease, but the adhesion of normal erythrocytes to endothelial cells has hardly been described. It was shown that calcium-loaded erythrocytes can adhere to endothelial cells. Because sickle erythrocyte adhesion to ECs can be enhanced by ultra-large von Willebrand factor multimers, we investigated whether calcium loading of erythrocytes could promote binding to endothelial cells via ultra-large von Willebrand factor multimers. We used (immunofluorescent) live-cell imaging of washed erythrocytes perfused over primary endothelial cells at venular flow rate. Using this approach, we show that calcium-loaded erythrocytes strongly adhere to histamine-stimulated primary human endothelial cells. This adhesion is mediated by ultra-large von Willebrand factor multimers. Von Willebrand factor knockdown or ADAMTS13 cleavage abolished the binding of erythrocytes to activated endothelial cells under flow. Platelet depletion did not interfere with erythrocyte binding to von Willebrand factor. Our results reveal platelet-independent adhesion of calcium-loaded erythrocytes to endothelium-derived von Willebrand factor. Erythrocyte adhesion to von Willebrand factor may be particularly relevant for venous thrombosis, which is characterized by the formation of erythrocyte-rich thrombi. PMID:28249049

  16. Wernher von Braun

    NASA Image and Video Library

    1961-10-19

    Dr. Wernher von Braun holds the coveted Hermarn Oberth award presented to him by Professor Oberth during the banquet hosted by the Alabama Section of the American Rocket Society (ARS), on October 19, 1961. The Oberth award was given for outstanding technical contributions to the field of astronautics or for the promotion and advancement of astronautical sciences.

  17. Dr. von Braun With Five of the Original Astronauts

    NASA Technical Reports Server (NTRS)

    1959-01-01

    Five of the seven original astronauts are seen with Dr. von Braun inspecting the Mercury-Redstone hardware in the Fabrication Laboratory of Army Ballistic Missile Agency (ABMA) in 1959. Left to right: Astronauts Walter Schirra, Alan Shepard, John Glenn, Scott Carpenter, Gordon Cooper, and Dr. von Braun.

  18. Von Kármán between Aachen and Pasadena

    NASA Astrophysics Data System (ADS)

    Krause, Egon; Kalkmann, Ulrich

    2013-05-01

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

  19. Mittelwert- und Arbeitstaktsynchrone Simulation von Dieselmotoren

    NASA Astrophysics Data System (ADS)

    Zahn, Sebastian

    Getrieben durch die immer restriktiveren Anforderungen an das Emissions- und Verbrauchsverhalten moderner Verbrennungsmotoren steigt die Komplexität von Motormanagementsystemen mit jeder Modellgeneration an. Damit geht nicht nur eine Zunahme des Softwareumfangs von Steuergeräten sondern zugleich ein deutlicher Anstieg des Applikations-, Vermessungs- und Testaufwandes einher. Zur Effizienzsteigerung des Software- und Funktionsentwicklungsprozesses haben sich daher in der Automobilindustrie sowie in Forschungsinstituten verschiedene modell- und simulationsbasierte Methoden wie die Model-in-the-Loop (MiL) Simulation, die Software-in-the-Loop (SiL) Simulation, das Rapid Control Prototyping (RCP) sowie die Hardware-in-the-Loop (HiL) Simulation etabliert.

  20. von Braun and German Publisher

    NASA Technical Reports Server (NTRS)

    1969-01-01

    In this photograph, Guenter Ogger of Capitol Magazine, West Germany, greets Marshall Space Flight Center Director, Dr. Wernher von Braun. Mr. Ogger interviewed the famous rocket scientist for his magazine.

  1. N-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor.

    PubMed

    O'Sullivan, J M; Aguila, S; McRae, E; Ward, S E; Rawley, O; Fallon, P G; Brophy, T M; Preston, R J S; Brady, L; Sheils, O; Chion, A; O'Donnell, J S

    2016-12-01

    Essentials von Willebrands factor (VWF) glycosylation plays a key role in modulating in vivo clearance. VWF glycoforms were used to examine the role of specific glycan moieties in regulating clearance. Reduction in sialylation resulted in enhanced VWF clearance through asialoglycoprotein receptor. Progressive VWF N-linked glycan trimming resulted in increased macrophage-mediated clearance. Click to hear Dr Denis discuss clearance of von Willebrand factor in a free presentation from the ISTH Academy SUMMARY: Background Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD). In addition, previous studies have demonstrated that VWF glycans play a key role in regulating in vivo clearance. However, the molecular mechanisms underlying VWF clearance remain poorly understood. Objective To define the molecular mechanisms through which VWF N-linked glycan structures influence in vivo clearance. Methods By use of a series of exoglycosidases, different plasma-derived VWF (pd-VWF) glycoforms were generated. In vivo clearance of these glycoforms was then assessed in VWF -/- mice in the presence or absence of inhibitors of asialoglycoprotein receptor (ASGPR), or following clodronate-induced macrophage depletion. Results Reduced amounts of N-linked and O-linked sialylation resulted in enhanced pd-VWF clearance modulated via ASGPR. In addition to this role of terminal sialylation, we further observed that progressive N-linked glycan trimming also resulted in markedly enhanced VWF clearance. Furthermore, these additional N-linked glycan effects on clearance were ASGPR-independent, and instead involved enhanced macrophage clearance that was mediated, at least in part, through LDL receptor-related protein 1. Conclusion The carbohydrate determinants expressed on VWF regulate susceptibility to proteolysis by ADAMTS-13. In addition, our findings now further demonstrate that non-sialic acid carbohydrate

  2. Eine selbstkonsistente Carleman Linearisierung zur Analyse von Oszillatoren

    NASA Astrophysics Data System (ADS)

    Weber, Harry; Mathis, Wolfgang

    2017-09-01

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

  3. Monte Carlo turbulence simulation using rational approximations to von Karman spectra

    NASA Technical Reports Server (NTRS)

    Campbell, C. W.

    1986-01-01

    Turbulence simulation is computationally much simpler using rational spectra, but turbulence falls off as f exp -5/3 in frequency ranges of interest to aircraft response and as predicted by von Karman's model. Rational approximations to von Karman spectra should satisfy three requirements: (1) the rational spectra should provide a good approximation to the von Karman spectra in the frequency range of interest; (2) for stability, the resulting rational transfer function should have all its poles in the left half-plane; and (3) at high frequencies, the rational spectra must fall off as an integer power of frequency, and since the -2 power is closest to the -5/3 power, the rational approximation should roll off as the -2 power at high frequencies. Rational approximations to von Karman spectra that satisfy these three criteria are presented, along with spectra from simulated turbulence. Agreement between the spectra of the simulated turbulence and von Karman spectra is excellent.

  4. Memory recall in arousing situations – an emotional von Restorff effect?

    PubMed Central

    Wiswede, Daniel; Rüsseler, Jascha; Hasselbach, Simone; Münte, Thomas F

    2006-01-01

    Background Previous research has demonstrated a relationship between memory recall and P300 amplitude in list learning tasks, but the variables mediating this P300-recall relationship are not well understood. In the present study, subjects were required to recall items from lists consisting of 12 words, which were presented in front of pictures taken from the IAPS collection. One word per list is made distinct either by font color or by a highly arousing background IAPS picture. This isolation procedure was first used by von Restorff. Brain potentials were recorded during list presentation. Results Recall performance was enhanced for color but not for emotional isolates. Event-related brain potentials (ERP) showed a more positive P300-component for recalled non-isolated words and color-isolated words, compared to the respective non-remembered words, but not for words isolated by arousing background. Conclusion Our findings indicate that it is crucial to take emotional mediator variables into account, when using the P300 to predict later recall. Highly arousing environments might force the cognitive system to interrupt rehearsal processes in working memory, which might benefit transfer into other, more stable memory systems. The impact of attention-capturing properties of arousing background stimuli is also discussed. PMID:16863589

  5. Wernher von Braun

    NASA Image and Video Library

    1959-01-21

    In this photo, (left to right) Army Ballistic Missile Agency (ABMA) Missile Firing Laboratory Chief Dr. Kurt Debus, Director of the ABMA Development Operations Division, Dr. von Braun and an unidentified individual in blockhouse during the CM-21 (Jupiter) firing. The Jupiter missile CM-21 became the first Chrysler production qualification missile to be fired and in March 1959 launched the Pioneer IV.

  6. Von Karman Vortices

    NASA Image and Video Library

    2017-12-08

    July 4th, 2002: Description: As air flows over and around objects in its path, spiraling eddies, known as Von Karman vortices, may form. The vortices in this image were created when prevailing winds sweeping east across the northern Pacific Ocean encountered Alaska’s Aleutian Islands. Source: Landsat 7 To learn more about the Landsat satellite go to: landsat.gsfc.nasa.gov/

  7. Wernher von Braun

    NASA Image and Video Library

    1954-07-01

    Dr. Wernher von Braun (center), then Chief of the Guided Missile Development Division at Redstone Arsenal, Alabama, discusses a "bottle suit" model with Dr. Heinz Haber (left), an expert on aviation medicine, and Willey Ley, a science writer on rocketry and space exploration. The three men were at the Disney studios appearing in the motion picture, entitled "Man in Space."

  8. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Shown viewing the Apollo telescope mockup are, from left to right, Charles Donlan, deputy associate administrator for manned space flight; Dr. Wernher Von Braun, Marshall Space Flight Center director; William Horton, astrionics lab; Dr. Thomas Paine, NASA deputy administrator; Warner Kuers, director of the ME lab.

  9. Wernher von Braun

    NASA Image and Video Library

    1963-03-28

    Dr. von Braun, Director of the Marshall Space Flight Center (MSFC), and Dr. Debus, Director of the Launch Operations Center, at Complex 34 prior to the Launch of the SA-4 (the fourth flight of Saturn I), March 28, 1963. The mission conducted the second "Project Highwater" experiment, which the upper stage ejected 30,000 gallons of ballast water in the upper atmosphere for a physics experiment.

  10. Wernher von Braun

    NASA Image and Video Library

    1968-10-01

    Dr. von Braun, Director of the Marshall Space Flight Center (MSFC), greets Commander of Apollo 7 mission, Walter M. Schirra, Jr., during the mission briefing at Kennedy Space Center (KSC). The Apollo 7 mission, boosted by a Saturn IB launch vehicle on October 11, 1968, was the first flight of the Apollo spacecraft with crew. Other crew members were Astronaut Donn Eisele and Astronaut Walter Cunningham.

  11. Measurements in Quantum Mechanics and von NEUMANN's Model

    NASA Astrophysics Data System (ADS)

    Mello, Pier A.; Johansen, Lars M.

    2010-12-01

    Many textbooks on Quantum Mechanics are not very precise as to the meaning of making a measurement: as a consequence, they frequently make assertions which are not based on a dynamical description of the measurement process. A model proposed by von Neumann allows a dynamical description of measurement in Quantum Mechanics, including the measuring instrument in the formalism. In this article we apply von Neumann's model to illustrate the measurement of an observable by means of a measuring instrument and show how various results, which are sometimens postulated without a dynamical basis, actually emerge. We also investigate the more complex, intriguing and fundamental problem of two successive measurements in Quantum Mechanics, extending von Neumann's model to two measuring instruments. We present a description which allows obtaining, in a unified way, various results that have been given in the literature.

  12. Test of Von Baer's law of the conservation of early development.

    PubMed

    Poe, Steven

    2006-11-01

    One of the oldest and most pervasive ideas in comparative embryology is the perceived evolutionary conservation of early ontogeny relative to late ontogeny. Karl Von Baer first noted the similarity of early ontogeny across taxa, and Ernst Haeckel and Charles Darwin gave evolutionary interpretation to this phenomenon. In spite of a resurgence of interest in comparative embryology and the development of mechanistic explanations for Von Baer's law, the pattern itself has been largely untested. Here, I use statistical phylogenetic approaches to show that Von Baer's law is an unnecessarily complex explanation of the patterns of ontogenetic timing in several clades of vertebrates. Von Baer's law suggests a positive correlation between ontogenetic time and amount of evolutionary change. I compare ranked position in ontogeny to frequency of evolutionary change in rank for developmental events and find that these measures are not correlated, thus failing to support Von Baer's model. An alternative model that postulates that small changes in ontogenetic rank are evolutionarily easier than large changes is tentatively supported.

  13. Memory recall in arousing situations - an emotional von Restorff effect?

    PubMed

    Wiswede, Daniel; Rüsseler, Jascha; Hasselbach, Simone; Münte, Thomas F

    2006-07-24

    Previous research has demonstrated a relationship between memory recall and P300 amplitude in list learning tasks, but the variables mediating this P300-recall relationship are not well understood. In the present study, subjects were required to recall items from lists consisting of 12 words, which were presented in front of pictures taken from the IAPS collection. One word per list is made distinct either by font color or by a highly arousing background IAPS picture. This isolation procedure was first used by von Restorff. Brain potentials were recorded during list presentation. Recall performance was enhanced for color but not for emotional isolates. Event-related brain potentials (ERP) showed a more positive P300-component for recalled non-isolated words and color-isolated words, compared to the respective non-remembered words, but not for words isolated by arousing background. Our findings indicate that it is crucial to take emotional mediator variables into account, when using the P300 to predict later recall. Highly arousing environments might force the cognitive system to interrupt rehearsal processes in working memory, which might benefit transfer into other, more stable memory systems. The impact of attention-capturing properties of arousing background stimuli is also discussed.

  14. Dr. von Braun Tries Out the Neutral Buoyancy Simulator (NBS)

    NASA Technical Reports Server (NTRS)

    1967-01-01

    Marshall Space Flight Center (MSFC) Director, Dr. von Braun, submerges after spending some time under water in the MSFC Neutral Buoyancy Simulator (NBS). Weighted to a neutrally buoyant condition, Dr. von Braun was able to perform tasks underwater which simulated weightless conditions found in space.

  15. Valence bond and von Neumann entanglement entropy in Heisenberg ladders.

    PubMed

    Kallin, Ann B; González, Iván; Hastings, Matthew B; Melko, Roger G

    2009-09-11

    We present a direct comparison of the recently proposed valence bond entanglement entropy and the von Neumann entanglement entropy on spin-1/2 Heisenberg systems using quantum Monte Carlo and density-matrix renormalization group simulations. For one-dimensional chains we show that the valence bond entropy can be either less or greater than the von Neumann entropy; hence, it cannot provide a bound on the latter. On ladder geometries, simulations with up to seven legs are sufficient to indicate that the von Neumann entropy in two dimensions obeys an area law, even though the valence bond entanglement entropy has a multiplicative logarithmic correction.

  16. Wernher von Braun with German Officers and Others

    NASA Technical Reports Server (NTRS)

    1942-01-01

    General Erich Fellgiebel, head of the German Army Information Service during World War II, congratulates members of the von Braun rocket team from Peenemunde for their October 3, 1942 A4 flight. Pictured front center is General Erich Fellgiebel. Shaking hands are General Walter Dornberger (left) and General Janssen, commanding officer of Peenemuende with Rudolph Hermarn to their right. Picture left to right in the back row are Wernher von Braun, Captain Stoelzel, Luftwaffe, and Dr. Gerhard Reisig.

  17. Die Kosmogonie Anton von Zachs.

    NASA Astrophysics Data System (ADS)

    Brosche, P.

    In his "Cosmogenische Betrachtungen" (1804), Anton von Zach rediscovered - probably independently - some aspects of the theories of Kant and Laplace. More originally, he envisaged also the consequences of an era of heavy impacts in the early history of the Earth.

  18. Dr. von Braun Tries Out the Neutral Buoyancy Simulator (NBS)

    NASA Technical Reports Server (NTRS)

    1967-01-01

    Marshall Space Flight Center (MSFC) Director, Dr. von Braun, is shown leaving the suiting-up van wearing a pressure suit prepared for a tryout in the MSFC Neutral Buoyancy Simulator (NBS). Weighted to a neutrally buoyant condition, Dr. von Braun was able to perform tasks underwater which simulated weightless conditions found in space.

  19. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Marshall Space Flight Center director Wernher Von Braun and his family were honored with a series of events prior to his relocation to Washington, D.C. where he was assigned duties at NASA headquarters as deputy associate administrator for planning. Here he is shown with General Richard Drury and Hazel Toftoy, widow of General H.N. Toftoy.

  20. Evaluation of the Utility of von Willebrand Factor Propeptide in the Differential Diagnosis of von Willebrand Disease and Acquired von Willebrand Syndrome.

    PubMed

    Stufano, Francesca; Boscarino, Marco; Bucciarelli, Paolo; Baronciani, Luciano; Maino, Alberto; Cozzi, Giovanna; Peyvandi, Flora

    2018-06-18

    An increased von Willebrand factor propeptide (VWFpp) to VWF antigen (VWF:Ag) ratio (VWFpp/VWF:Ag) indicates an enhanced clearance of VWF. This finding has been described in von Willebrand disease (VWD) and in acquired von Willebrand syndrome (AVWS). A distinction between these two diseases, one congenital and the other acquired, is primarily based on family and personal history of bleeding. However, if this information is scanty, the diagnosis might be challenging due to the lack of an effective diagnostic biomarker. In this cross-sectional study, we assessed the ability of VWFpp/VWF:Ag for the differential diagnosis between VWD and AVWS. VWFpp/VWF:Ag was measured in a group of 153 patients (125 with VWD and 28 with AVWS). Most patients with AVWS and VWD showed an increased VWFpp/VWF:Ag, although to variable degrees. A marked increase of VWFpp/VWF:Ag was mainly associated with the diagnosis of AVWS and VWD type 1 Vicenza. A receiver operating characteristic curve was used to identify the optimal cutoff of VWFpp/VWF:Ag for discrimination of patients with a modestly increased (most VWD cases) versus those with a markedly increased clearance (AVWS and VWD type 1 Vicenza), and this cutoff was identified at the value of 3.9 (sensitivity: 0.70, specificity: 0.97). The ROC curve sorting from a logistic model containing VWFpp/VWF:Ag, age, and sex had an area under the curve (AUC) of 0.88 (95% confidence interval: 0.80-0.95). A subsequent molecular evaluation discriminated VWD type 1 Vicenza from AVWS. In conclusion, VWFpp/VWF:Ag appears helpful to discriminate patients with a markedly increase VWF clearance (AVWS or VWD type 1 Vicenza) from those with a modestly increased clearance (most VWD patients). Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  1. Zuverlässigkeit digitaler Schaltungen unter Einfluss von intrinsischem Rauschen

    NASA Astrophysics Data System (ADS)

    Kleeberger, V. B.; Schlichtmann, U.

    2011-08-01

    Die kontinuierlich fortschreitende Miniaturisierung in integrierten Schaltungen führt zu einem Anstieg des intrinsischen Rauschens. Um den Einfluss von intrinsischem Rauschen auf die Zuverlässigkeit zukünftiger digitaler Schaltungen analysieren zu können, werden Methoden benötigt, die auf CAD-Verfahren wie Analogsimulation statt auf abschätzenden Berechnungen beruhen. Dieser Beitrag stellt eine neue Methode vor, die den Einfluss von intrinsischem Rauschen in digitalen Schaltungen für eine gegebene Prozesstechnologie analysieren kann. Die Amplituden von thermischen, 1/f und Schrotrauschen werden mit Hilfe eines SPICE Simulators bestimmt. Anschließend wird der Einfluss des Rauschens auf die Schaltungszuverlässigkeit durch Simulation analysiert. Zusätzlich zur Analyse werden Möglichkeiten aufgezeigt, wie die durch Rauschen hervorgerufenen Effekte im Schaltungsentwurf mit berücksichtigt werden können. Im Gegensatz zum Stand der Technik kann die vorgestellte Methode auf beliebige Logikimplementierungen und Prozesstechnologien angewendet werden. Zusätzlich wird gezeigt, dass bisherige Ansätze den Einfluss von Rauschen bis um das Vierfache überschätzen.

  2. mRNAs for PRPs, statherin, and histatins in von Ebner's gland tissues.

    PubMed

    Azen, E A; Hellekant, G; Sabatini, L M; Warner, T F

    1990-11-01

    A search was made for expression of genes for proline-rich proteins (PRPs) and other salivary-type proteins, including statherin and histatins, in taste-bud tissues of mice and primates because of previous genetic findings in mice (Azen et al., 1986) that Prp and taste genes for certain bitter substances are either the same or closely linked. Taste-bud tissues and other tissues were tested for specific mRNAs with labeled DNA probes by Northern blotting and in situ hybridization. It was found that PRP mRNAs were present in von Ebner's glands of mice and macaques, and that there was a much greater degree of PRP mRNA induction in mouse parotid (16-fold) than in von Ebner's gland (two-fold) after in vivo isoproterenol stimulation. This difference may be due, in part, to differences in autonomic nerve innervation. Statherin and histatin mRNAs were found in macaque taste-bud tissues containing von Ebner's gland, and statherin protein was found in human von Ebner's gland by immunohistochemistry. The finding of PRP gene expression in von Ebner's gland, whose secretions have been suggested to play a role in taste stimulation, adds further support to a possible function of PRPs in bitter tasting. The possible functions of statherin and histatins in von Ebner's gland secretions may be related to statherin's regulation of salivary calcium and histatins' antibacterial and antifungal properties.

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

    ERIC Educational Resources Information Center

    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…

  4. Wernher von Braun

    NASA Image and Video Library

    1966-06-21

    Dr. Joseph Randall, a laser expert at Marshall Space Flight Center (MSFC), explains one of the projects he is working on to a group composed of Federal Republic of Germany and MSFC officials. From left are: Dr. Randall; Minister for Scientific Research of Federal Republic of Germany, Dr. Gerhard Stolenberg; Director of MSFC Astrionics Lab, Dr. Walter Haeusserman; Head of Space Research Federal Republic of Germany, Max Mayer; MSFC Director Dr. von Braun; MSFC Deputy Director Dr. Elberhard Rees.

  5. Wernher von Braun

    NASA Image and Video Library

    1968-10-01

    Dr. von Braun inside the KC-135 in flight. The KC-135 provide NASA's Reduced-Gravity Program the unique weightlessness or zero-g environment of space flight for testing and training of human and hardware reactions. The recent version, KC-135A, is a specially modified turbojet transport which flies parabolic arcs to produce weightlessness periods of 20 to 25 seconds and its cargo bay test area is approximately 60 feet long, 10 feet wide, and 7 feet high.

  6. Physik gestern und heute Von der Metallstange zum Hochenergielaser

    NASA Astrophysics Data System (ADS)

    Heering, Peter

    2002-05-01

    Im Mai 1752 wurde in Marly bei Paris auf Anregung des amerikanischen Forschers und Politikers Benjamin Franklin erstmals die elektrische Natur des Blitzes nachgewiesen. Damals beschrieb Franklin auch eine technische Vorrichtung, die als Schutz von Gebäuden vor Blitzschlägen dienen sollte: den Blitzableiter. Diese aus heutiger Sicht scheinbar triviale Vorrichtung wurde aber keineswegs unmittelbar akzeptiert. Und bis heute ist die Forschung zum Schutz von Einrichtungen vor Blitzschlägen nicht abgeschlossen.

  7. von Baer's law for the ages: lost and found principles of developmental evolution.

    PubMed

    Abzhanov, Arhat

    2013-12-01

    In 1828, Karl Ernst von Baer formulated a series of empirically defined rules, which became widely known as the 'Law of Development' or 'von Baer's law of embryology'. This was one the most significant attempts to define the principles that connected morphological complexity and embryonic development. Understanding this relation is central to both evolutionary biology and developmental genetics. Von Baer's ideas have been both a source of inspiration to generations of biologists and a target of continuous criticism over many years. With advances in multiple fields, including paleontology, cladistics, phylogenetics, genomics, and cell and developmental biology, it is now possible to examine carefully the significance of von Baer's law and its predictions. In this review, I argue that, 185 years after von Baer's law was first formulated, its main concepts after proper refurbishing remain surprisingly relevant in revealing the fundamentals of the evolution-development connection, and suggest that their explanation should become the focus of renewed research. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Antiviral activities of Clinacanthus nutans (Burm.f.) Lindau extract against Cyprinid herpesvirus 3 in koi (Cyprinus carpio koi).

    PubMed

    Haetrakul, T; Dunbar, S G; Chansue, N

    2018-04-01

    Cyprinid herpesvirus 3 (CyHV-3) or koi herpesvirus (KHV) is a virulent viral infection in common carp and koi. The disease has caused global epizootic and economic loss in fish aquaculture and in the wild. Clinacanthus nutans (Burm. f.) Lindau is a well-known medicinal plant used in Thai traditional medicine. Virucidal effects of the plant extract against human herpes simplex virus have been reported. In this study, C. nutans crude extract was tested for antiviral activities against CyHV-3 in koi carp. Results showed effective antiviral activity against CyHV-3 pre- and post-infection. The 50% lethal concentration (LC 50 ) of extract was higher than 5 mg/ml. The 50% effective dose (ED 50 ) was 0.99 mg/ml, 0.78 mg/ml, 0.75 mg/ml and 0.71 mg/ml at 1, 2, 3 and 4 hr pre-infection, respectively. The ED 50 from post-infection tests was 2.05 mg/ml and 2.34 mg/ml at 0 and 24 hr, respectively. These results demonstrated that crude extract expressed antiviral activity against CyHV-3 and can be applied as a therapeutic agent in common carp and koi aquaculture. © 2018 John Wiley & Sons Ltd.

  9. Dr. von Braun Tries Out the Neutral Buoyancy Simulator (NBS)

    NASA Technical Reports Server (NTRS)

    1967-01-01

    Astronaut L. Gordon Cooper checks the neck ring of a space suit worn by Marshall Space Flight Center (MSFC) Director, Dr. von Braun before he submerges into the water of the MSFC Neutral Buoyancy Simulator (NBS). Wearing a pressurized suit and weighted to a neutrally buoyant condition, Dr. von Braun was able to perform tasks underwater which simulated weightless conditions found in space.

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

    NASA Astrophysics Data System (ADS)

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

    2010-10-01

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

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

    PubMed

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

    2010-10-28

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

  12. [Precocious puberty and von Recklinghausen's disease].

    PubMed

    Barg, Ewa; Wikiera, Beata; Basiak, Aleksander; Głab, Ewa

    2006-01-01

    Von Recklinghausen's disease belongs to a group of neurocutaneous syndromes and is characterised by skin, nerve and bone abnormalities. We present a case of von Recklinghausen's disease and precocious puberty in 7-year-old boy. At the age of three café au lait spots on the skin and an incranial tumour situated near the optic chiasm--qualified as inoperable--were discovered. At the age of 7 first signs of precocious puberty appeared (pubic hair P3 and enlargement of the testes (15 ml) and penis). Laboratory measurements included: LH 7.5 mIU/ml, FSH 1.1 mIU/ml, testosterone 183 ng/ml, assessment of bone age: 9 years. The response to LHRH stimulation was characteristic for true precocious puberty (LH 15.9 mIU/ml and FSH 1.5 mIU/ml after 30 minutes). The MRI of the brain showed a tumour of the suprasellar region with compression of pituitary stalk. True precocious puberty was diagnosed. Treatment with Diphereline was introduced. At present the boy is 9 years old and has been treated with Diphereline for 16 months. The volume of the testicles has decreased to 7 ml and loss of pubic hair was noted. The MRI does not show any progression in tumour growth. The authors would like to underline the need of close observation of children with von Reclinghausen disease with regard to possibility of uncovering true precocious puberty which is critical for rapid diagnosis and introduction of correct treatment.

  13. The smooth entropy formalism for von Neumann algebras

    NASA Astrophysics Data System (ADS)

    Berta, Mario; Furrer, Fabian; Scholz, Volkher B.

    2016-01-01

    We discuss information-theoretic concepts on infinite-dimensional quantum systems. In particular, we lift the smooth entropy formalism as introduced by Renner and collaborators for finite-dimensional systems to von Neumann algebras. For the smooth conditional min- and max-entropy, we recover similar characterizing properties and information-theoretic operational interpretations as in the finite-dimensional case. We generalize the entropic uncertainty relation with quantum side information of Tomamichel and Renner and discuss applications to quantum cryptography. In particular, we prove the possibility to perform privacy amplification and classical data compression with quantum side information modeled by a von Neumann algebra.

  14. The smooth entropy formalism for von Neumann algebras

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Berta, Mario, E-mail: berta@caltech.edu; Furrer, Fabian, E-mail: furrer@eve.phys.s.u-tokyo.ac.jp; Scholz, Volkher B., E-mail: scholz@phys.ethz.ch

    2016-01-15

    We discuss information-theoretic concepts on infinite-dimensional quantum systems. In particular, we lift the smooth entropy formalism as introduced by Renner and collaborators for finite-dimensional systems to von Neumann algebras. For the smooth conditional min- and max-entropy, we recover similar characterizing properties and information-theoretic operational interpretations as in the finite-dimensional case. We generalize the entropic uncertainty relation with quantum side information of Tomamichel and Renner and discuss applications to quantum cryptography. In particular, we prove the possibility to perform privacy amplification and classical data compression with quantum side information modeled by a von Neumann algebra.

  15. Von Bertalanffy's dynamics under a polynomial correction: Allee effect and big bang bifurcation

    NASA Astrophysics Data System (ADS)

    Leonel Rocha, J.; Taha, A. K.; Fournier-Prunaret, D.

    2016-02-01

    In this work we consider new one-dimensional populational discrete dynamical systems in which the growth of the population is described by a family of von Bertalanffy's functions, as a dynamical approach to von Bertalanffy's growth equation. The purpose of introducing Allee effect in those models is satisfied under a correction factor of polynomial type. We study classes of von Bertalanffy's functions with different types of Allee effect: strong and weak Allee's functions. Dependent on the variation of four parameters, von Bertalanffy's functions also includes another class of important functions: functions with no Allee effect. The complex bifurcation structures of these von Bertalanffy's functions is investigated in detail. We verified that this family of functions has particular bifurcation structures: the big bang bifurcation of the so-called “box-within-a-box” type. The big bang bifurcation is associated to the asymptotic weight or carrying capacity. This work is a contribution to the study of the big bang bifurcation analysis for continuous maps and their relationship with explosion birth and extinction phenomena.

  16. Hazardous Waste Cleanup: Von Roll Isola USA Incorporated in Schenectady, New York

    EPA Pesticide Factsheets

    The Riverview facility is a 52-acre manufacturing facility located on Von Roll Drive in Schenectady, New York. The facility is owned and operated by Von Roll Isola USA, Inc., and produces solid and liquid insulating materials and tapes for the electrical

  17. Die nuklearen Anlagen von Hanford (1943-1987) Eine Fallstudie über die Schnittstellen von Physik, Biologie und die US-amerikanische Gesellschaft zur Zeit des Kalten Krieges

    NASA Astrophysics Data System (ADS)

    Macuglia, Daniele

    Die Geschichte des Kalten Krieges eröffnet viele Möglichkeiten, sich näher mit den Schnittstellen von Physik und Biologie während des 20. Jahrhunderts zu befassen. Nicht nur das Unglück in Tschernobyl aus dem Jahr 1986, auch das Beispiel der nuklearen Anlagen in Hanford in den Vereinigten Staaten zeigt die biologischen Folgen von nuklearer Physik.

  18. Von Neumann entropy in a Rashba-Dresselhaus nanodot; dynamical electronic spin-orbit entanglement

    NASA Astrophysics Data System (ADS)

    Safaiee, Rosa; Golshan, Mohammad Mehdi

    2017-06-01

    The main purpose of the present article is to report the characteristics of von Neumann entropy, thereby, the electronic hybrid entanglement, in the heterojunction of two semiconductors, with due attention to the Rashba and Dresselhaus spin-orbit interactions. To this end, we cast the von Neumann entropy in terms of spin polarization and compute its time evolution; with a vast span of applications. It is assumed that gate potentials are applied to the heterojunction, providing a two dimensional parabolic confining potential (forming an isotropic nanodot at the junction), as well as means of controlling the spin-orbit couplings. The spin degeneracy is also removed, even at electronic zero momentum, by the presence of an external magnetic field which, in turn, leads to the appearance of Landau states. We then proceed by computing the time evolution of the corresponding von Neumann entropy from a separable (spin-polarized) initial state. The von Neumann entropy, as we show, indicates that electronic hybrid entanglement does occur between spin and two-dimensional Landau levels. Our results also show that von Neumann entropy, as well as the degree of spin-orbit entanglement, periodically collapses and revives. The characteristics of such behavior; period, amplitude, etc., are shown to be determined from the controllable external agents. Moreover, it is demonstrated that the phenomenon of collapse-revivals' in the behavior of von Neumann entropy, equivalently, electronic hybrid entanglement, is accompanied by plateaus (of great importance in quantum computation schemes) whose durations are, again, controlled by the external elements. Along these lines, we also make a comparison between effects of the two spin-orbit couplings on the entanglement (von Neumann entropy) characteristics. The finer details of the electronic hybrid entanglement, which may be easily verified through spin polarization measurements, are also accreted and discussed. The novel results of the present

  19. The molecular genetics of von Willebrand disease.

    PubMed

    Berber, Ergül

    2012-12-01

    Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.

  20. Wernher von Braun

    NASA Image and Video Library

    1965-05-25

    This image depicts the tension in the Launch Control Center of the Launch Complex 37 at Cape Canaveral, Florida, during the SA-8 on May 25, 1965. Pointing, center is Dr. Kurt Debus, Director, Launch Operations Directorate, MSFC. To the right is Dr. Hans Gruene, Deputy Director, Launch Operations Directorate, MSFC; Dr. von Braun, Director, Marshall Space Flight Center (MSFC); and leaning, Dr. Eberhard Rees, Director, Deputy Director for Research and Development, MSFC. The SA-8 mission, with a Saturn I launch vehicle, made the first night launch and deployed Pegasus II, micrometeoroid detection satellite.

  1. Fibroblast growth factor-10 signals development of von Brunn's nests in the exstrophic bladder

    PubMed Central

    Eastman, Rocky; Leaf, Elizabeth M.; Zhang, Dianzhong; True, Lawrence D.; Sweet, Robert M.; Seidel, Kristy; Siebert, Joseph R.; Grady, Richard; Mitchell, Michael E.

    2010-01-01

    von Brunn's nests have long been recognized as precursors of benign lesions of the urinary bladder mucosa. We report here that von Brunn's nests are especially prevalent in the exstrophic bladder, a birth defect that predisposes the patient to formation of bladder cancer. Cells of von Brunn's nest were found to coalesce into a stratified, polarized epithelium which surrounds itself with a capsule-like structure rich in types I, III, and IV collagen. Histocytochemical analysis and keratin profiling demonstrated that nested cells exhibited a phenotype similar, but not identical, to that of urothelial cells of transitional epithelium. Immunostaining and in situ hybridization analysis of exstrophic tissue demonstrated that the FGF-10 receptor is synthesized and retained by cells of von Brunn's nest. In contrast, FGF-10 is synthesized and secreted by mesenchymal fibroblasts via a paracrine pathway that targets basal epithelial cells of von Brunn's nests. Small clusters of 10pRp cells, positive for both FGF-10 and its receptor, were observed both proximal to and inside blood vessels in the lamina propria. The collective evidence points to a mechanism where von Brunn's nests develop under the control of the FGF-10 signal transduction system and suggests that 10pRp cells may be the original source of nested cells. PMID:20719973

  2. Voluntarism in early psychology: the case of Hermann von Helmholtz.

    PubMed

    De Kock, Liesbet

    2014-05-01

    The failure to recognize the programmatic similarity between (post-)Kantian German philosophy and early psychology has impoverished psychology's historical self-understanding to a great extent. This article aims to contribute to recent efforts to overcome the gaps in the historiography of contemporary psychology, which are the result of an empiricist bias. To this end, we present an analysis of the way in which Hermann von Helmholtz's theory of perception resonates with Johann Gottlieb Fichte's Ego-doctrine. It will be argued that this indebtedness is particularly clear when focusing on the foundation of the differential awareness of subject and object in perception. In doing so, the widespread reception of Helmholtz's work as proto-positivist or strictly empiricist is challenged, in favor of the claim that important elements of his theorizing can only be understood properly against the background of Fichte's Ego-doctrine. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  3. VHL c.505 T>C mutation confers a high age related penetrance but no increased overall mortality

    PubMed Central

    Bender, B.; Eng, C.; Olschewski, M.; Berger, D.; Laubenberger, J.; Altehofer, C.; Kirste, G.; Orszagh, M.; van Velthoven, V.; Miosczka, H.; Schmidt, D.; Neumann, H.

    2001-01-01

    BACKGROUND—Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect.
METHODS—This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carrying VHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed.
RESULTS—Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHL germline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany.
CONCLUSIONS—Our results are an important example that a specific genotype, at least in the case of VHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and

  4. Chromosome 3p allele loss in early invasive breast cancer: detailed mapping and association with clinicopathological features

    PubMed Central

    Martinez, A; Walker, R A; Shaw, J A; Dearing, S J; Maher, E R; Latif, F

    2001-01-01

    Aims—Chromosome 3p allele loss is a frequent event in many common sporadic cancers including lung, breast, kidney, ovarian, and head and neck cancer. To analyse the extent and frequency of 3p allelic losses in T1N0 and T1N1 invasive sporadic breast cancer, 19 microsatellite markers spread along 3p were analysed in 40 such breast carcinomas with known clinicopathological parameters. Methods—Loss of heterozygosity analysis was carried out using 3p microsatellite markers that were non-randomly distributed and chosen to represent regions that show hemizygous and/or homozygous losses in lung cancer (lung cancer tumour suppressor gene region 1 ( LCTSGR1) at 3p21.3 and LCTSGR2 at 3p12), and regions demonstrating suppression of tumorigenicity in breast, kidney, lung, and ovarian cancer. Results—Allelic loss was seen at one or more loci in 22 of these clinically early stage sporadic breast tumours, but none had complete 3p allele loss. Several regions with non-overlapping deletions were defined, namely: (1) 18 tumours showed loss at 3p21–22, a physical distance of 12 Mb; (2) 11 tumours showed loss at 3p12 within a physical distance of 1 Mb, this region is contained within LCTSGR2; (3) six tumours showed loss at 3p25–24, including the von Hippel-Lindau (VHL) locus; (4) five tumours showed loss at 3p14.2, including the fragile histidine triad (FHIT) locus. Conclusions—This is the largest study to date defining the extent and range of 3p allelic losses in early stage invasive breast cancer and the results indicate that region 3p21–22 containing LCTSGR1 and a region at 3p12 within LCTSGR2 are the most frequent sites of 3p allelic loss in these breast carcinomas. This suggests that tumour suppressor genes located in these regions may play important roles in the development of breast cancer. There was an association between increasing 3p allelic loss and increasing tumour grade and loss of progesterone (p = 0.0098) and oestrogen (p = 0.0472) receptor expression

  5. Chromosome 3p allele loss in early invasive breast cancer: detailed mapping and association with clinicopathological features.

    PubMed

    Martinez, A; Walker, R A; Shaw, J A; Dearing, S J; Maher, E R; Latif, F

    2001-10-01

    Chromosome 3p allele loss is a frequent event in many common sporadic cancers including lung, breast, kidney, ovarian, and head and neck cancer. To analyse the extent and frequency of 3p allelic losses in T1N0 and T1N1 invasive sporadic breast cancer, 19 microsatellite markers spread along 3p were analysed in 40 such breast carcinomas with known clinicopathological parameters. Loss of heterozygosity analysis was carried out using 3p microsatellite markers that were non-randomly distributed and chosen to represent regions that show hemizygous and/or homozygous losses in lung cancer (lung cancer tumour suppressor gene region 1 ( LCTSGR1) at 3p21.3 and LCTSGR2 at 3p12), and regions demonstrating suppression of tumorigenicity in breast, kidney, lung, and ovarian cancer. Allelic loss was seen at one or more loci in 22 of these clinically early stage sporadic breast tumours, but none had complete 3p allele loss. Several regions with non-overlapping deletions were defined, namely: (1) 18 tumours showed loss at 3p21-22, a physical distance of 12 Mb; (2) 11 tumours showed loss at 3p12 within a physical distance of 1 Mb, this region is contained within LCTSGR2; (3) six tumours showed loss at 3p25-24, including the von Hippel-Lindau (VHL) locus; (4) five tumours showed loss at 3p14.2, including the fragile histidine triad (FHIT) locus. This is the largest study to date defining the extent and range of 3p allelic losses in early stage invasive breast cancer and the results indicate that region 3p21-22 containing LCTSGR1 and a region at 3p12 within LCTSGR2 are the most frequent sites of 3p allelic loss in these breast carcinomas. This suggests that tumour suppressor genes located in these regions may play important roles in the development of breast cancer. There was an association between increasing 3p allelic loss and increasing tumour grade and loss of progesterone (p = 0.0098) and oestrogen (p = 0.0472) receptor expression, indicating a link between 3p allelic loss and the

  6. A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma.

    PubMed

    Pal, Sumanta K; Drabkin, Harry A; Reeves, James A; Hainsworth, John D; Hazel, Susan E; Paggiarino, Dario A; Wojciak, Jon; Woodnutt, Gary; Bhatt, Rupal S

    2017-02-15

    Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc. A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations. The encouraging OS and favorable safety profile observed with

  7. Targeting renal cell carcinoma with a HIF-2 antagonist.

    PubMed

    Chen, Wenfang; Hill, Haley; Christie, Alana; Kim, Min Soo; Holloman, Eboni; Pavia-Jimenez, Andrea; Homayoun, Farrah; Ma, Yuanqing; Patel, Nirav; Yell, Paul; Hao, Guiyang; Yousuf, Qurratulain; Joyce, Allison; Pedrosa, Ivan; Geiger, Heather; Zhang, He; Chang, Jenny; Gardner, Kevin H; Bruick, Richard K; Reeves, Catherine; Hwang, Tae Hyun; Courtney, Kevin; Frenkel, Eugene; Sun, Xiankai; Zojwalla, Naseem; Wong, Tai; Rizzi, James P; Wallace, Eli M; Josey, John A; Xie, Yang; Xie, Xian-Jin; Kapur, Payal; McKay, Renée M; Brugarolas, James

    2016-11-03

    Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1β) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1β, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when

  8. Radiosurgery for hemangioblastoma: results of a multiinstitutional experience.

    PubMed

    Patrice, S J; Sneed, P K; Flickinger, J C; Shrieve, D C; Pollock, B E; Alexander, E; Larson, D A; Kondziolka, D S; Gutin, P H; Wara, W M; McDermott, M W; Lunsford, L D; Loeffler, J S

    1996-06-01

    , which is particularly important for patients with Von Hippel-Lindau Syndrome; and that (c) better control rates are associated with higher doses and smaller tumor volumes.

  9. A rapid method to visualize von willebrand factor multimers by using agarose gel electrophoresis, immunolocalization and luminographic detection.

    PubMed

    Krizek, D R; Rick, M E

    2000-03-15

    A highly sensitive and rapid clinical method for the visualization of the multimeric structure of von Willebrand Factor in plasma and platelets is described. The method utilizes submerged horizontal agarose gel electrophoresis, followed by transfer of the von Willebrand Factor onto a polyvinylidine fluoride membrane, and immunolocalization and luminographic visualization of the von Willebrand Factor multimeric pattern. This method distinguishes type 1 from types 2A and 2B von Willebrand disease, allowing timely evaluation and classification of von Willebrand Factor in patient plasma. It also allows visualization of the unusually high molecular weight multimers present in platelets. There are several major advantages to this method including rapid processing, simplicity of gel preparation, high sensitivity to low concentrations of von Willebrand Factor, and elimination of radioactivity.

  10. Balanced Branching in Transcription Termination

    NASA Technical Reports Server (NTRS)

    Harrington, K. J.; Laughlin, R. B.; Liang, S.

    2001-01-01

    The theory of stochastic transcription termination based on free-energy competition requires two or more reaction rates to be delicately balanced over a wide range of physical conditions. A large body of work on glasses and large molecules suggests that this should be impossible in such a large system in the absence of a new organizing principle of matter. We review the experimental literature of termination and find no evidence for such a principle but many troubling inconsistencies, most notably anomalous memory effects. These suggest that termination has a deterministic component and may conceivably be not stochastic at all. We find that a key experiment by Wilson and von Hippel allegedly refuting deterministic termination was an incorrectly analyzed regulatory effect of Mg(2+) binding.

  11. Wernher von Braun: Reflections on His Contributions to Space Exploration

    NASA Technical Reports Server (NTRS)

    Goldman, Arthur E.

    2012-01-01

    In 1950, Dr. Wernher von Braun and approximately 100 of his team members came to Huntsville, Alabama, to begin work with the Army on what would later become America's historic space program. He would later serve as the first director of the Marshall Space Flight Center and led the development of the Saturn V launch vehicle that launched seven crewed American mission to the moon, as well as America s first space station, Skylab. Von Braun is best known for his team s technical achievements. He realized his dream of exploring outer space by helping place humans on the moon. His engineering and managerial talent during the Apollo era had contributed to a technological revolution. He was by all accounts a good engineer, but he was only one among many. What set Von Braun apart were his charisma, his vision, and his leadership skills. He inspired loyalty and dedication in the people around him. He understood the importance of communicating his vision to his team, to political and business leaders and the public. Today, the Marshall Center continues his vision by pursuing engineering and scientific projects that will continue to open space to exploration. This presentation will discuss Von Braun's impact on Huntsville, the Marshall Center, the nation and the world and look at his contributions in context of where world space exploration is today.

  12. Update zum klinischen Einsatz von Inhibitoren mutierter Phosphokinasen beim Melanom.

    PubMed

    Cosgarea, Ioana; Ritter, Cathrin; Becker, Jürgen C; Schadendorf, Dirk; Ugurel, Selma

    2017-09-01

    Die Behandlungsstrategie beim metastasierten Melanom hat sich mit der Identifizierung therapeutisch angreifbarer molekularer Zielstrukturen innerhalb zellulärer Signalwege radikal geändert. Durch die Zulassung von Substanzen, die gezielt an den zentralen Schaltmolekülen, den Phosphokinasen, angreifen, können diese Signalwege selektiv abgeschaltet werden. Dies ist insbesondere bei denjenigen Tumoren von Interesse, deren Signalwege durch aktivierende Mutationen der für die Schaltmoleküle kodierenden Gene konstitutiv aktiviert sind. Aktuell ist diese therapeutische Strategie insbesondere für Patienten bedeutsam, deren Melanome eine Mutation im BRAF-Gen aufweisen. Diese Patienten können durch eine Kombinationstherapie aus Inhibitoren der Phosphokinasen BRAF und MEK langfristig mit sehr guter Krankheitskontrolle behandelt werden. Unter dieser Kombinationstherapie wird aktuell ein progressionsfreies Überleben von über zehn Monaten und ein Gesamtüberleben von mehr als zwei Jahren bei guter Lebensqualität erzielt. Da unter längerfristiger Therapie mit Kinaseinhibitoren jedoch bei einem Großteil der Patienten eine Resistenzbildung auftritt, sind aktuelle klinische Therapiestudien auf die Suche nach geeigneten Kombinationspartnern unter Blockierung anderer Signalwege oder unter Aktivierung der T-Zell-vermittelten Immunantwort ausgerichtet. Der vorliegende Übersichtsartikel stellt sowohl die aktuell verfügbaren als auch die in der klinischen Testung befindlichen zukünftigen Optionen der zielgerichteten Therapie des Melanoms dar. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  13. Wernher von Braun

    NASA Image and Video Library

    1959-03-01

    In this photo, Director of the U.S. Army Ballistic Missile Agency's (ABMA) Development Operations Division, Dr. Wernher von Braun, and Director of Missile Firing Division, Dr. Kurt Debus, are shown with unidentified individuals, discussing two components that would make up the Pioneer IV Lunar Probe. The mercury batteries (left) were used to power the radio transmitter, cosmic radiation counter and other instruments in Pioneer IV. The conical shroud placed over the instruments of Pioneer IV was plated with gold to improve conductivity. The metal surface also served as the anterna for the probe's instruments signaling back to the Earth receiving stations.

  14. The British Interplanetary Society - Val Cleaver and Wernher von Braun

    NASA Astrophysics Data System (ADS)

    Willhite, I. P.

    This article is concerned with the early relationship between Wernher von Braun and the British Interplanetary Society (BIS). The BIS/Wernher von Braun/Val Cleaver correspondence files located here at the US Space & Rocket Center in Huntsville, Alabama are unparalleled. As one reads the stimulating comments between Cleaver and von Braun, the need to share their thoughts prevails. Following is an excerpt from one letter that whets ones appetite for more. 10 June 1951 Cleaver writes, “I'm so glad you enjoyed my last letter, and look forward to your promised further contribution to our discussion of the ethics of science in general and astronautics in particu- lar. As regards the one particular point on which you found yourself unable to hold your fire, I should say there are really two distinct issues at stake:. . .” This article attempts to represent the best of the letters as they goad each other on scientific principles, means to prevent wars, and other philosophic ideas.

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

    PubMed

    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. Von eingebetteten Systemen zu Cyber-Physical Systems

    NASA Astrophysics Data System (ADS)

    Wedde, Rorst F.; Lehnhoff, Sebastian; Rehtanz, Christian; Krause, Olav

    Das Hauptanliegen des Papiers ist, ein Paradigma für Probleme mit neuartigen Integrationsanforderungen für Forschung und Entwicklung in verteilten eingebetteten Echtzeitsystemen zu motivieren und vorzustellen, nämlich den Begriff Cyber-Physical Systems. Bei einer in letzter Zeit stark zunehmenden Anzahl von Realzeitanwendungen können ohne die Berücksichtigung solcher Forderungen keine praktisch brauchbaren Lösungen erwartet werden. Einige Anwendungsfelder werden angesprochen. Im Einzelnen werden dann für Elektroautos, die mit erneuerbaren Energien betrieben werden sollen, einerseits die Management-, verteilte Verhandlungs- und Verteilungsprobleme der benötigten Energie in einem bottom-up Ansatz gelöst. Andererseits wird als Teil unserer Projektarbeit die Bereitstellung von Reserveenergie für den allgemeinen Bedarf durch Autobatterien vorgestellt. Es zeigt sich, dass dies effizienter und wesentlich kurzfristiger in unserem verteilten Vorgehen geschehen kann als in traditionellen Verfahren.

  17. Aufnahme, Analyse und Visualisierung von Bewegungen nativer Herzklappen in-vitro

    NASA Astrophysics Data System (ADS)

    Weiß, Oliver; Friedl, Sven; Kondruweit, Markus; Wittenberg, Thomas

    Die hohe Zahl an Transplantationen von Herzklappen und viele nötige Re-Operationen machen eine detaillierte Analyse der Strömungen und Klappenbewegungen klinisch interessant. Ein neuer Ansatz ist hierbei der Einsatz von Hochgeschwindigkeitskameras um Bewegungsabl äufe der Herzklappen beobachten und auswerten zu können. Die hohen Datenraten erfordern allerdings eine möglichst automatisierte Analyse und möglichst komprimierte Darstellung des Schwingungsverhaltens. In dieser Arbeit wird ein Ansatz vorgestellt, bei dem Bewegungen nativer Herzklappen in-vitro aufgenommen, analysiert und kompakt visualisiert werden.

  18. Identification and characterization of the elusive mutation causing the historical von Willebrand Disease type IIC Miami.

    PubMed

    Obser, T; Ledford-Kraemer, M; Oyen, F; Brehm, M A; Denis, C V; Marschalek, R; Montgomery, R R; Sadler, J E; Schneppenheim, S; Budde, U; Schneppenheim, R

    2016-09-01

    Essentials Von Willebrand disease IIC Miami features high von Willebrand factor (VWF) with reduced function. We aimed to identify and characterize the elusive underlying mutation in the original family. An inframe duplication of VWF exons 9-10 was identified and characterized. The mutation causes a defect in VWF multimerization and decreased VWF clearance from the circulation. Background A variant of von Willebrand disease (VWD) type 2A, phenotype IIC (VWD2AIIC), is characterized by recessive inheritance, low von Willebrand factor antigen (VWF:Ag), lack of VWF high-molecular-weight multimers, absence of VWF proteolytic fragments and mutations in the VWF propeptide. A family with dominantly inherited VWD2AIIC but markedly elevated VWF:Ag of > 2 U L(-1) was described as VWD type IIC Miami (VWD2AIIC-Miami) in 1993; however, the molecular defect remained elusive. Objectives To identify the molecular mechanism underlying the phenotype of the original VWD2AIIC-Miami. Patients and Methods We studied the original family with VWD2AIIC-Miami phenotypically and by genotyping. The identified mutation was recombinantly expressed and characterized by standard techniques, confocal imaging and in a mouse model, respectively. Results By Multiplex ligation-dependent probe amplification we identified an in-frame duplication of VWF exons 9-10 (c.998_1156dup; p.Glu333_385dup) in all patients. Recombinant mutant (rm)VWF only presented as a dimer. Co-expressed with wild-type VWF, the multimer pattern was indistinguishable from patients' plasma VWF. Immunofluorescence studies indicated retention of rmVWF in unusually large intracellular granules in the endoplasmic reticulum. ADAMTS-13 proteolysis of rmVWF under denaturing conditions was normal; however, an aberrant proteolytic fragment was apparent. A decreased ratio of VWF propeptide to VWF:Ag and a 1-desamino-8-d-arginine vasopressin (DDAVP) test in one patient indicated delayed VWF clearance, which was supported by clearance data after

  19. Von Donuts und Zucker: Mit Neutronen biologische Makromoleküle erforschen

    NASA Astrophysics Data System (ADS)

    May, Roland P.

    2003-05-01

    Für die Erforschung von Biomolekülen bieten Neutronen einzigartige Eigenschaften. Vor allem ihre unterschiedliche Wechselwirkung mit dem natürlichen Wasserstoff und seinem schweren Isotop Deuterium ermöglicht tiefe Einblicke in Struktur, Funktion und Dynamik von Proteinen, Nukleinsäuren und Biomembranen. Bei vielen Fragestellungen zur Strukturaufklärung gibt es kaum oder keine Alternative zum Neutron. Das Institut Laue-Langevin trägt Bahnbrechendes zum Erfolg der Neutronen-Methoden in der Biologie bei.

  20. The von Auwers reaction - history and synthetic applications.

    PubMed

    Dumeunier, Raphaël; Jaeckh, Simon

    2014-01-01

    Dienones obtained from the facile dearomatization of phenols, can be further transformed to semi-benzenes prone to rearomatize in clean, but sometimes unexpected, fashion. Over a hundred years ago, K. von Auwers found that adding Grignards on dienones would lead spontaneously to subsequent dehydration and a novel aromatizing rearrangement. This reaction was ignored for 50 years before Melvin Newman re-investigated these findings, studied the mechanism, and developed variations on the same theme. Since then, despite the tremendous potential of the reactions, those studies were only rarely mentioned, before finally falling into oblivion. This review aims to provide the reader with a detailed history and comprehensive bibliography of the von Auwers rearrangement, some of its synthetic applications, and new unpublished material in the hope to open new perspectives on this forgotten reaction.

  1. Vasorelaxant effects of Brillantaisia nitens Lindau (Acanthaceae) extracts on isolated rat vascular smooth muscle.

    PubMed

    Dimo, T; Mtopi, O-S Bopda; Nguelefack, T B; Kamtchouing, P; Zapfack, L; Asongalem, E A; Dongo, E

    2007-04-20

    Brillantaisia nitens Lindau (Acanthaceae) is traditionally used in Cameroon for the treatment of many diseases including cardiovascular disorders. We have studied its vasorelaxant effects in rat vascular smooth muscle. In this study, aqueous, methylene chloride, methanol, and methylene chloride/methanol leaves extracts of Brillantaisia nitens were tested for their relaxing ability in vitro. Strips of rat aorta, with or without intact endothelium, were mounted in tissue baths, contracted with KCl (60mM) or norepinephrine (10(-4)M), and then exposed to the plant extracts. These extracts exhibited concentration-dependent vasorelaxations of norepinephrine-induced contractions of intact aortic strips. The EC(50) were 0.42+/-0.01mg/ml (aqueous extract), 0.63+/-0.02mg/ml (methylene chloride extract), 0.73+/-0.02mg/ml (methanol extract) and 0.36+/-0.02mg/ml (methylene chloride/methanol extract). The methylene chloride/methanol (CH(2)Cl(2)/CH(3)OH) extract was the most potent relaxing extract. It caused a concentration-dependent and endothelium-independent relaxation of the rat aortic strips contracted by KCl or norepinephrine. On the NE-induced contraction, its maximal relaxant activity (109%) due to the dose of 1.5mg/ml, was not significantly modified by the pretreatment of aortic strips with indomethacin (89%, P>0.05) or with l-NAME (103%, P>0.05). This suggests that the vasorelaxation elicited by CH(2)Cl(2)/CH(3)OH extract was not mediated via endothelium-derived prostacyclin or nitric oxide. In contrast, this relaxation was markedly reduced by tetraethylammonium, a blocker of non-selective K(+) channels and glibenclamide, a blocker of ATP-sensitive K(+) channels. The CH(2)Cl(2)/CH(3)OH extract significantly inhibited Ca(2+)-induced concentration-contraction and the Ca(2+) influx in aortic strips incubated with 60mM KCl. These results indicate that the vasorelaxant effect of the CH(2)Cl(2)/CH(3)OH extract of Brillantaisia nitens is due to an inhibition of Ca(2+) influx

  2. Dr. von Braun Tours the North American Aviation

    NASA Technical Reports Server (NTRS)

    1962-01-01

    Dr. Wernher von Braun, Director of the Marshall Space Flight Center (MSFC), during his tour of the Space information Division of North American Aviation (NAA) in Downey, California, where the Saturn SII stage was developed.

  3. Dr. von Braun tours the North American Aviation

    NASA Technical Reports Server (NTRS)

    1962-01-01

    Dr. Wernher von Braun, Director of the Marshall Space Flight Center (MSFC), during his tour of the Space Information Division of North American Aviation (NAA) in Downey, California, where the Saturn SII stage was developed.

  4. Design of inside cut von koch fractal UWB MIMO antenna

    NASA Astrophysics Data System (ADS)

    Tharani, V.; Shanmuga Priya, N.; Rajesh, A.

    2017-11-01

    An Inside Cut Hexagonal Von Koch fractal MIMO antenna is designed for UWB applications and its characteristics behaviour are studied. Self-comparative and space filling properties of Koch fractal structure are utilized in the antenna design which leads to the desired miniaturization and wideband characteristics. The hexagonal shaped Von Koch Fractal antenna with Defected Ground Structure (DGS) is designed on FR4 substrate with a compact size of 30mm x 20mm x 1.6mm. The antenna achieves a maximum of -44dB and -51dB at 7.1GHz for 1-element and 2-element case respectively.

  5. Elliptical Instability of Rotating Von Karman Street

    NASA Astrophysics Data System (ADS)

    Stegner, A.; Pichon, T.; Beunier, M.

    Clouds often reveal a meso-scale vortex shedding in the wake of mountainous islands. Unlike the classical bi-dimensional Von-Karman street, these observed vortex street are affected by the earth rot ation and vertical stratification. Theses effects could induce a selective destabilization of anticyclonic vortices. It is well known that inertial instability (also called centrifugal instability) induce a three- dimensional destabilization of anticyclonic structures when the absolute vorticity is larger than the local Coriolis parameter. However, we have shown, by the mean of laboratory experiments, that it is a different type of instability which is mainly responsible for asymmetric rotating Von-Karman street. A serie of experiments were performed to study the wake of a cylinder in a rotating fluid, at medium Reynolds number and order one Rossby number. We have shown that the vertical structure of unstable anticyclonic vortices is characteristic of an elliptical instability. Besides, unlike the inertial instability, the vertical unstable wavelength depends on the Rossby number.

  6. Inattentional blindness and the von Restorff effect.

    PubMed

    Schmidt, Stephen R; Schmidt, Constance R

    2015-02-01

    Sometimes we fail to notice distinctive or unusual items (inattentional blindness), while other times we remember distinctive items more than expected items (the von Restorff effect). A three-factor framework is presented and tested in two experiments in an attempt to reconcile these seemingly contradictory phenomena. Memory for different types of unexpected stimuli was tested after an easy or difficult Stroop color-naming task. Highly arousing taboo words were well remembered even when the difficult Stroop task limited attentional resources. However, a conceptual isolation effect was only observed when the nature of the category change was highlighted by the Stroop task, the Stroop task was easy, and/or the isolated targets enjoyed a retrieval advantage relative to comparison targets. As proposed in the three-factor framework, the arousing qualities of the stimuli, the attentional demands of the primary task, and the relevance of isolated features at encoding and retrieval combine to produce inattentional blindness and the von Restorff effect.

  7. The Magic Background of Pearl Harbor. Volume 2 (May 12, 1941 - August 6, 1941)

    DTIC Science & Technology

    1977-01-01

    sistance in an Axis move against India.617 German Ambassador Franz von Papen and Foreign Minister Shukru Saracoglu signed a Turkish-German Pact...sadorB rlinportedTokyonJu7,941thatitw sthpinion of Chancellor Hitler and Foreign Minister von Ribbentrop that the United States would hesi...particularlyinregardtowaragainstEngland,HerrHessmighthavebeenanxioustoleaveGermany.ItwasalsoknownthathepossessedagreatdislikeforForeignMin- ister von

  8. Strong positive cooperativity in binding to the A3T3 repeat by Hoechst 33258 derivatives attaching the quinoline units at the end of a branched linker.

    PubMed

    Koda, Hironori; Brazier, John Alan; Onishi, Ippei; Sasaki, Shigeki

    2015-08-01

    Hoechst 33258 derivatives with additional interacting moieties attached at the ends of branched linkers were synthesized, and their DNA binding properties were investigated with regard to the A3T3 repeat by measuring fluorescence spectra. The binding property of the ligand was investigated by fluorescence titration, and the titration data were analyzed using the McGhee-von Hippel method. Ligand 6Q with the quinolin-6-yloxyacetyl group and Ligand IQ with isoquinolin-6-yloxyacetyl group at the ends of the branched linkers exhibit highly positive cooperativity for the DNA having 5 A3T3 sites with 3 base-insertions between them with sequence selectivity. The strategy developed in this study may be generally applicable for designing ligands for repetitive DNA sequences. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Von Willebrand's disease: case report and review of literature.

    PubMed

    Echahdi, Hanae; El Hasbaoui, Brahim; El Khorassani, Mohamed; Agadr, Aomar; Khattab, Mohamed

    2017-01-01

    Von Willebrand Disease (VWD) is the most common human inherited bleeding disorder due to a defect of Von Willebrand Factor (VWF), which a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels < 50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50IU/dL). Von willebrand factor is a complex multimeric protein with two functions: it forms a bridge between the platelets and areas of vascular damage and it binds to and stabilizes factor VIII, which is necessary for the clotting cascade. By taking a clinical history of bleeding (mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is possible) it is important to think about VWD and to make the appropriate diagnosis. If the VWD is suspected diagnostic tests should include an activated partial thromboplastin time, bleeding time, factor VIII: C Ristocetin cofactor and vWF antigen. Additional testing of ristocetin induced plattlet adhesion (RIPA) the multimeric structure and collagen binding test and genanalysis allow diagnosing the different types of von. Willebrand Disease. The treatment of choice in mild forms is the synthetic agent desmopressin. In patients with severe type 1, type 2B, 2N and type 3 or in people who do not response to desmopressin, the appropriate treatment is a factor VIII concentrate that is rich of VWF. We report a case of infant in 27-month-old boy who had been referred due to haemorrhagic shock. His birth histories, his familie's social history and developmental milestones were unremarkable. He was born at full term with no antenatal or perinatal complications. Prior to

  10. Segmentierung von Aortenaneurysmen in CTA-Bildern mit dem statistischen Verfahren der Active Appearance Models

    NASA Astrophysics Data System (ADS)

    Greiner, Katharina; Egger, Jan; Großkopf, Stefan; Kaftan, Jens N.; Dörner, Ralf; Freisleben, Bernd

    In diesem Beitrag werden Active Appearance Models (AAMs) zur Segmentierung der äußeren Kontur von Aortenaneurysmen eingesetzt. Diese Aufgabe ist wegen des geringen Kontrastes zum umliegenden Gewebe und des Aufbaus der teils thrombotisierten oder kalzifizierten Gefäßwände im Bereich eines Aneurysmas so komplex, dass sie aufgrund der Vielgestalt der Kontur in CT-Angiographie-Bildern die Verwendung eines statistischen Modells für Form und eingeschlossene Textur rechtfertigt. Für die Evaluation des Verfahrens wurden verschiedene statistische Modelle aus Schichten von neun CTA-Datensätzen trainiert und die Segmentierung anhand von Leave-One-Out-Tests überprüft.

  11. Dr. von Braun Visits Huntsville Boys Club

    NASA Technical Reports Server (NTRS)

    1961-01-01

    Dr. von Braun, Director of Marshall Space Flight Center (MSFC) and chairman of this year's United Givers Fund (UGF) drive at MSFC, takes time out from the problems of sending a man to the Moon to talk baseball with 11-year-old Randy Smith at the Huntsville Boys Club.

  12. Gebrauch von Komplementärmedizin bei Patienten mit metastasierendem Melanom unter Therapie mit Ipilimumab innerhalb einer klinischen Studie.

    PubMed

    Huebner, Jutta; Mohr, Peter; Simon, Jan-Christoph; Fluck, Michael; Berking, Carola; Zimmer, Lisa; Loquai, Carmen

    2016-05-01

    In Deutschland wenden 40-90 % aller Krebspatienten Methoden der komplementären and alternativen Medizin (KAM) an. Bis dato gibt es kein Datenmaterial zum Einsatz der KAM bei Melanompatienten. Das Ziel unserer Studie war es, Daten über den Gebrauch, die Informationsquellen und Ziele von Patienten mit metastasierendem Melanom zu erfassen. Einhundertsechsundfünfzig Patienten aus 25 Studienzentren nahmen an der DecOG-MM-PAL Multibasket Studie teil. Die beteiligten Personen wurden auch gebeten, an einer Nebenstudie teilzunehmen, die ihren Gebrauch von KAM erfassen sollte. Dazu wurde während der Behandlung ein standardisierter Fragebogen zu genau festgelegten Zeitpunkten ausgeteilt. Insgesamt gingen 55 Fragebögen von 32 (21 %) Melanompatienten ein. Von diesen gaben 17 (53 %) ein Interesse an KAM an, und sieben (22 %) machten von KAM Gebrauch. Die Hauptinformationsquellen (31 %) waren Familienmitglieder und Freunde, gefolgt von Ärzten (19 %). Die Hauptgründe für die Anwendung von KAM waren die Stärkung des Immunsystems (41 %) und des Körpers (34 %). Nahrungsergänzungsmittel (Vitamine und Spurenelemente) wurden am häufigsten angewendet (28 %). Eine relativ hohe Anzahl an Patienten mit metastasierendem Melanom machte trotz Teilnahme an einer klinischen Studie von KAM Gebrauch. Wechselwirkungen könnten durch biologisch basierte KAM auftreten, und hier besonders bei immunmodulierenden KAM- Strategien. Um Risiken zu vermeiden, sollte die Kommunikation zwischen den Ärzten und den Patienten verbessert werden. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  13. Trizentrische Analyse von Kofaktoren und Komorbidität des Pyoderma gangraenosum.

    PubMed

    Jockenhöfer, Finja; Herberger, Katharina; Schaller, Jörg; Hohaus, Katja Christina; Stoffels-Weindorf, Maren; Ghazal, Philipp Al; Augustin, Matthias; Dissemond, Joachim

    2016-10-01

    Das Pyoderma gangraenosum (PG) ist eine seltene, inflammatorische destruktiv-ulzerierende neutrophile Erkrankung mit weitgehend unklarer Pathophysiologie. In dieser Studie wurden die potenziell relevanten Kofaktoren und Begleiterkrankungen von Patienten mit PG aus drei dermatologischen Wundzentren in Deutschland differenziert ausgewertet. Von den insgesamt 121 analysierten Patienten waren Frauen (66,9 %) häufiger betroffen als Männer. Das Alter der Patienten war 18-96 Jahre (Mittelwert [MW]: 59,8); die Wunden hatten eine Größe von 1-600 cm² (MW: 65,6 cm²) und waren überwiegend sehr schmerzhaft (VAS 1-10, MW: 7). Die Unterschenkel waren am häufigsten (71,9 %) betroffen. Bei 12 (9,9 %) Patienten bestanden chronisch entzündliche Darmerkrankungen (5,8 % Colitis ulcerosa; 4,1 % Morbus Crohn), bei 14,1 % der Patienten wurde eine Begleiterkrankung aus dem rheumatischen Formenkreis beschrieben. Neoplasien bestanden bei 20,6 % der Patienten, von denen 6,6 % als hämatologische und 14,1 % als solide Neoplasien klassifiziert wurden. Aus dem Kreis des metabolischen Syndroms wurde bei 69,4 % Patienten eine Adipositas, bei 57,9 % eine arterielle Hypertonie und bei 33,9 % ein Diabetes mellitus diagnostiziert. Diese Datenanalyse bestätigt Assoziationen des PG mit dem metabolischen Syndrom und mit Neoplasien, die zukünftig frühzeitig bei einer zielgerichteten Diagnostik der Patienten beachtet und behandelt werden sollten. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  14. (Never) Mind your p's and q's: Von Neumann versus Jordan on the foundations of quantum theory

    NASA Astrophysics Data System (ADS)

    Duncan, A.; Janssen, M.

    2013-03-01

    In 1927, in two papers entitled "On a new foundation [Neue Begründung] of quantum mechanics," Pascual Jordan presented his version of what came to be known as the Dirac-Jordan statistical transformation theory. Jordan and Paul Dirac arrived at essentially the same theory independently of one another at around the same time. Later in 1927, partly in response to Jordan and Dirac and avoiding the mathematical difficulties facing their approach, John von Neumann developed the modern Hilbert space formalism of quantum mechanics. We focus on Jordan and von Neumann. Central to the formalisms of both are expressions for conditional probabilities of finding some value for one quantity given the value of another. Beyond that Jordan and von Neumann had very different views about the appropriate formulation of problems in quantum mechanics. For Jordan, unable to let go of the analogy to classical mechanics, the solution of such problems required the identification of sets of canonically conjugate variables, i.e., p's and q's. For von Neumann, not constrained by the analogy to classical mechanics, it required only the identification of a maximal set of commuting operators with simultaneous eigenstates. He had no need for p's and q's. Jordan and von Neumann also stated the characteristic new rules for probabilities in quantum mechanics somewhat differently. Jordan and Dirac were the first to state those rules in full generality. Von Neumann rephrased them and, in a paper published a few months later, sought to derive them from more basic considerations. In this paper we reconstruct the central arguments of these 1927 papers by Jordan and von Neumann and of a paper on Jordan's approach by Hilbert, von Neumann, and Nordheim. We highlight those elements in these papers that bring out the gradual loosening of the ties between the new quantum formalism and classical mechanics. This paper was written as part of a joint project in the history of quantum physics of the Max Planck

  15. An Alternative Perspective on von Winterfeldt et al.'s (1997) Test of Consequence Monotonicity

    ERIC Educational Resources Information Center

    Ho, Moon-Ho R.; Regenwetter, Michel; Niederee, Reinhard; Heyer, Dieter

    2005-01-01

    D. von Winterfeldt, N.-K. Chung, R. D. Luce, and Y. Cho (see record 1997-03378-008) provided several tests for consequence monotonicity of choice or judgment, using certainty equivalents of gambles. The authors reaxiomatized consequence monotonicity in a probabilistic framework and reanalyzed von Winterfeldt et al.'s main experiment via a…

  16. [Carl Friedrich von Weizsäcker and the Bethe-Weizsäcker cycle].

    PubMed

    Wiescher, Michael

    2014-01-01

    The Carbon- or Bethe-Weizsäcker Cycle plays an important role in astrophysics as one of the most important energy sources for a quiescent and explosive hydrogen burning in stars. This paper presents the historical background and the contributions by Carl Friedrich von Weizsäcker and Hans Bethe who provided the first predictions of the cycle. Furthermore, it discussed the experimental verification of the predicted process in the following decades. Also discussed is the extension of the initial Carbon cycle to the CNO multi-cycles and the hot CNO cycles which followed from the detailed experimental studies of the associated nuclear reactions. Finally discussed is the impact of the experimental and theoretical results on our present understanding of hydrogen burning in different stellar environments and on our understanding of the chemical evolution of our universe.

  17. [Scientific theoretical founding of medicine as a natural science by Hermann von Helmholtz (1821-1894)].

    PubMed

    Neumann, J N

    1994-01-01

    In this study an attempt will be made to discuss the epistemological problems in the theory and practice of modern technical medicine in the writings of Hermann von Helmholz. An inquiry into the relationship between von Helmholtz' thinking and the critical philosophy of Immanuel Kant is followed by the characteristics of von Helmholtz' philosophy of science which he himself called "empirical theory". The question of medicine as a science finally leads to the main problem of medical epistemology, viz., the relationship between theoretical knowledge and practice in medicine. In this context the anthropological dimension is brought into consideration.

  18. Physical Realization of von Neumann Lattices in Rotating Bose Gases with Dipole Interatomic Interactions.

    PubMed

    Cheng, Szu-Cheng; Jheng, Shih-Da

    2016-08-22

    This paper reports a novel type of vortex lattice, referred to as a bubble crystal, which was discovered in rapidly rotating Bose gases with long-range interactions. Bubble crystals differ from vortex lattices which possess a single quantum flux per unit cell, while atoms in bubble crystals are clustered periodically and surrounded by vortices. No existing model is able to describe the vortex structure of bubble crystals; however, we identified a mathematical lattice, which is a subset of coherent states and exists periodically in the physical space. This lattice is called a von Neumann lattice, and when it possesses a single vortex per unit cell, it presents the same geometrical structure as an Abrikosov lattice. In this report, we extend the von Neumann lattice to one with an integral number of flux quanta per unit cell and demonstrate that von Neumann lattices well reproduce the translational properties of bubble crystals. Numerical simulations confirm that, as a generalized vortex, a von Neumann lattice can be physically realized using vortex lattices in rapidly rotating Bose gases with dipole interatomic interactions.

  19. Identifikationsverfahren zur Analyse von EEG-Signalen bei Epilepsie mit Reaktions-Diffusions Netzwerken

    NASA Astrophysics Data System (ADS)

    Gollas, F.; Tetzlaff, R.

    2007-06-01

    Partielle Differentialgleichungen des Reaktions-Diffusions-Typs beschreiben Phänomene wie Musterbildung, nichtlineare Wellenausbreitung und deterministisches Chaos und werden oft zur Untersuchung komplexer Vorgänge auf den Gebieten der Biologie, Chemie und Physik herangezogen. Zellulare Nichtlineare Netzwerke (CNN) sind eine räumliche Anordnung vergleichsweise einfacher dynamischer Systeme, die eine lokale Kopplung untereinander aufweisen. Durch eine Diskretisierung der Ortsvariablen können Reaktions-Diffusions-Gleichungen häufig auf CNN mit nichtlinearen Gewichtsfunktionen abgebildet werden. Die resultierenden Reaktions-Diffusions-CNN (RD-CNN) weisen dann in ihrer Dynamik näherungsweise gleiches Verhalten wie die zugrunde gelegten Reaktions-Diffusions-Systeme auf. Werden RD-CNN zur Identifikation neuronaler Strukturen anhand von EEG-Signalen herangezogen, so besteht die Möglichkeit festzustellen, ob das gefundene Netzwerk lokale Aktivität aufweist. Die von Chua eingeführte Theorie der lokalen Aktivität Chua (1998); Dogaru und Chua (1998) liefert eine notwendige Bedingung für das Auftreten von emergentem Verhalten in zellularen Netzwerken. Änderungen in den Parametern bestimmter RD-CNN könnten auf bevorstehende epileptische Anfälle hinweisen. In diesem Beitrag steht die Identifikation neuronaler Strukturen anhand von EEG-Signalen durch Reaktions-Diffusions-Netzwerke im Vordergrund der dargestellten Untersuchungen. In der Ergebnisdiskussion wird insbesondere auch die Frage nach einer geeigneten Netzwerkstruktur mit minimaler Komplexität behandelt.

  20. Interaktive Visualisierung von Abständen und Ausdehnungen anatomischer Strukturen für die Interventionsplanung

    NASA Astrophysics Data System (ADS)

    Rössling, Ivo; Cyrus, Christian; Dornheim, Lars; Hahn, Peter; Preim, Bernhard; Boehm, Andreas

    Im Rahmen der Interventionsplanung muss der Chirurg therapierelevante Entscheidungen auf Basis räumlicher Relationen anatomischer Strukturen treffen. Interaktive 3D-Visualisierungen unterstützen diesen Prozess qualitativ. Quantitative Fragestellungen (Tumorausdehnung, Infiltrationstiefe, etc.) erfordern die Integration einer Bemaßung, deren Nutzen wesentlich von einer geeigneten Darstellung abhängt. In dieser Arbeit haben wir allgemeine Kriterien für die Eignung von Visualisierungen von Bemaßungen in interaktiven 3D-Szenen erarbeitet. Daran orientierend haben wir verschiedene Varianten der Darstellung von Abständen und Ausdehnungen anatomischer Strukturen betrachtet und ihr Erscheinungsbild hierzu zweckmäßig parametrisiert. Die Ausprägungen dieser Darstellungsparameter wurden in einer Studie auf ihre visuellen Wirkung hin an Chirurgen evaluiert. Es zeigte sich, dass die befragten Mediziner höchsten Wert auf Kohärenz und klare Zuordnung der Bemaßung setzten und überraschenderweise dafür sogar Abstriche in der direkten Lesbarkeit in Kauf nahmen.

  1. Einstellung und Wissen von Lehramtsstudierenden zur Evolution - ein Vergleich zwischen Deutschland und der Türkei

    NASA Astrophysics Data System (ADS)

    Graf, Dittmar; Soran, Haluk

    Es wird eine Untersuchung vorgestellt, in der Wissen und Überzeugungen von Lehramtsstudierenden aller Fächer zum Thema Evolution an zwei Universitäten in Deutschland und der Türkei erhoben worden sind. Die Befragung wurde in Dortmund und in Ankara durchgeführt. Es stellte sich heraus, dass ausgeprägte Defizite im Verständnis der Evolutionsmechanismen herrschen. Viele Studierende, insbesondere aus der Türkei, sind nicht von der Faktizität der Evolution überzeugt. Dies gilt sowohl für Studierende mit Fach Biologie als auch für Studierende mit anderen Fächern. Näher untersucht worden sind die Faktoren, die die Überzeugungen zur Evolution beeinflussen können, was ja in Anbetracht der hohen Ablehnungsrate der Evolution von besonderem Interesse ist. Das Vertrauen in die Wissenschaft spielt hierbei eine besondere Rolle: Wer der Wissenschaft vertraut, ist auch eher von der Evolution überzeugt, als diejenigen, die skeptisch gegenüber der Wissenschaft sind.

  2. Identification of a His54Gln substitution in von Willebrand factor from a patient with defective binding of factor VIII.

    PubMed

    Rick, M E; Krizek, D M

    1996-04-01

    A patient with type 2N ("Normandy" variant) von Willebrand's disease is described. Her von Willebrand factor level was borderline low, while her factor VIII was markedly decreased to 7%. Her plasma von Willebrand factor demonstrated a decreased ability to complex with factor VIII in vitro, binding less than 10% when compared to normal plasma von Willebrand factor. The factor VIII released into the circulation after the patient received DDAVP had a shortened survival in vivo. Nucleotide sequence analysis revealed a T-to-A transition at nucleotide 2451 on both alleles. This transition results in a substitution of Gln for His at amino acid 54 in the mature subunit of von Willebrand factor.

  3. Guido von Pirquet: Austrian pioneer of astronautics

    NASA Technical Reports Server (NTRS)

    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.

  4. Von Willebrand factor regulation of blood vessel formation.

    PubMed

    Randi, Anna M; Smith, Koval E; Castaman, Giancarlo

    2018-06-04

    Several important physiological processes, from permeability to inflammation to haemostasis, take place at the vessel wall and are regulated by endothelial cells (EC). Thus, proteins that have been identified as regulators of one process are increasingly found to be involved in other vascular functions. Such is the case for Von Willebrand Factor (VWF), a large glycoprotein best known for its critical role in haemostasis. In vitro and in vivo studies have shown that lack of VWF causes enhanced vascularisation, both constitutively and following ischemia. This evidence is supported by studies on blood outgrowth endothelial cells (BOEC) from patients with lack of VWF synthesis (type 3 von Willebrand disease [VWD]). The molecular pathways are likely to involve VWF binding partners, such as integrin αvβ3, and components of Weibel Palade bodies (WPB), such as Angiopoietin-2 and Galectin-3, whose storage is regulated by VWF; these converge on the master regulator of angiogenesis and endothelial homeostasis, vascular endothelial growth factor (VEGF) signalling. Recent studies suggest that the roles of VWF may be tissue-specific. The ability of VWF to regulate angiogenesis has clinical implications for a subset of VWD patients with severe, intractable gastrointestinal bleeding due to vascular malformations. In this article, we review the evidence showing that VWF is involved in blood vessel formation, discuss the role of VWF high molecular weight multimers in regulating angiogenesis, and the value of studies on BOEC in developing a precision medicine approach to validate novel treatments for angiodysplasia in congenital VWD and acquired von Willebrand syndrome. Copyright © 2018 American Society of Hematology.

  5. Untersuchung der Störwirkung von LTE auf SRD Anwendungen bei 868 MHz

    NASA Astrophysics Data System (ADS)

    Welpot, M.; Wunderlich, S.; Gaspard, I.

    2014-11-01

    Moderne Hausautomatisierungssysteme, Alarmanlagen oder auch Funk-Zugangssysteme in Haus und Automobil setzen auf frei nutzbare Frequenzen in ISM/SRD-Bändern. Die rasante Zunahme an privaten und kommerziell genutzten Applikationen im SRD-Band bei 868 MHz und der Ausbau der LTE-Mobilfunknetze im Frequenzbereich unterhalb von 1 GHz ("Digital Dividend") wirft zunehmend die Frage nach der Funkverträglichkeit dieser Systeme untereinander auf. Während die SRD-Funkmodule auf eine geringe Sendeleistung von ~ +14 dBm beschränkt sind (Ralf and Thomas, 2009), beträgt die maximale LTE-Sendeleistung im Uplink nach (ETSI-Norm, 2011) +23 dBm. Zusammen mit der Einführung von LTE im Frequenzbereich unterhalb 1 GHz als DSL-Ersatz vor allem in ländlichen Gebieten, ergibt sich damit als mögliches Störszenario, dass durch die Aussendung des LTE-Endgerätes im Bereich von ca. 850 MHz die SRD-Funkverbindungen bei 868 MHz insbesondere dann gestört werden, wenn die Antennen beider Funksysteme räumlich nahe zueinander angeordnet sind und folglich nur eine geringe zusätzliche Entkopplung der Systeme bieten. In der vorliegenden Arbeit wird das LTE-Störpotential auf SRD-Empfänger praxisnah untersucht.

  6. Planungsunterstützung für Pankreasoperationen bei Hyperinsulinismus von Kindern

    NASA Astrophysics Data System (ADS)

    Dornheim, J.; Preim, B.; Preim, U.; Mohnike, K.; Blankenstein, O.; Füchtner, F.; Mohnike, W.; Empting, S.; Mohnike, K.

    Auf Basis von sechs PET/CT-Datensätzen des Pankreas wird eine Computerunterstützung für die Teilresektion der Bauchspeicheldr üse (Pankreas) bei fokalem Hyperinsulinismus von Kindern entwickelt. Ziel ist es, die Lokalisation des krankhaften Fokus im Pankreasgewebe präoperativ dreidimensional zu visualisieren, um so die Sicherheit des Eingriffs zu erhöhen. Die relevanten anatomischen Strukturen werden im CT segmentiert und anschließend dreidimensional visualisiert. Der im PET erkennbare Fokus wird in diese anatomische 3D-Visualisierung eingeblendet. Es zeigt sich eine klare Erkennbarkeit des Fokus in allen sechs Fällen.

  7. Visualisierung analoger Schaltungen durch 3-D Animation von transienten SPICE-Simulationen

    NASA Astrophysics Data System (ADS)

    Becker, J.; Manoli, Y.

    2007-06-01

    Für das Zeichnen analoger Schaltpläne wird oft versucht, die Potentialverteilung in der entsprechenden Schaltung auszunutzen, um eine Platzierung der Bauteile nach abfallendem Potential vorzunehmen. Mit Hilfe von Computerunterstützung gelingt es, eine verallgemeinerte dreidimensionale Platzierungsstrategie anzuwenden, die allein auf Grund der Potentialwerte einer Schaltung die automatische Generierung einer technisch exakten Potentialdarstellung erlaubt. Somit ist es möglich, die Ergebnisse von transienten SPICE-Simulationen in jedem Zeitschritt darzustellen und eine Animation des zeitlichen Verhaltens zu erzeugen. Die Umsetzung dieser Methode zur Einbettung in eine webbasierte Lern - und Arbeitsplattform wird im Folgenden erläutert.

  8. In memory of Eugene (Jenő) von Gothard: a pioneering nineteenth century Hungarian astrophysicist

    NASA Astrophysics Data System (ADS)

    Vincze, Ildikő J.; Jankovics, István

    2012-07-01

    Eugene von Gothard was a Hungarian engineer/scientist, instrument-maker and astrophysicist who founded the Herény Astrophysical Observatory in 1881 and carried out pioneering work in astronomical photography and spectroscopy. In this paper we provide biographical material about von Gothard and describe his observatory, before discussing his astronomical observations and the contribution that hemade to the early development of astrophysics.

  9. Dr. Wernher Von Braun

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. Thomas Paine, Deputy Administrator of the National Aeronautics and Space Administration, examines an ordinary man's shoe outfitted for use in the Saturn I workshop. Pictured from the left in the Saturn I workshop mockup are William Brooksbank, propulsion and vehicle engineering laboratory; Dr. Paine; Dr. Wernher Von Braun, Marshall Center director; Colonel Clare F. Farley, Executive Officer in the Office Of The Administrator; and Charles J. Donlan, Deputy Associate Administrator for Manned Space Flight, Technical. the shoe Dr. Paine is holding has a unique fastener built into the sole to allow an astronaut to move about on the workshop floor and to remain in one position if he desires.

  10. Von Braun Rocket Team at Fort Bliss, Texas

    NASA Technical Reports Server (NTRS)

    1940-01-01

    The German Rocket Team, also known as the Von Braun Rocket Team, poses for a group photograph at Fort Bliss, Texas. After World War II ended in 1945, Dr. Wernher von Braun led some 120 of his Peenemuende Colleagues, who developed the V-2 rocket for the German military during the War, to the United Sttes under a contract to the U.S. Army Corps as part of Operation Paperclip. During the following five years the team worked on high altitude firings of the captured V-2 rockets at the White Sands Missile Range in New Mexico, and a guided missile development unit at Fort Bliss, Texas. In April 1950, the group was transferred to the Army Ballistic Missile Agency (ABMA) at Redstone Arsenal in Huntsville, Alabama, and continued to work on the development of the guided missiles for the U.S. Army until transferring to a newly established field center of the National Aeronautic and Space Administration (NASA), George C. Marshall Space Flight Center (MSFC).

  11. Wernher von Braun

    NASA Image and Video Library

    2004-04-15

    A pioneer of America's space program, Dr. von Braun stands by the five F-1 engines of the Saturn V launch vehicle. This Saturn V vehicle is an actual test vehicle which has been displayed at the U.S. Space Rocket Center in Huntsville, Alabama. Designed and developed by Rocketdyne under the direction of the Marshall Space Flight Center, a cluster of five F-1 engines was mounted on the Saturn V S-IC (first) stage. The engines measured 19-feet tall by 12.5-feet at the nozzle exit and burned 15 tons of liquid oxygen and kerosene each second to produce 7,500,000 pounds of thrust. The S-IC stage is the first stage, or booster, of a 364-foot long rocket that ultimately took astronauts to the Moon.

  12. The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease.

    PubMed

    Makris, M; Federici, A B; Mannucci, P M; Bolton-Maggs, P H B; Yee, T T; Abshire, T; Berntorp, E

    2015-05-01

    Recurrent gastrointestinal bleeding is one of the most challenging complications encountered in the management of patients with von Willebrand disease (VWD). The commonest cause is angiodysplasia, but often no cause is identified due to the difficulty in making the diagnosis. The optimal treatment to prevent recurrences remains unknown. We performed a retrospective study of VWD patients with occult or angiodysplastic bleeding within the setting of the von Willebrand Disease Prophylaxis Network (VWD PN) to describe diagnostic and treatment strategies. Centres participating in the VWD PN recruited subjects under their care with a history of congenital VWD and gastrointestinal (GI) bleeding due to angiodysplasia, or cases in which the cause was not identified despite investigation. Patients with acquired von Willebrand syndrome or those for whom the GI bleeding was due to another cause were excluded. Forty-eight patients from 18 centres in 10 countries were recruited. Seven individuals had a family history of GI bleeding and all VWD types except 2N were represented. Angiodysplasia was confirmed in 38%, with video capsule endoscopy and GI tract endoscopies being the most common methods of making the diagnosis. Recurrent GI bleeding in VWD is associated with significant morbidity and required hospital admission on up to 30 occasions. Patients were treated with multiple pharmacological agents with prophylactic von Willebrand factor concentrate being the most efficient in preventing recurrence of the GI bleeding. The diagnosis and treatment of recurrent GI bleeding in congenital VWD remains challenging and is associated with significant morbidity. Prophylactic treatment with von Willebrand factor concentrate was the most effective method of preventing recurrent bleeding but its efficacy remains to be confirmed in a prospective study. © 2014 John Wiley & Sons Ltd.

  13. Johann Bernhard Aloys von Gudden and the Mad King of Bavaria

    PubMed Central

    Bhattacharyya, Kalyan B.

    2017-01-01

    Bernhard von Gudden was a psychiatrist in Prussia and he was summoned in March 1886 to examine King Ludwig II for his apparently insane activities like, profligate spending and erratic behaviour. A team of four estimable psychiatrists pronounced that he was not capable ruling. Consequently, he was dethroned and kept in a castle under supervision of von Gudden. Gudden championed the idea of 'no restraint' and advocated free movement of insane persons and one evening in June, he accompanied the King during an evening stroll to a lake. A few hours later, the corpus of both of them were recovered under mysterious circumstances. Autopsy suggested that the King was drowned but no post-mortem examination was performed on von Gudden. There are plenty of controversies regarding their death like, murder, accidental death or even natural death from cardiac arrest following immersion in cold water, but no incontrovertible conclusion could be arrived at, even after scrupulous analysis by historians and even the diagnosis of insanity of the King has been doubted. Some even suggested that the opinion of psychiatrists were sought as a pretense in order to depose the King. PMID:29184335

  14. Director von Braun Presents General Medaris With Golf Bag

    NASA Technical Reports Server (NTRS)

    1959-01-01

    Marshall Space Flight Center Director Wernher von Braun presents General J.B. Medaris with a new golf bag. General Medaris, (left) was a Commander of the Army Ballistic Missile Agency (ABMA) in Redstone Arsenal, Alabama during 1955 to 1958.

  15. The proliferative and chronotropic effects of Brillantaisia nitens Lindau (Acanthaceae) extracts on pluripotent stem cells and their cardiomyocytes derivatives.

    PubMed

    Nembo, Erastus Nembu; Dimo, Theophile; Bopda, Orelien Sylvain Mtopi; Hescheler, Jürgen; Nguemo, Filomain

    2014-10-28

    Brillantaisia nitens Lindau (Acanthaceae) leaves are commonly used in traditional medicine in Africa for the treatment of many disorders including heart diseases and malaria. In this study, we therefore evaluated the effect of the methylene chloride/methanol leaf extract of Brillantaisia nitens on the proliferation of mouse pluripotent stem cells and their cardiomyocyte derivatives. In this study, we combined two emerging technologies, pluripotent stem cell-derived cardiomyocytes and modern electrophysiology systems (impedance-based real-time) to assess the cytotoxicity of Brillantaisia nitens extract (BNE). Undifferentiated pluripotent cells and cardiomyocytes were exposed to different concentrations of BNE. Cell viability and contraction were monitored by impedance using the xCELLigence system for short- and long-term treatment whereas the excitability of single cardiomyocytes was captured by patch clamp technique after BNE acute exposure. Brillantaisia nitens extract inhibited the proliferation and increased cytotoxicity of embryonic stem cells in a concentration-dependent manner. With the increase in concentration of BNE, beating rate and the contractile amplitude of cardiomyocytes changed significantly. Spontaneous rhythmic activity of cardiomyocytes was completely suppressed after 48 and 24h exposures to relatively low (4.16 mg/ml) and high (8.32 mg/ml) concentrations of BNE, respectively. Moreover, acute application of 4.16 mg/ml of BNE led to a significant alteration of action potential (AP) parameters such as beating frequency, amplitude and AP duration at 90% of repolarization. Brillantaisia nitens extract inhibits the proliferative capacity of pluripotent stem cells and reduces electrical activity of cardiomyocytes, confirming its depressant action on the heart. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Alexander von Humboldt and the Origins of Landscape Archaeology.

    ERIC Educational Resources Information Center

    Mathewson, Kent

    1986-01-01

    Reviews the life, theories, and influence of Alexander von Humboldt, the early nineteenth century founder of modern geography. Maintains that Humboldt's novel approaches to the study of landscape antiquities have value for contemporary students in cultural and historical geography. (JDH)

  17. Wernher von Braun

    NASA Image and Video Library

    1971-07-26

    During the Apollo 15 launch activities in the launch control center's firing room 1 at Kennedy Space Center, Dr. Wernher von Braun, NASA's Deputy Associate Administrator for planning, takes a closer look at the launch pad through binoculars. The fifth manned lunar landing mission, Apollo 15 (SA-510), carrying a crew of three astronauts: Mission commander David R. Scott, Lunar Module pilot James B. Irwin, and Command Module pilot Alfred M. Worden Jr., lifted off on July 26, 1971. Astronauts Scott and Irwin were the first to use a wheeled surface vehicle, the Lunar Roving Vehicle, or the Rover, which was designed and developed by the Marshall Space Flight Center, and built by the Boeing Company. Astronauts spent 13 days, nearly 67 hours, on the Moon's surface to inspect a wide variety of its geological features.

  18. GPU-basierte Smart Visibility Techniken für die Planung von Tumor-Operationen

    NASA Astrophysics Data System (ADS)

    Tietjen, Christian; Kubisch, Christoph; Hiller, Stefan; Preim, Bernhard

    Bei der Planung von Tumoroperationen ist die Einschätzung von Abständen und Infiltrationen zu vitalen Strukturen wichtig. Im Bereich der medizinischen Visualisierung wurden hierfür bereits zahlreiche Techniken entwickelt, die unter dem Begriff Smart Visibility zusammengefasst werden. Zu diesen zählen Ghost Views und Section Views. In diesem Beitrag wird eine GPU-basierte Realisierung dieser Techniken für polygonale Daten vorgestellt. Die Parametrisierung der Techniken erfolgt automatisch, um einen klinischen Einsatz ermöglichen zu können.

  19. The Influence of Field Marshal Colmar Von Der Goltz on Ottoman Military Effectiveness in Mesopotamia: December 1915 to April 1916

    DTIC Science & Technology

    2012-02-23

    SUBTITLE The Influence of Field Marshal Colmar Von Der Goltz on Ottoman Military Effectiveness in Mesopotamia: December 1915 to April 1916 5a...SUPPLEMENTARY NOTES N/A 14. ABSTRACT This paper discusses the contributions made by Field Marshal Colmar von der Goltz on the development of Ottoman...Kut. 15. SUBJECT TERMS Colmar von der Goltz ; Military advisor; Mesopotamian Campaign; Ottoman; Ottoman military effectiveness; British; Kut; World

  20. Laboratory Testing for von Willebrand Disease: The Past, Present, and Future State of Play for von Willebrand Factor Assays that Measure Platelet Binding Activity, with or without Ristocetin.

    PubMed

    Just, Sarah

    2017-02-01

    von Willebrand disease (VWD) was first described nearly a century ago in 1924 by Erik Adolf von Willebrand. Diagnostic testing at the time was very limited and it was not until the mid to late 1900s that more tests became available to assist with the diagnosis and classification of VWD. Two of these tests are based on ristocetin, one being ristocetin-induced platelet aggregation (RIPA) and the other the von Willebrand factor (VWF) ristocetin cofactor assay (VWF:RCo). The VWF:RCo assay provides functional assessment of in vitro VWF binding to the platelet glycoprotein (Gp) complex, GPIb-IX-V. Despite some advancements and newer technologies utilizing the principles of the original VWF:RCo assay, the original assay is still referred to as the gold standard for measurement of VWF activity. This article will review the history of VWD diagnostic assays, including RIPA and VWF:RCo over the past 40 years, as well as the newer assays that measure platelet binding with or without ristocetin, and which have been developed with the aim to potentially replace platelet-based ristocetin-dependent assays. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  1. Potential supplementary utility of combined PFA-100 and functional von Willebrand factor testing for the laboratory assessment of desmopressin and factor concentrate therapy in von Willebrand disease.

    PubMed

    Favaloro, Emmanuel J; Thom, Jim; Patterson, David; Just, Sarah; Baccala, Maria; Dixon, Tracy; Meiring, Muriel; Koutts, Jerry; Rowell, John; Baker, Ross

    2009-09-01

    We performed a retrospective audit of cross-laboratory testing of desmopressin and factor concentrate therapy to assess the potential utility of supplementary testing using the PFA-100 with functional von Willebrand factor (VWF) activity testing. Data were evaluated for a large number of patients with von Willebrand disease of type 1, type 2A or type 2M, as well as a comparative subset of individuals with haemophilia or carriers of haemophilia. Laboratory testing comprised pre and postdesmopressin, or pre and postconcentrate, evaluation of factor VIII, VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity as traditionally performed, supplemented with collagen-binding (VWF:CB) testing and PFA-100 closure times. In brief, both therapies tended to normalize VWF test parameters and closure times in individuals with type 1 von Willebrand disease, with the level of correction in closure times related to the level of normalization of VWF, particularly the VWF:CB. However, although occasional correction of closure times was observed in patients with type 2A or type 2M von Willebrand disease, these did not in general normalize PFA-100 closure times either with desmopressin or factor concentrate therapy. In these patients, improvement in closure times was more likely in those in whom VWF:CB values normalized or when VWF:CB/VWF:Ag ratios normalized. This study confirms that there is a strong relationship between the presenting levels of plasma VWF and PFA-100 closure times, and that the supplementary combination of PFA-100 and VWF:CB testing might provide added clinical utility to current broadly applied testing strategies limited primarily to VWF:Ag, VWF ristocetin cofactor and factor VIII:coagulant. Future prospective investigations are warranted to validate these relationships and to investigate their therapeutic implications.

  2. Brain-stem hemangioblastomas: The seemingly innocuous lesion in a perilous location.

    PubMed

    Joseph, Jeena; Behari, Sanjay; Gupta, Shruti; Bhaisora, Kamlesh Singh; Gandhi, Anish; Srivastava, Arun; Jaiswal, Awadhesh K

    2018-01-01

    Hemangioblastomas [75% sporadic, 25% with Von Hippel Lindau (VHL) disease] are highly vascular, benign lesions. The surgical nuances, management, and complication avoidance in brain-stem hemangioblastomas (BHs) have been studied. Over 18 years, 27(mean age: 29 years; range 15-60 years) consecutive cases of BH underwent microsurgical excision. All patients were assessed clinico-radiologically for neurological deficits and screened for VHL disease. Outcome of the patients was based on Karnofsky Performance Status scale (KPS). 12 out of 19 (70.4%) patients with hydrocephalus underwent a cerebrospinal fluid (CSF) diversion procedure. Lower cranial nerve palsy was present in 10 (37%) patients and motor weakness in 13 (48%). The tumours [mean size 3.34 ± 1.06 cm, range: 1.4-5.5 cm; 11 solid, rest solid-cystic; 18 (66.7%) subpial and 9 (33.33%) intramedullary] were divided into four categories based on size: A: <2 cm (n = 5,18.5%); B: 2-3 cm (n = 10,37%); C: 3-4 cm (n = 6,22.2%); D: >4 cm (n = 6,22.2%). Their location was at posterior cervicomedullary junction (n = 12); pontomedullary junction (n = 7); pons (n = 3), medulla (n = 3) and ponto-mesencephalic region (n = 2). Multiple flow voids were seen in >50% patients with tumour >2 cm. 5 patients had syringomyelia; and, 8 had diffuse cervical cord expansion. Two patients with a large vascular tumour underwent preoperative embolization. Six patients had VHL disease; one underwent bilateral adrenalectomy for refractory hypertension; and, the another, nephrectomy for renal cell carcinoma. Twenty-six patients underwent a midline suboccipital craniectomy; and, 1 with a cerebellopontine angle tumour, a retromastoid craniectomy. 15 patients underwent total excision; 10 patients, near-total (<10% remaining) excision, and 2 patients, a subtotal (>10% remaining)) excision. Three patients (2 with VHL disease) expired due to exsanguinating hemorrhage, spreading venous thrombosis and aspiration pneumonitis, respectively. At follow

  3. Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in the treatment of renal cell carcinomas.

    PubMed

    Roskoski, Robert

    2017-06-01

    One Von Hippel-Lindau (VHL) tumor suppressor gene is lost in most renal cell carcinomas while the nondeleted allele exhibits hypermethylation-induced inactivation or inactivating somatic mutations. As a result of these genetic modifications, there is an increased production of VEGF-A and pro-angiogenic growth factors in this disorder. The important role of angiogenesis in the pathogenesis of renal cell carcinomas and other tumors has focused the attention of investigators on the biology of VEGFs and VEGFR1-3 and to the development of inhibitors of the intricate and multifaceted angiogenic pathways. VEGFR1-3 contain an extracellular segment with seven immunoglobulin-like domains, a transmembrane segment, a juxtamembrane segment, a protein kinase domain with an insert of about 70 amino acid residues, and a C-terminal tail. VEGF-A stimulates the activation of preformed VEGFR2 dimers by the auto-phosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signalling by the ERK1/2, AKT, Src, and p38 MAP kinase pathways. VEGFR1 modulates the activity of VEGFR2, which is the chief pathway in vasculogenesis and angiogenesis. VEGFR3 and its ligands (VEGF-C and VEGF-D) are involved primarily in lymphangiogenesis. Small molecule VEGFR1/2/3 inhibitors including axitinib, cabozantinib, lenvatinib, sorafenib, sunitinib, and pazopanib are approved by the FDA for the treatment of renal cell carcinomas. Most of these agents are type II inhibitors of VEGFR2 and inhibit the so-called DFG-Asp out inactive enzyme conformation. These drugs are steady-state competitive inhibitors with respect to ATP and like ATP they form hydrogen bonds with the hinge residues that connect the small and large protein kinase lobes. Bevacizumab, a monoclonal antibody that binds to VEGF-A, is also approved for the treatment of renal cell carcinomas. Resistance to these agents invariably occurs

  4. A comparative study of results of the von Langenbeck and the V-Y pushback palatoplasties.

    PubMed

    Krause, C J; Tharp, R F; Morris, H L

    1976-01-01

    The incidence of velopharyngeal competence noted in 267 cleft palate patients following palatoplsty has been reviewed. Comparisons have been drawn with regard to the cleft type and the surgical technique performed. Since there were relatively small numbers of subjects in some categories, differences in age at last examination between the von Langenbeck and V-Y palatoplasty groups, some patients were very young at time of evaluation, and a number of different surgeons at different levels of training and experience performed the surgery, the differences in velopharyngeal competence found should be viewed as trends and this report as preliminary. In general, there was a trend toward smaller percentages of patients attaining acceptable velopharyngeal competence as the severity of the cleft increased. Of those with clefts of the soft palate only 86 per cent achieved competence. Among those patients with clefts of the palate only, 67 per cent achieved competence, whereas only 57 per cent of those with clefts of the lip and palate were able to do so. When comparing all cleft types, the V-Y palatoplasty resulted in a significantly higher percentage of velopharyngeal competence (74 per cent) than did the von Langenbeck method (56 per cent), although the data for the V-Y group are probably less reliable than those for the von Langenbeck group. In the soft palate only category, the results were slightly better with the von Langenbeck technique, though not significantly so. In all other cleft types, the results with the V-Y method were better than those with the von Langenbeck.

  5. Wilhelm von Humboldt's Idea of "Bildung" and Education.

    ERIC Educational Resources Information Center

    Stubbs, Elsina

    The importance of Wilhelm von Humboldt's work in educational philosophy is little known outside of Germany and even there he is more often criticized than praised. This is unfortunate because his contributions to education and other areas had an important impact on other philosophers of his period and are well worth considering today. In his main…

  6. [Hildegards von Bingen 'Liber simplicis medicinae' in the Mainz 'Garden of Health'].

    PubMed

    Riethe, Peter

    2005-01-01

    The "Garden of Health" (Gart der Gesundheit) is the first illustrated book of herbs in German language. Its author, Johann Wonnecke from Kaub on the Rhine, was born in 1430 and worked as a city doctor in Frankfurt/Main until his death in 1503 or 1504. In his book, he refers to "proven Greek, Latin and Arabic masters of medicine" (bewerte meister in der artzeney), whose writings he was instructed to collect by Bernard von Breidenbach in 1480. Wonnecke carried out he task in a special way, deceiving five generations of historians of science, who proceeded from the false assumption, that the Gart der Gesundheit was compiled and translated from Latin sources. Wonnecke established the desired authors skilfully in his report, but under a more detailed investigation they reveal themselves as not taken from Latin sources but copied off from native language scriptures, e.g. Alterer deutscher Macer and Buch der Natur by Konrad von Megenberg. To these hitherto known sources used by him now the Speyrer Kräuterbuch is added, which supplied the medical knowledge of Hildegard von Bingen to the "Gart".

  7. "'And They Lived Happily Ever After": The Fairy Tale of Radical Constructivism and Von Glasersfeld's Ethical Disengagement

    ERIC Educational Resources Information Center

    d'Agnese, Vasco

    2015-01-01

    Is von Glasersfeld's constructivism actually radical? In this article, I respond to this question by analyzing von Glasersfeld's main works. I argue that the essential theoretical move of radical constructivism--namely the assertion that reality is the construction of a human mind that only responds to the subjective perception of "what…

  8. Comparative analysis of von Willebrand factor profiles after implantation of left ventricular assist device and total artificial heart.

    PubMed

    Reich, H J; Morgan, J; Arabia, F; Czer, L; Moriguchi, J; Ramzy, D; Esmailian, F; Lam, L; Dunhill, J; Volod, O

    2017-08-01

    Essentials Bleeding is a major source of morbidity during mechanical circulatory support. von Willebrand factor (VWF) multimer loss may contribute to bleeding. Different patterns of VWF multimer loss were seen with the two device types. This is the first report of total artificial heart associated VWF multimer loss. Background Bleeding remains a challenge during mechanical circulatory support and underlying mechanisms are incompletely understood. Functional von Willebrand factor (VWF) impairment because of loss of high-molecular-weight multimers (MWMs) produces acquired von Willebrand disease (VWD) after left ventricular assist device (LVAD). Little is known about VWF multimers with total artificial hearts (TAHs). Here, VWF profiles with LVADs and TAHs are compared using a VWD panel. Methods VWD evaluations for patients with LVAD or TAH (2013-14) were retrospectively analyzed and included: VWF activity (ristocetin cofactor, VWF:RCo), VWF antigen (VWF:Ag), ratio of VWF:RCo to VWF:Ag, and quantitative VWF multimeric analysis. Results Twelve patients with LVADs and 12 with TAHs underwent VWD evaluation. All had either normal (47.8%) or elevated (52.2%) VWF:RCo, normal (26.1%) or elevated (73.9%) VWF:Ag and 50.0% were disproportional (ratio ≤ 0.7). Multimeric analysis showed abnormal patterns in all patients with LVADs: seven with high MWM loss; five with highest MWM loss. With TAH, 10/12 patients had abnormal patterns: all with highest MWM loss. High MWM loss correlated with presence of LVAD and highest MWM loss with TAH. Increased low MWMs were detected in 22/24. Conclusion Using VWF multimeric analysis, abnormalities after LVAD or TAH were detected that would be missed with measurements of VWF level alone: loss of high MWM predominantly in LVAD, loss of highest MWM in TAH, and elevated levels of low MWM in both. This is the first study to describe TAH-associated highest MWM loss, which may contribute to bleeding. © 2017 International Society on Thrombosis and

  9. Gesellschaft, Lebensgemeinschaft, Ökosystem - Über die Kongruenz von politischen und ökologischen Theorien der Entwicklung

    NASA Astrophysics Data System (ADS)

    Voigt, Annette

    Im Jahr 1859 veröffentlichte Charles Darwin "On the Origin of Species“. Seine Evolutionstheorie ist das wohl spektakulärste Beispiel einer naturwissenschaftlichen Theorie großer gesellschaftlicher Relevanz. Ihre verschiedenen Facetten wurden in der Öffentlichkeit kontrovers diskutiert, unter anderem auch ihre Anwendung zur Erklärung von Zuständen und Prozessen menschlicher Gesellschaften. Zum Teil wurde die Seiensweise der Natur - scheinbar unabhängig von gesellschaftlichen Interessen - für die Erklärung und Legitimation gesellschaftlicher Zustände oder die Legitimation von politischen Ideologien herangezogen (Sozialdarwinismus). Denn Gesellschaft funktioniere ja so, wie Darwin die Natur erklärt habe: es herrsche z. B. Konkurrenzkampf, Auslese und Arbeitsteilung, Erfolg hätten diejenigen, die sich an die Bedingungen am Besten anpassten.

  10. Ernst von Glasersfeld's Radical Constructivism and Truth as Disclosure

    ERIC Educational Resources Information Center

    Joldersma, Clarence W.

    2011-01-01

    In this essay Clarence Joldersma explores radical constructivism through the work of its most well-known advocate, Ernst von Glasersfeld, who combines a sophisticated philosophical discussion of knowledge and truth with educational practices. Joldersma uses Joseph Rouse's work in philosophy of science to criticize the antirealism inherent in…

  11. Spin torque oscillator neuroanalog of von Neumann's microwave computer.

    PubMed

    Hoppensteadt, Frank

    2015-10-01

    Frequency and phase of neural activity play important roles in the behaving brain. The emerging understanding of these roles has been informed by the design of analog devices that have been important to neuroscience, among them the neuroanalog computer developed by O. Schmitt and A. Hodgkin in the 1930s. Later J. von Neumann, in a search for high performance computing using microwaves, invented a logic machine based on crystal diodes that can perform logic functions including binary arithmetic. Described here is an embodiment of his machine using nano-magnetics. Electrical currents through point contacts on a ferromagnetic thin film can create oscillations in the magnetization of the film. Under natural conditions these properties of a ferromagnetic thin film may be described by a nonlinear Schrödinger equation for the film's magnetization. Radiating solutions of this system are referred to as spin waves, and communication within the film may be by spin waves or by directed graphs of electrical connections. It is shown here how to formulate a STO logic machine, and by computer simulation how this machine can perform several computations simultaneously using multiplexing of inputs, that this system can evaluate iterated logic functions, and that spin waves may communicate frequency, phase and binary information. Neural tissue and the Schmitt-Hodgkin, von Neumann and STO devices share a common bifurcation structure, although these systems operate on vastly different space and time scales; namely, all may exhibit Andronov-Hopf bifurcations. This suggests that neural circuits may be capable of the computational functionality as described by von Neumann. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. Recombinant von Willebrand factor: preclinical development.

    PubMed

    Plaimauer, B; Schlokat, U; Turecek, P L; Mitterer, A; Mundt, W; Auer, W; Pichler, L; Gritsch, H; Schwarz, H P

    2001-08-01

    Von Willebrand factor (vWF) is a multimeric glycoprotein (GP) that attracts platelets to the site of vascular injury, mediates platelet-platelet interaction, and stabilizes factor VIII (FVIII) in the circulation. Quantitative and qualitative defects of vWF result in von Willebrand disease (vWD), manifested by modest to severe bleeding episodes. Substitution therapy, with plasma-derived FVIII/vWF complex concentrates, is used for patients suffering the more severe forms of vWD. Efficacy of these preparations is often unsatisfactory because inadvertent proteolytic degradation during the manufacturing process causes them to lack the hemostatically most active high-molecular-weight multimers. In contrast, recombinant vWF (r-vWF), which is constitutively expressed at high yields in Chinese hamster ovary (CHO) cells and secreted into the conditioned medium under perfusion fermentation in "protein-free" medium, has high-molecular-weight multimers of extraordinary structural integrity. Functional analysis has shown that r-vWF promotes ristocetin cofactor-mediated platelet aggregation, collagen interaction and FVIII binding, and platelet-collagen adhesion under shear stress. Infusing vWF-deficient animals with r-vWF corrected vWF concentration and reduced blood loss, subsequently stabilizing endogenous FVIII associated with the reduction of bleeding time. Compared with plasma-derived vWF preparations, r-vWF was found to have a prolonged half-life, further enhancing the potential value of r-vWF as a therapeutic agent for treating patients suffering from vWD.

  13. Dr. Wernher Von Braun near the mobile launcher.

    NASA Technical Reports Server (NTRS)

    1999-01-01

    Dr. George Mueller, NASA associate administrator for manned space flight, and Dr. Wernher Von Braun (right), director of the Marshall Space Flight Center, are seen near the mobile launcher carrying a 363 foot tall Saturn V space launch vehicle as the rocket is rolled from the vehicle assembly building at KSC for its three mile trip to the launch pad.

  14. Dr. von Braun With a Model of a Launch Vehicle

    NASA Technical Reports Server (NTRS)

    1950-01-01

    Dr. von Braun stands beside a model of the upper stage (Earth-returnable stage) of the three-stage launch vehicle built for the series of the motion picture productions of space flight produced by Walt Disney in the mid-1950's.

  15. Remembrances of Ulf Svante von Euler.

    PubMed

    Igić, Rajko

    2018-05-21

    I first met Ulf Svante von Euler when he came to Belgrade, in 1968, to attend an international symposium on the occasion of the 50 th anniversary of the Medical Faculty. I was at that time a graduate student at the Medical Faculty in Sarajevo, and a new researcher. I had finished medical school in Belgrade and had worked for two years as a physician in the northern part of Serbia. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  16. Robuste Verzweigungserkennung von Gefäßen in CTA-Datensätzen zur modellbasierten Extraktion der Centerline

    NASA Astrophysics Data System (ADS)

    Beck, Thomas; Fritz, Dominik; Biermann, Christina; Dillmann, Rüdiger

    Bei der Befundung und Visualisierung von Blutgefäßen ist deren Centerline von zentraler Bedeutung. Die Unterscheidung zwischen unverzweigten Abschnitten des Gefäßes und Verzweigungsbereichen ermöglicht den Einsatz spezialisierter und sehr effizienter Algorithmen zur modellbasierten Extraktion der Centerline. In diesem Artikel wird ein robustes Verfahren zur Verzweigungserkennung vorgestellt. Das Verfahren beruht auf einem Front-Propagation-Ansatz mit dynamisch angepassten Schwellwerten und einer anschließenden Clusteranalyse. Die vorgestellte Methode zur Verzweigungserkennung wurde als Komponente einer Architektur zur Extraktion der Centerline auf handannotierten Datensätzen getestet. Erste Ergebnisse sind sehr vielversprechend und ermöglichen auch bei pathologischen Gefäßen eine robuste Detektion von Gefäßverzweigungen.

  17. Versuche zur Gewinnung von katalytischen Antikörpern zur Hydrolyse von Arylcarbamaten und Arylharnstoffen. (English Title: Attempts to produce catalytic antibodies for hydrolysis of arylcarbamates and arylureas)

    NASA Astrophysics Data System (ADS)

    Werner, Deljana

    2002-05-01

    Im Rahmen dieser Arbeit gelang es, katalytische Antikörper zur Hydrolyse von Benzylphenylcarbamaten sowie zahlreiche monoklonale Antikörper gegen Haptene herzustellen. Es wurden verschiedene Hapten-Protein-Konjugate unter Verwendung unterschiedlicher Kopplungsmethoden hergestellt und charakterisiert. Zur Generierung der hydrolytisch aktiven Antikörper wurden Inzuchtmäuse mit KLH-Konjugaten von 4 Übergangszustandsanaloga (ÜZA) immunisiert. Mit Hilfe der Hybridomtechnik wurden verschiedene monoklonale Antikörper gegen diese ÜZA gewonnen. Dabei wurden sowohl verschiedene Immunisierungsschemata als auch verschiedene Inzuchtmausstämme und Fusionstechniken verwendet. Insgesamt wurden 32 monoklonale Antikörper gegen die verwendeten ÜZA selektiert. Diese Antikörper wurden in groen Mengen hergestellt und gereinigt. Zum Nachweis der Antikörper-vermittelten Katalyse wurden verschiedene Methoden entwickelt und eingesetzt, darunter immunologische Nachweismethoden mit Anti-Substrat- und Anti-Produkt-Antikörpern und eine photometrische Methode mit Dimethylaminozimtaldehyd. Der Nachweis der hydrolytischen Aktivität gelang mit Hilfe eines Enzymsensors, basierend auf immobilisierter Tyrosinase. Die Antikörper N1-BC1-D11, N1-FA7-C4, N1-FA7-D12 und R3-LG2-F9 hydrolysierten die Benzylphenylcarbamate POCc18, POCc19 und Substanz 27. Der Nachweis der hydrolytischen Aktivität dieser Antikörper gelang auch mit Hilfe der HPLC. Der katalytische Antikörper N1-BC1-D11 wurde kinetisch und thermodynamisch untersucht. Es wurde eine Michaelis-Menten-Kinetik mit Km von 210 µM, vmax von 3 mM/min und kcat von 222 min-1 beobachtet. Diese Werte korrelieren mit den Werten der wenigen bekannten Diphenylcarbamat-spaltenden Abzyme. Die Beschleunigungsrate des Antikörpers N1-BC1-D11 betrug 10. Das ÜZA Hei3 hemmte die hydrolytische Aktivität. Dies beweist, dass die Hydrolyse in der Antigenbindungsstelle stattfindet. Weiter wurde zwischen der Antikörperkonzentration und der

  18. The education of Ehrenfried Walther von Tschirnhaus (1651-1708).

    PubMed

    Adler, Jacob

    2015-02-01

    Ehrenfried Walther von Tschirnhaus, mathematician, inventor, and correspondent of Spinoza, is often thought to have studied medicine at Leiden, though documentation of this fact has been lacking. Tschirnhaus' medical education is here documented, along with the nature of his medical practice. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  19. S2k-Leitlinie zum Gebrauch von Präparationen zur lokalen Anwendung auf der Haut (Topika).

    PubMed

    Wohlrab, Johannes; Staubach, Petra; Augustin, Matthias; Eisert, Lisa; Hünerbein, Andreas; Nast, Alexander; Reimann, Holger; Strömer, Klaus; Mahler, Vera

    2018-03-01

    Diese Leitlinie richtet sich an Assistenz- und Fachärzte der Dermatologie sowie an Kostenträger und politische Entscheidungsgremien. Die Leitlinie wurde im formellen Konsensusverfahren (S2k) von Dermatologen unter Einbindung von Apothekern erstellt. Die Leitlinie stellt allgemeine Aspekte der Pharmakokinetik sowie der regulatorischen Begrifflichkeiten dar. Es werden Empfehlungen zur Indikation von Magistralrezepturen sowie deren Qualitätssicherung gegeben. Die Bedeutung der galenischen Grundlagen und die Problematik bei einer Substitution gegeneinander verschiedener Grundlagen werden dargestellt. Die Leitlinie umfasst Kriterien zur Auswahl einer adäquaten Grundlage sowie spezifische Aspekte zur Therapieplanung. Die Leitlinie gibt Empfehlungen zum Management bei Unverträglichkeiten gegenüber Bestandteilen der Grundlagen oder Hilfsstoffe. © 2018 The Authors | Journal compilation © Blackwell Verlag GmbH, Berlin.

  20. Superfluid high REynolds von Kármán experiment.

    PubMed

    Rousset, B; Bonnay, P; Diribarne, P; Girard, A; Poncet, J M; Herbert, E; Salort, J; Baudet, C; Castaing, B; Chevillard, L; Daviaud, F; Dubrulle, B; Gagne, Y; Gibert, M; Hébral, B; Lehner, Th; Roche, P-E; Saint-Michel, B; Bon Mardion, M

    2014-10-01

    The Superfluid High REynolds von Kármán experiment facility exploits the capacities of a high cooling power refrigerator (400 W at 1.8 K) for a large dimension von Kármán flow (inner diameter 0.78 m), which can work with gaseous or subcooled liquid (He-I or He-II) from room temperature down to 1.6 K. The flow is produced between two counter-rotating or co-rotating disks. The large size of the experiment allows exploration of ultra high Reynolds numbers based on Taylor microscale and rms velocity [S. B. Pope, Turbulent Flows (Cambridge University Press, 2000)] (Rλ > 10000) or resolution of the dissipative scale for lower Re. This article presents the design and first performance of this apparatus. Measurements carried out in the first runs of the facility address the global flow behavior: calorimetric measurement of the dissipation, torque and velocity measurements on the two turbines. Moreover first local measurements (micro-Pitot, hot wire,…) have been installed and are presented.

  1. Superfluid high REynolds von Kármán experiment

    NASA Astrophysics Data System (ADS)

    Rousset, B.; Bonnay, P.; Diribarne, P.; Girard, A.; Poncet, J. M.; Herbert, E.; Salort, J.; Baudet, C.; Castaing, B.; Chevillard, L.; Daviaud, F.; Dubrulle, B.; Gagne, Y.; Gibert, M.; Hébral, B.; Lehner, Th.; Roche, P.-E.; Saint-Michel, B.; Bon Mardion, M.

    2014-10-01

    The Superfluid High REynolds von Kármán experiment facility exploits the capacities of a high cooling power refrigerator (400 W at 1.8 K) for a large dimension von Kármán flow (inner diameter 0.78 m), which can work with gaseous or subcooled liquid (He-I or He-II) from room temperature down to 1.6 K. The flow is produced between two counter-rotating or co-rotating disks. The large size of the experiment allows exploration of ultra high Reynolds numbers based on Taylor microscale and rms velocity [S. B. Pope, Turbulent Flows (Cambridge University Press, 2000)] (Rλ > 10000) or resolution of the dissipative scale for lower Re. This article presents the design and first performance of this apparatus. Measurements carried out in the first runs of the facility address the global flow behavior: calorimetric measurement of the dissipation, torque and velocity measurements on the two turbines. Moreover first local measurements (micro-Pitot, hot wire,…) have been installed and are presented.

  2. Kinematic α tensors and dynamo mechanisms in a von Kármán swirling flow.

    PubMed

    Ravelet, F; Dubrulle, B; Daviaud, F; Ratié, P-A

    2012-07-13

    We provide experimental and numerical evidence of in-blades vortices in the von Kármán swirling flow. We estimate the associated kinematic α-effect tensor and show that it is compatible with recent models of the von Kármán sodium (VKS) dynamo. We further show that depending on the relative frequency of the two impellers, the dominant dynamo mechanism may switch from α2 to α - Ω dynamo. We discuss some implications of these results for VKS experiments.

  3. Clinical and laboratory diagnosis of von Willebrand disease: A synopsis of the 2008 NHLBI/NIH guidelines

    PubMed Central

    Nichols, William L.; Rick, Margaret E.; Ortel, Thomas L.; Montgomery, Robert R.; Sadler, J. Evan; Yawn, Barbara P.; James, Andra H.; Hultin, Mae B.; Manco-Johnson, Marilyn J.; Weinstein, Mark

    2017-01-01

    Von Willebrand factor (VWF) mediates blood platelet adhesion and accumulation at sites of blood vessel injury, and also carries coagulation factor VIII (FVIII) that is important for generating procoagulant activity. Von Willebrand disease (VWD), the most common inherited bleeding disorder, affects males and females, and reflects deficiency or defects of VWF that may also cause decreased FVIII. It may also occur less commonly as an acquired disorder (acquired von Willebrand syndrome). This article briefly summarizes selected features of the March 2008 evidence-based clinical and laboratory diagnostic recommendations from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel for assessment for VWD or other bleeding disorders or risks. Management of VWD is also addressed in the NHLBI guidelines, but is not summarized here. The VWD guidelines are available at the NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd). PMID:19415721

  4. Measuring Changes in Tactile Sensitivity in the Hind Paw of Mice Using an Electronic von Frey Apparatus

    PubMed Central

    Martinov, Tijana; Mack, Madison; Sykes, Akilah; Chatterjea, Devavani

    2013-01-01

    Measuring inflammation-induced changes in thresholds of hind paw withdrawal from mechanical pressure is a useful technique to assess changes in pain perception in rodents. Withdrawal thresholds can be measured first at baseline and then following drug, venom, injury, allergen, or otherwise evoked inflammation by applying an accurate force on very specific areas of the skin. An electronic von Frey apparatus allows precise assessment of mouse hind paw withdrawal thresholds that are not limited by the available filament sizes in contrast to classical von Frey measurements. The ease and rapidity of measurements allow for incorporation of assessment of tactile sensitivity outcomes in diverse models of rapid-onset inflammatory and neuropathic pain as multiple measurements can be taken within a short time period. Experimental measurements for individual rodent subjects can be internally controlled against individual baseline responses and exclusion criteria easily established to standardize baseline responses within and across experimental groups. Thus, measurements using an electronic von Frey apparatus represent a useful modification of the well-established classical von Frey filament-based assays for rodent mechanical allodynia that may also be applied to other nonhuman mammalian models. PMID:24378519

  5. Professor Oberth and Dr. von Braun at ARS Banquet

    NASA Technical Reports Server (NTRS)

    1961-01-01

    Dr. Wernher von Braun holds the coveted Hermarn Oberth award presented to him by Professor Oberth during the banquet hosted by the Alabama Section of the American Rocket Society (ARS), on October 19, 1961. The Oberth award was given for outstanding technical contributions to the field of astronautics or for the promotion and advancement of astronautical sciences.

  6. Phenotypic correction of von Willebrand disease type 3 blood-derived endothelial cells with lentiviral vectors expressing von Willebrand factor

    PubMed Central

    De Meyer, Simon F.; Vanhoorelbeke, Karen; Chuah, Marinee K.; Pareyn, Inge; Gillijns, Veerle; Hebbel, Robert P.; Collen, Désiré; Deckmyn, Hans; VandenDriessche, Thierry

    2006-01-01

    Von Willebrand disease (VWD) is an inherited bleeding disorder, caused by quantitative (type 1 and 3) or qualitative (type 2) defects in von Willebrand factor (VWF). Gene therapy is an appealing strategy for treatment of VWD because it is caused by a single gene defect and because VWF is secreted into the circulation, obviating the need for targeting specific organs or tissues. However, development of gene therapy for VWD has been hampered by the considerable length of the VWF cDNA (8.4 kb [kilobase]) and the inherent complexity of the VWF protein that requires extensive posttranslational processing. In this study, a gene-based approach for VWD was developed using lentiviral transduction of blood-outgrowth endothelial cells (BOECs) to express functional VWF. A lentiviral vector encoding complete human VWF was used to transduce BOECs isolated from type 3 VWD dogs resulting in high-transduction efficiencies (95.6% ± 2.2%). Transduced VWD BOECs efficiently expressed functional vector-encoded VWF (4.6 ± 0.4 U/24 hour per 106 cells), with normal binding to GPIbα and collagen and synthesis of a broad range of multimers resulting in phenotypic correction of these cells. These results indicate for the first time that gene therapy of type 3 VWD is feasible and that BOECs are attractive target cells for this purpose. PMID:16478886

  7. Interpolatability distinguishes LOCC from separable von Neumann measurements

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Childs, Andrew M.; Leung, Debbie; Mančinska, Laura

    2013-11-15

    Local operations with classical communication (LOCC) and separable operations are two classes of quantum operations that play key roles in the study of quantum entanglement. Separable operations are strictly more powerful than LOCC, but no simple explanation of this phenomenon is known. We show that, in the case of von Neumann measurements, the ability to interpolate measurements is an operational principle that sets apart LOCC and separable operations.

  8. Hardware-Abbildung eines videobasierten Verfahrens zur echtzeitfähigen Auswertung von Winkelhistogrammen auf eine modulare Coprozessor-Architektur

    NASA Astrophysics Data System (ADS)

    Flatt, H.; Tarnowsky, A.; Blume, H.; Pirsch, P.

    2010-10-01

    Dieser Beitrag behandelt die Abbildung eines videobasierten Verfahrens zur echtzeitfähigen Auswertung von Winkelhistogrammen auf eine modulare Coprozessor-Architektur. Die Architektur besteht aus mehreren dedizierten Recheneinheiten zur parallelen Verarbeitung rechenintensiver Bildverarbeitungsverfahren und ist mit einem RISC-Prozessor verbunden. Eine konfigurierbare Architekturerweiterung um eine Recheneinheit zur Auswertung von Winkelhistogrammen von Objekten ermöglicht in Verbindung mit dem RISC eine echtzeitfähige Klassifikation. Je nach Konfiguration sind für die Architekturerweiterung auf einem Xilinx Virtex-5-FPGA zwischen 3300 und 12 000 Lookup-Tables erforderlich. Bei einer Taktfrequenz von 100 MHz können unabhängig von der Bildauflösung pro Einzelbild in einem 25-Hz-Videodatenstrom bis zu 100 Objekte der Größe 256×256 Pixel analysiert werden. This paper presents the mapping of a video-based approach for real-time evaluation of angular histograms on a modular coprocessor architecture. The architecture comprises several dedicated processing elements for parallel processing of computation-intensive image processing tasks and is coupled with a RISC processor. A configurable architecture extension, especially a processing element for evaluating angular histograms of objects in conjunction with a RISC processor, provides a real-time classification. Depending on the configuration of the architecture extension, 3 300 to 12 000 look-up tables are required for a Xilinx Virtex-5 FPGA implementation. Running at a clock frequency of 100 MHz and independently of the image resolution per frame, 100 objects of size 256×256 pixels are analyzed in a 25 Hz video stream by the architecture.

  9. Modeling of Cavitating Flow through Waterjet Propulsors

    DTIC Science & Technology

    2015-02-18

    1-0197 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jules W. Lindau 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING...RESPONSIBLE PERSON Jules W. Lindau 19b. TELEPONE NUMBER (Include area code) 814-865-8938 ^\\6^G%013 Standard Form 298 (Rev. 8-98) Prescribed by ANSI-Std...239-18 Modeling of Cavitating Flow through Waterjet Propulsors Jules W. Lindau The Pennsylvania State University, Applied Research Laboratory, State

  10. Space: The Long-Range Future: An Interview with Jesco von Puttkamer.

    ERIC Educational Resources Information Center

    Lawler, Andrew

    1985-01-01

    Jesco von Puttkamer manages long-range planning in NASA's Office of Space Flight. He believes that space offers the opportunity to ease global tensions, help the developing world, and create a new global culture off the planet. (Author/RM)

  11. A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments

    PubMed Central

    2014-01-01

    Background The measurement of mechanosensitivity is a key method for the study of pain in animal models. This is often accomplished with the use of von Frey filaments in an up-down testing paradigm. The up-down method described by Chaplan et al. (J Neurosci Methods 53:55–63, 1994) for mechanosensitivity testing in rodents remains one of the most widely used methods for measuring pain in animals. However, this method results in animals receiving a varying number of stimuli, which may lead to animals in different groups receiving different testing experiences that influences their later responses. To standardize the measurement of mechanosensitivity we developed a simplified up-down method (SUDO) for estimating paw withdrawal threshold (PWT) with von Frey filaments that uses a constant number of five stimuli per test. We further refined the PWT calculation to allow the estimation of PWT directly from the behavioral response to the fifth stimulus, omitting the need for look-up tables. Results The PWT estimates derived using SUDO strongly correlated (r > 0.96) with the PWT estimates determined with the conventional up-down method of Chaplan et al., and this correlation remained very strong across different levels of tester experience, different experimental conditions, and in tests from both mice and rats. The two testing methods also produced similar PWT estimates in prospective behavioral tests of mice at baseline and after induction of hyperalgesia by intraplantar capsaicin or complete Freund’s adjuvant. Conclusion SUDO thus offers an accurate, fast and user-friendly replacement for the widely used up-down method of Chaplan et al. PMID:24739328

  12. Structure and Reversibility of 2D von Neumann Cellular Automata Over Triangular Lattice

    NASA Astrophysics Data System (ADS)

    Uguz, Selman; Redjepov, Shovkat; Acar, Ecem; Akin, Hasan

    2017-06-01

    Even though the fundamental main structure of cellular automata (CA) is a discrete special model, the global behaviors at many iterative times and on big scales could be a close, nearly a continuous, model system. CA theory is a very rich and useful phenomena of dynamical model that focuses on the local information being relayed to the neighboring cells to produce CA global behaviors. The mathematical points of the basic model imply the computable values of the mathematical structure of CA. After modeling the CA structure, an important problem is to be able to move forwards and backwards on CA to understand their behaviors in more elegant ways. A possible case is when CA is to be a reversible one. In this paper, we investigate the structure and the reversibility of two-dimensional (2D) finite, linear, triangular von Neumann CA with null boundary case. It is considered on ternary field ℤ3 (i.e. 3-state). We obtain their transition rule matrices for each special case. For given special triangular information (transition) rule matrices, we prove which triangular linear 2D von Neumann CAs are reversible or not. It is known that the reversibility cases of 2D CA are generally a much challenged problem. In the present study, the reversibility problem of 2D triangular, linear von Neumann CA with null boundary is resolved completely over ternary field. As far as we know, there is no structure and reversibility study of von Neumann 2D linear CA on triangular lattice in the literature. Due to the main CA structures being sufficiently simple to investigate in mathematical ways, and also very complex to obtain in chaotic systems, it is believed that the present construction can be applied to many areas related to these CA using any other transition rules.

  13. Inzidenz von bullösen Autoimmunerkrankungen in Serbien: eine retrospektive Studie über 20 Jahre.

    PubMed

    Milinković, Mirjana; Janković, Slavenka; Medenica, Ljiljana; Nikolić, Miloš; Reljić, Vesna; Popadić, Svetlana; Janković, Janko

    2016-10-01

    Die meisten früheren Arbeiten zu den klinisch-epidemiologischen Merkmalen von bullösen Autoimmunerkrankungen (AIBD) konzentrierten sich vor allem auf eine einzige Krankheitsentität oder nur eine Krankheitsgruppe; nur in wenigen Studien wurde die Inzidenz verschiedener AIBD untersucht. Bei der vorliegenden Studie war es unser Ziel, das gesamte Spektrum der AIBD zu betrachten, die Inzidenz der häufigsten AIBD zu ermitteln und die zeitlichen Trends ihres Auftretens in Zentralserbien über einen Zeitraum von 20 Jahren zu untersuchen. Wir rekrutierten retrospektiv 1161 AIBD-Fälle, die in Zentralserbien von Januar 1991 bis Dezember 2010 neu diagnostiziert wurden. Die Diagnose stützte sich auf eine strikte klinische, histologische und immunhistologische Beurteilung. Folgende Inzidenzraten wurden für die einzelnen Erkrankungen ermittelt: 4,35 pro eine Million Einwohner/Jahr (pME/Jahr) für Pemphigus, 4,47 pME/Jahr für Pemphigoid, 1,42 pME/Jahr für Dermatitis herpetiformis (DH), 0,25 pME/Jahr IgA-Dermatose und 0,08 pME/Jahr für Epidermolysis bullosa acquisita. Im betrachteten Zeitraum stieg die altersbereinigte Inzidenzrate für Pemphigus und insbesondere für Pemphigoid signifikant an, während sie für DH, allerdings nicht signifikant, abnahm. Unsere Studie befasst sich zum ersten Mal mit den Inzidenzraten des gesamten Spektrums der AIBD in Serbien und untersucht die zeitlichen Trends ihres Auftretens über einen Zeitraum von 20 Jahren. Nach unserem besten Wissen wurde ein ähnlicher Befund wie der unsere, dass nämlich die Inzidenzraten von Pemphigus und Pemphigoid vergleichbar sind, bisher noch nicht publiziert. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  14. Generalization of von Neumann analysis for a model of two discrete half-spaces: The acoustic case

    USGS Publications Warehouse

    Haney, M.M.

    2007-01-01

    Evaluating the performance of finite-difference algorithms typically uses a technique known as von Neumann analysis. For a given algorithm, application of the technique yields both a dispersion relation valid for the discrete time-space grid and a mathematical condition for stability. In practice, a major shortcoming of conventional von Neumann analysis is that it can be applied only to an idealized numerical model - that of an infinite, homogeneous whole space. Experience has shown that numerical instabilities often arise in finite-difference simulations of wave propagation at interfaces with strong material contrasts. These interface instabilities occur even though the conventional von Neumann stability criterion may be satisfied at each point of the numerical model. To address this issue, I generalize von Neumann analysis for a model of two half-spaces. I perform the analysis for the case of acoustic wave propagation using a standard staggered-grid finite-difference numerical scheme. By deriving expressions for the discrete reflection and transmission coefficients, I study under what conditions the discrete reflection and transmission coefficients become unbounded. I find that instabilities encountered in numerical modeling near interfaces with strong material contrasts are linked to these cases and develop a modified stability criterion that takes into account the resulting instabilities. I test and verify the stability criterion by executing a finite-difference algorithm under conditions predicted to be stable and unstable. ?? 2007 Society of Exploration Geophysicists.

  15. Von recklinghausen neurofibromatosis-pachydermatocele causing lower limb gigantism: a case report.

    PubMed

    Rekha, Arcot; Gopalan, T R

    2006-03-01

    Gigantism of the lower limb can occur because of plexiform neurofibromas. This condition is seen with café au lait patches and multiple neurofibromatosis in this case of von Recklinghausen neurofibromatosis. We report our patient and review literature of this uncommon condition.

  16. Advancement and Application of Multi-Phase CFD Modeling to High Speed Supercavitating Flows

    DTIC Science & Technology

    2013-08-13

    5a. CONTRACT NUMBER 5b. GRANT NUMBER N00014-09-1-0042 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jules W. Lindau and Michael P. Kinzel 5d. PROJECT...REPORT U b. ABSTRACT U c. THIS PAGE U 17. LIMITATION OF ABSTRACT U 18. NUMBER OF PAGES 29 19a. NAME OF RESPONSIBLE PERSON Jules W. Lindau...Application of Multi-Phase CFD Modeling to High Speed Supercavitating Flows Michael P. Kinzel Jules W. Lindau Penn State University Applied Research

  17. Delboeuf and Janet as influences in Freud's treatment of Emmy von N.

    PubMed

    Macmillan, M B

    1979-10-01

    An analysis is made of Freud's treatment of the patient known as Emmy von N. in which for the first time he used what he called "Breuer's technique of investigation under hypnosis." It is shown that the main component of Freud's therapy owed nothing to Breuer: the patient's traumatic memories were altered by direct suggestion under hypnosis. The abreaction which did take place seems to have resulted from Freud's expectation that it should occur. Two cases published by Delboeuf and Janet in late 1888 and early 1889 were treated by a then unusual method which analysis demonstrates to have been virtually identical to the technique used by Freud. Evidence is presented that the Delboeuf and Janet cases could have been known to Freud before he began his treatment of Emmy von N.

  18. Recurrent haematomas of the thigh: a case of von Willebrand's disease presenting to a sports clinic

    PubMed Central

    Owens, S.; Baglin, T.

    2000-01-01

    Von Willebrand's disease is a relatively common mild form of haemophilia. It should be suspected in assessing sports injuries when excessive bleeding occurs in response to relatively mild trauma. Those with the disease should remain active but avoid contact sports. They should not take aspirin or non-steroidal anti-inflammatory drugs, which may exacerbate bleeding, and should be given supportive treatment to cover dental extraction, surgery, or significant bleeding episodes. Key Words: von Willebrand's disease; haemophilia; haematoma; sports clinic PMID:10786868

  19. Salivary histatins in human deep posterior lingual glands (of von Ebner).

    PubMed

    Piludu, Marco; Lantini, Maria Serenella; Cossu, Margherita; Piras, Monica; Oppenheim, Frank G; Helmerhorst, Eva J; Siqueira, Walter; Hand, Arthur R

    2006-11-01

    Human saliva contains a family of low molecular weight histidine-rich proteins, named histatins, characterised by bactericidal and fungicidal activities in vitro against several microbial pathogens, such as Streptococcus mutans and Candida albicans. They represent a major component of an innate host non-immune defense system. In an earlier study we described the distribution of histatins in the glandular parenchyma of human major salivary glands, confirming that all human major salivary glands are involved in the secretion of histatins into saliva. In the present study we determined the expression and localisation of histatins in human posterior deep lingual glands (von Ebner's glands) by means of immunoelectron microscopy. Thin sections of normal human salivary glands, embedded in Epon resin, were incubated with rabbit polyclonal antibodies specific for human histatins and successively with a gold conjugated goat anti-rabbit IgG used as secondary antibody. Sections incubated with medium devoid of primary antibody or containing non-immune serum were used as controls. The serous secreting cells represented the main source of histatins in the glandular parenchyma of von Ebner's glands. At the electron microscopic level, labeling was associated with rough endoplasmic reticulum, Golgi complex and secretory granules that represented the main cytoplasmic site of histatin localisation. However, variability in the intensity of labeling was observed among adjacent cells. The present results show for the first time that human von Ebner's glands produce and represent a significant source of histatins, supporting the hypothesis of their important role in preventing microbial assaults on the tissues in the posterior region of the tongue and in the circumvallate papillae.

  20. Optimal spinneret layout in Von Koch curves of fractal theory based needleless electrospinning process

    NASA Astrophysics Data System (ADS)

    Yang, Wenxiu; Liu, Yanbo; Zhang, Ligai; Cao, Hong; Wang, Yang; Yao, Jinbo

    2016-06-01

    Needleless electrospinning technology is considered as a better avenue to produce nanofibrous materials at large scale, and electric field intensity and its distribution play an important role in controlling nanofiber diameter and quality of the nanofibrous web during electrospinning. In the current study, a novel needleless electrospinning method was proposed based on Von Koch curves of Fractal configuration, simulation and analysis on electric field intensity and distribution in the new electrospinning process were performed with Finite element analysis software, Comsol Multiphysics 4.4, based on linear and nonlinear Von Koch fractal curves (hereafter called fractal models). The result of simulation and analysis indicated that Second level fractal structure is the optimal linear electrospinning spinneret in terms of field intensity and uniformity. Further simulation and analysis showed that the circular type of Fractal spinneret has better field intensity and distribution compared to spiral type of Fractal spinneret in the nonlinear Fractal electrospinning technology. The electrospinning apparatus with the optimal Von Koch fractal spinneret was set up to verify the theoretical analysis results from Comsol simulation, achieving more uniform electric field distribution and lower energy cost, compared to the current needle and needleless electrospinning technologies.

  1. Dreams of death: Von Weizsäcker's Dreams in so-called endogenic anorexia: a research note.

    PubMed

    Jackson, C; Beumont, P J; Thornton, C; Lennerts, W

    1993-04-01

    Viktor Von Weizsäcker's paper "Dreams in so-called endogenic Magersucht (anorexia," first published in the Deutsche Medizinische Wochenschrift in 1937 (translation in M. Kaufman & M. Heiman [1964]. Evolution of psychosomatic concepts: Anorexia nervosa: A paradigm (pp. 181-197), New York: International Universities Press, has been described as a noteworthy and historically important contribution to the recognition of anorexia nervosa as a psychosomatic illness. Von Weizsäcker analyzed the dreams of patients he was treating for "endogenous anorexia" (magersucht). He claimed that in the bulimic phase his patients experienced nightmares dealing with themes of death, but that in the anorectic phases of restricted eating more pleasant dreams dealt with themes of blissful contentment. The authors draw current attention to his work as another early example of the treatment of the theme of death and death symbolism in the literature on eating disorders, and suggest some reappraisal of von Weizsäcker's interpretations of his own material.

  2. Optical Coherence Tomography Findings of Exophytic Retinal Capillary Hemangiomas of the Posterior Pole

    PubMed Central

    Chin, Eric K.; Trikha, Rupan; Morse, Lawrence S.; Zawadzki, Robert J.; Werner, John S.; Park, Susanna S.

    2013-01-01

    Exophytic retinal capillary hemangiomas (RCH) can be a diagnostic challenge in subjects without von Hippel-Lin-dau disease (VHL). This report of two cases describes the optical coherence tomographic (OCT) characteristics of RCH in two eyes of a subject with VHL and in one eye of an otherwise normal subject. Three different OCT instruments were used (Stratus, Cirrus and/or custom high resolution Fourier-domain OCT with 4.5 μm axial resolution) depending on availability. All instruments localized the tumor to the outer retina. A sharp border between the tumor and overlying inner retina was noted. The tumor bulged into the subretinal space and showed marked shadowing. Associated cystoid macular edema and sub-retinal fluid were noted. High-resolution Fourier-domain OCT showed a focal photoreceptor layer rip in the adjacent tumor-free macula in one eye with poor vision after treatment. OCT may be a useful tool in diagnosing RCH and studying associated morphologic changes. PMID:20337341

  3. Pheochromocytoma: clinical review based on a rare case in adolescence

    PubMed Central

    Alface, Marisa Maibel; Moniz, Patricia; Jesus, Susana; Fonseca, Cândida

    2015-01-01

    Pheochromocytomas are rare tumours originating in chromaffin cells, representing 0.1–1% of all secondary hypertension (HT) cases. The majority are benign and unilateral, characterised by the production of catecholamines and other neuropeptides. Mainly located in the adrenal gland, they are more frequent between the 3rd and 5th decades of life; however, 10–25% can be associated with genetic familial syndromes (multiple endocrine neoplasia type 2 (MEN 2), type 1 neurofibromatosis and Von-Hippel-Landau disease in younger ages. The authors present a rare case of secondary HT due to a pheochromocytoma in a 15-year-old patient, whose metanephrine assay confirmed the diagnosis, and abdominal ultrasound and CT localised the tumour in the adrenal gland. HT was controlled with α and β blockers, with posterior retroperitoneal laparoscopic surgical intervention and subsequent resolution of HT. Age and concomitant hyperparathyroidism compelled genetic testing for the exclusion of MEN 2, which was negative. PMID:26243750

  4. Mutant botrocetin-2 inhibits von Willebrand factor-induced platelet agglutination.

    PubMed

    Matsui, T; Hori, A; Hamako, J; Matsushita, F; Ozeki, Y; Sakurai, Y; Hayakawa, M; Matsumoto, M; Fujimura, Y

    2017-03-01

    Essentials Botrocetin-2 (Bot2) binds to von Willebrand factor (VWF) and induces platelet agglutination. We identified Bot2 residues that are required for binding to VWF and glycoprotein (GP) Ib. We produced a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Mutant Bot2 could be used as a potential anti-thrombotic reagent to block VWF-GPIb interaction. Background Botrocetin-2 (Bot2) is a botrocetin-like protein composed of α and β subunits that have been cloned from the snake Bothrops jararaca. Bot2 binds specifically to von Willebrand factor (VWF), and the complex induces glycoprotein (GP) Ib-dependent platelet agglutination. Objectives To exploit Bot2's VWF-binding capacity in order to attempt to create a mutant Bot2 that binds to VWF but inhibits platelet agglutination. Methods and Results Several point mutations were introduced into Bot2 cDNA, and the recombinant protein (recombinant Bot2 [rBot2]) was purified on an anti-botrocetin column. The mutant rBot2 with either Ala at Asp70 in the β subunit (Aspβ70Ala), or Argβ115Ala and Lysβ117Ala, showed reduced platelet agglutination-inducing activity. rBot2 with Aspβ70Ala showed little binding activity towards immobilized VWF on an ELISA plate, whereas rBot2 with Argβ115Ala/Lysβ117Ala showed reduced binding activity towards GPIb (glycocalicin) after forming a complex with VWF. rBot2 point-mutated to oppositely charged Glu at both Argβ115 and Lysβ117 showed normal binding activity towards VWF but no platelet-agglutinating activity. Furthermore, this doubly mutated protein inhibited ristocetin-induced or high shear stress-induced platelet aggregation, and restrained thrombus formation under flow conditions. Conclusions Asp70 in the β subunit of botrocetin is important for VWF binding, and Arg115 and Lys117 in the β subunit are essential for interaction with GPIb. Doubly mutated rBot2, with Argβ115Glu and Lysβ117Glu, repels GPIb and might have potential as an antithrombotic reagent that

  5. Wirksamkeit und Sicherheit von Fumarsäureestern in Kombination mit Phototherapie bei Patienten mit moderater bis schwerer Plaque-Psoriasis (FAST).

    PubMed

    Weisenseel, Peter; Reich, Kristian; Griemberg, Wiebke; Merten, Katharina; Gröschel, Christine; Gomez, Natalie Nunez; Taipale, Kirsi; Bräu, Beate; Zschocke, Ina

    2017-02-01

    Die Behandlung von Psoriasis-Patienten mit einer Kombination aus Fumarsäureestern (FSE, Fumaderm ® ) und Phototherapie (UV) ist verbreitet, wurde aber im Rahmen von Studien wenig untersucht. Bisher liegen lediglich Daten aus einer kleinen Pilotstudie vor. Intention dieser Studie war, eine FSE/UV-Kombinationsbehandlung an einem größeren Patientenkollektiv mit mittelschwerer bis schwerer Psoriasis zu untersuchen. In dieser prospektiven, multizentrischen, nichtinterventionellen Studie wurden Daten von Patienten mit FSE/UV-Kombinationstherapie hinsichtlich der Wirksamkeit (PGA' PASI, DLQI, EQ-5D), Sicherheit und Dosierung über einen Zeitraum von zwölf Monaten erfasst und mit Daten einer retrospektiven Studie mit FSE-Monotherapie verglichen. Es wurden Daten von 363 Patienten ausgewertet. Unter der Kombinationstherapie verbesserten sich alle Wirksamkeitsparameter deutlich. Im Vergleich zur Monotherapie mit FSE konnte durch die Kombination mit UV ein schnellerer Wirkeintritt erzielt werden, wobei nach zwölf Monaten kein Unterschied in der Wirksamkeit bestand. Die Dauer und Art der Phototherapie zeigte keinen Einfluss auf die Wirksamkeitsparameter. Allgemein wurde die Kombinationstherapie gut vertragen. Unerwünschte Ereignisse wurden bei 7 % der Patienten berichtet. Die FSE/UV Kombinationstherapie zeigt eine gute Wirksamkeit und Verträglichkeit und kann zu einem schnelleren Wirkeintritt führen. Eine Kombinationstherapie erscheint vor allem in den ersten drei Monaten der FSE Behandlung sinnvoll. © 2017 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  6. Optimal projection method determination by Logdet Divergence and perturbed von-Neumann Divergence.

    PubMed

    Jiang, Hao; Ching, Wai-Ki; Qiu, Yushan; Cheng, Xiao-Qing

    2017-12-14

    Positive semi-definiteness is a critical property in kernel methods for Support Vector Machine (SVM) by which efficient solutions can be guaranteed through convex quadratic programming. However, a lot of similarity functions in applications do not produce positive semi-definite kernels. We propose projection method by constructing projection matrix on indefinite kernels. As a generalization of the spectrum method (denoising method and flipping method), the projection method shows better or comparable performance comparing to the corresponding indefinite kernel methods on a number of real world data sets. Under the Bregman matrix divergence theory, we can find suggested optimal λ in projection method using unconstrained optimization in kernel learning. In this paper we focus on optimal λ determination, in the pursuit of precise optimal λ determination method in unconstrained optimization framework. We developed a perturbed von-Neumann divergence to measure kernel relationships. We compared optimal λ determination with Logdet Divergence and perturbed von-Neumann Divergence, aiming at finding better λ in projection method. Results on a number of real world data sets show that projection method with optimal λ by Logdet divergence demonstrate near optimal performance. And the perturbed von-Neumann Divergence can help determine a relatively better optimal projection method. Projection method ia easy to use for dealing with indefinite kernels. And the parameter embedded in the method can be determined through unconstrained optimization under Bregman matrix divergence theory. This may provide a new way in kernel SVMs for varied objectives.

  7. Synesthesia and memory: color congruency, von Restorff, and false memory effects.

    PubMed

    Radvansky, Gabriel A; Gibson, Bradley S; McNerney, M Windy

    2011-01-01

    In the current study, we explored the influence of synesthesia on memory for word lists. We tested 10 grapheme-color synesthetes who reported an experience of color when reading letters or words. We replicated a previous finding that memory is compromised when synesthetic color is incongruent with perceptual color. Beyond this, we found that, although their memory for word lists was superior overall, synesthetes did not exhibit typical color- or semantic-defined von Restorff isolation effects (von Restorff, 1933) compared with control participants. Moreover, our synesthetes exhibited a reduced Deese-Roediger-McDermott false memory effect (Deese, 1959; Roediger & McDermott, 1995). Taken as a whole, these findings are consistent with the idea that color-grapheme synesthesia can lead people to place a greater emphasis on item-specific processing and surface form characteristics of words in a list (e.g., the letters that make them up) relative to relational processing and more meaning-based processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

  8. von Willebrand factor, Jedi knight of the bloodstream.

    PubMed

    Springer, Timothy A

    2014-08-28

    When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use "the Force" to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended thread-like in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables postsecretion regulation of VWF length. Mutations in VWF in von Willebrand disease contribute to and are illuminated by VWF biology. I attempt to integrate classic studies on the physiology of hemostatic plug formation into modern molecular understanding, and point out what remains to be learned. © 2014 by The American Society of Hematology.

  9. The Digital Von Fahrenheid Pyramid

    NASA Astrophysics Data System (ADS)

    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.

  10. On the history of Ludwig von Bertalanffy's "general systemology", and on its relationship to cybernetics - Part II: Contexts and developments of the systemological hermeneutics instigated by von Bertalanffy

    NASA Astrophysics Data System (ADS)

    Pouvreau, David

    2014-02-01

    The history of "general system theory" is investigated in order to clarify its meanings, vocations, foundations and achievements. It is characterized as the project of a science of the systemic interpretation of the "real", renamed here "general systemology". The contexts and modes of its elaboration, publication and implementation are discussed. The paper mostly focuses on the works of its instigator: Ludwig von Bertalanffy. However, general systemology was a collective project: the main contributions of other "systemologists", from the 1950s until the 1970s, are hence also considered. Its solidarity with the history of the Society for General Systems Research is notably discussed. A reconstruction of the systemological hermeneutics is undertaken on this basis. It finds out the potential systematic unity underlying the diversity of the contributions to this both scientific and philosophical project. Light is thus shed on the actual scope of von Bertalanffy's works.

  11. Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

    PubMed Central

    Grainick, H R; Williams, S B; McKeown, L P; Rick, M E; Maisonneuve, P; Jenneau, C; Sultan, Y

    1985-01-01

    We have investigated and characterized the abnormalities in four unrelated patients with von Willebrand's disease (vWd) who have (a) enhanced ristocetin-induced platelet aggregation (RIPA) at low ristocetin concentrations, (b) absence of the largest plasma von Willebrand factor (vWf) multimers, and (c) thrombocytopenia. The platelet-rich plasma of these patients aggregates spontaneously without the addition of any agonists. When isolated normal platelets are resuspended in patient plasma spontaneous aggregation occurs; however, the patients' plasmas did not induce platelet aggregation of normal washed formalinized platelets. When the patients' platelets are suspended in normal plasma, spontaneous aggregation is not observed. The spontaneous platelet aggregation (SPA) is associated with dense granule secretion as measured by ATP release and alpha granule release as measured by beta-thromboglobulin and platelet factor 4 release. The SPA is totally inhibited by 5 mM EDTA, prostaglandin I2, and dibutryl cyclic AMP, while it is only partially inhibited by 1 mM EDTA, acetylsalicylic acid, or apyrase. A monoclonal antibody directed against glycoprotein Ib (GPIb) and/or a monoclonal antibody against the glycoprotein IIb/IIIa (GPIIb/IIIa) complex totally inhibits the SPA. The vWf was isolated from the plasma of one of these patients. The purified vWf induced platelet aggregation of normal platelets resuspended in either normal or severe vWd plasma, but the vWf did not induce platelet aggregation of normal platelets resuspended in afibrinognemic plasma. Sialic acid and galactose quantification of the patient's vWf revealed approximately a 50% reduction compared with normal vWf. These studies indicate that a form of vWd exists, which is characterized by SPA that is induced by the abnormal plasma vWf. The SPA is dependent on the presence of plasma fibrinogen, and the availability of the GPIb and the GPIIb/IIIa complex. In this variant form of vWd the abnormal vWf causes

  12. Albert Einstein and Wernher von Braun - the two great German-American physicists seen in a historical perspective.

    NASA Astrophysics Data System (ADS)

    Winterberg, Friedwardt

    2008-04-01

    It was Albert Einstein who for the first time changed our view of the universe to be a non-euclidean curved space-time. And it was Wernher von Braun who blazed the trail to take us into this universe, leaving for the first time the gravitational field of our planet earth, with the landing a man on the moon the greatest event in human history. Both these great physicists did this on the shoulders of giants. Albert Einstein on the shoulders of his landsman, the mathematician Bernhard Riemann, and Wernher von Braun on the shoulders of Goddard and Oberth. Both Einstein and von Braun made a Faustian pact with the devil, von Braun by accepting research funds from Hitler, and Einstein by urging Roosvelt to build the atom bomb (against Hitler). Both of these great men later regretted the use of their work for the killing of innocent bystanders, even though in the end the invention of nuclear energy and space flight is for the benefit of man. Their example serves as a warning for all of us. It can be formulated as follows: ``Can I in good conscience accept research funds from the military to advance scientific knowledge, for weapons developed against an abstract enemy I never have met in person?'' Weapons if used do not differentiate between the scientist, who invented these weapons, and the non-scientist.

  13. Spontaneous haemothorax: a cause of sudden death in von Recklinghausen's disease.

    PubMed Central

    Griffiths, A. P.; White, J.; Dawson, A.

    1998-01-01

    Vasculopathy is a relatively frequent but poorly recognised manifestation of von Recklinghausen's neurofibromatosis. One of its more dramatic presentations is as spontaneous haemothorax. Clinicians and pathologists should be aware of this syndrome as a cause of sudden death in patients with neurofibromatosis. Images Figure 1 Figure 2 PMID:10197217

  14. Surface, Interface, and Bulk Properties of High Tc Superconductors

    DTIC Science & Technology

    1989-06-30

    Superconductors Phys. Rev. B 39, 823, (1989) Z.-X. Shen, P.A.P. Lindberg, B.O. Wells, D.B. Mitzi , I. Lindau, W.E. Spicer and A. Kapitulnik Valence Band...Lindau, W.E. Spicer, P. Soukiassian, D.B. Mitzi , C.B. Eom, A. Kapitulnik and T.H. Geballe Surface and Electronic Structure of Bi-Ca-Sr-Cu-O...P.A.P. Lindberg, D.S. Dessau, I. Lindau, W.E. Spicer, D.B. Mitzi , I. Bozvic and A. Kapitulnik Photoelectron energy loss study of the Bi 2CaSr 2Cu20 8

  15. Two errors in enteric epidemiology: the stories of Austin Flint and Max von Pettenkofer.

    PubMed

    Evans, A S

    1985-01-01

    The misconceptions of two physicians, Austin Flint and Max von Pettenkofer, in interpreting epidemiologic data on the water transmission of enteric disease are reviewed. Austin Flint failed to recognize the transmission of typhoid fever from well water in an epidemic he investigated in North Boston, New York, in 1843. He later discovered and freely admitted his error. Max von Pettenkofer, who had studied cholera in the 1854 outbreak and in many subsequent outbreaks, failed to confirm John Snow's observations in England on the water transmission of cholera. Pettenkofer eventually swallowed live cholera bacilli and did not develop cholera. He remained convinced to the end of his life that cholera is not directly transmitted by drinking water.

  16. Effects of Turbulence Model and Numerical Time Steps on Von Karman Flow Behavior and Drag Accuracy of Circular Cylinder

    NASA Astrophysics Data System (ADS)

    Amalia, E.; Moelyadi, M. A.; Ihsan, M.

    2018-04-01

    The flow of air passing around a circular cylinder on the Reynolds number of 250,000 is to show Von Karman Vortex Street Phenomenon. This phenomenon was captured well by using a right turbulence model. In this study, some turbulence models available in software ANSYS Fluent 16.0 was tested to simulate Von Karman vortex street phenomenon, namely k- epsilon, SST k-omega and Reynolds Stress, Detached Eddy Simulation (DES), and Large Eddy Simulation (LES). In addition, it was examined the effect of time step size on the accuracy of CFD simulation. The simulations are carried out by using two-dimensional and three- dimensional models and then compared with experimental data. For two-dimensional model, Von Karman Vortex Street phenomenon was captured successfully by using the SST k-omega turbulence model. As for the three-dimensional model, Von Karman Vortex Street phenomenon was captured by using Reynolds Stress Turbulence Model. The time step size value affects the smoothness quality of curves of drag coefficient over time, as well as affecting the running time of the simulation. The smaller time step size, the better inherent drag coefficient curves produced. Smaller time step size also gives faster computation time.

  17. Richard von Volkmann

    PubMed Central

    Willy, Christian; Schneider, Peter; Engelhardt, Michael; Hargens, Alan R.

    2008-01-01

    Richard von Volkmann (1830–1889), one of the most important surgeons of the 19th century, is regarded as one of the fathers of orthopaedic surgery. He was a contemporary of Langenbeck, Esmarch, Lister, Billroth, Kocher, and Trendelenburg. He was head of the Department of Surgery at the University of Halle, Germany (1867–1889). His popularity attracted doctors and patients from all over the world. He was the lead physician for the German military during two wars. From this experience, he compared the mortality of civilian and war injuries and investigated the general poor hygienic conditions in civilian hospitals. This led him to introduce the “antiseptic technique” to Germany that was developed by Lister. His powers of observation and creativity led him to findings and achievements that to this day bear his name: Volkmann’s contracture and the Hueter-Volkmann law. Additionally, he was a gifted writer; he published not only scientific literature but also books of children’s fairy tales and poems under the pen name of Richard Leander, assuring him a permanent place in the world of literature as well as orthopaedics. PMID:18196438

  18. Gravity Effects in Diffusive Coarsening of Bubble Lattices: von Neumann's Law

    NASA Technical Reports Server (NTRS)

    Noever, David A.

    2000-01-01

    von Neumann modelled the evolution of two-dimensional soap froths as a purely diffusive phenomenon; the area growth of a given cell was found to depend only on the geometry of the bubble lattice. In the model, hexagons are stable, pentagons shrink and heptagons grow. The simplest equivalent to the area growth law is / approximately t(sub beta). The result depends on assuming (1) an incompressible gas; (2) bubble walls which meet at 120 deg and (3) constant wall thickness and curvature. Each assumption is borne out in experiments except the last one: bubble wall thickness between connecting cells varies in unit gravity because of gravity drainage. The bottom part of the soap membrane is thickened, the top part is thinned, such that gas diffusion across the membrane shows a complex dependence on gravity. As a result, experimental tests of von Neumann's law have been influenced by effects of gravity; fluid behavior along cell borders can give non-uniform wall thicknesses and thus alter the effective area and gas diffusion rates between adjacent bubbles. For area plotted as a function of time, Glazier (J.A. Glazier, S.P. Gross, and I. Stavans, Phys. Rev. A. 36, 306 (1987); J. Stavans, J.A, Glazier, Phys. Rev. Lett. 62, 1318 (1989).) suggest that in some cases their failure to observe von Neumann's predicted growth exponent ((sup beta)theor(sup =1; beta)exp(sup =0.70 + 0.10)) may have been the result of such "fluid drainage onto the lower glass plate". Additional experiments which varied plate spacing gave different beta exponents in a fashion consistent with this suggestion. During preliminary long duration experiments (approximately 100 h) aboard Spacelab-J, a low-gravity test of froth coarsening has examined (1) power law scaling of von Neumann's law (beta values) in the appropriate diffusive limits; (2) new bubble lattice dynamics such as greater fluid wetting behavior on froth membranes in low gravity; and (3) explicit relations for the gravity

  19. Book Review: John von Neumann and the foundations of quantum physics. (Vienna Circle Institute yearbook (2000), 8) Miklos Redei and Michael Stoltzner (Eds.); Kluwer Academic Publishers, Dordrecht, 2001, pp., US 125, ISBN 0792368126

    NASA Astrophysics Data System (ADS)

    Lupher, Tracy

    2003-12-01

    Some people may be surprised to learn that John von Neumann's work on the foundations of quantum physics went far beyond what is contained within the pages of his Mathematical Foundations of Quantum Mechanics (MFQM) (von Neumann, 1955). However, this narrow focus often ignores von Neumann's later work on quantum logic and what are now called in his honor, von Neumann algebras. This volume honoring von Neumann's contributions to physics is unique in that, while it contains 12 papers that examine various aspects of von Neumann's work, it also contains two of his previously unpublished papers and some of his previously unpublished correspondence.

  20. [Franz Günther von Stockert between politics and science--a study in the history of the neurology and psychiatry in the GDR].

    PubMed

    Kumbier, E; Haack, K; Herpertz, S C

    2009-05-01

    1945 marked the beginning of the so-called anti-fascist democratic transformation in the Soviet occupied zone and later GDR, which also included radical reforms in the higher education system. The aim of these reforms was to establish a "new intelligence" that was to spread Marxist-Leninist teaching in universities and colleges. However, in practice the new rulers had to rely on the old "erudite elite" which led to considerable problems. Against this socio-political background this study analyses the affairs at the neuropsychiatric clinic Gehlsheim at Rostock University, in particular those around Franz Günther von Stockert (1899-1967), who was head of the department between 1954 and 1958. Archival sources, not accessible till now, shed light on the background and motives that finally led to his dismissal and short-term imprisonment, and the consequences for the clinic. The analysis of this example also shows how external factors can influence science and the disciplinary differentiation. This case from the field of psychiatry and neurology is a contribution to the broader history of science in the GDR until 1961.

  1. [Urology and National Socialism: the fate of Alexander von Lichtenberg 1880-1949].

    PubMed

    Moll, F H; Krischel, M; Rathert, P; Fangerau, H

    2010-09-01

    Alexander von Lichtenberg (1880-1949) was one of the famous members of the German Urological Society (DGU) in pre-war Germany. He introduced excretion urography and a special TURP Instrument. In 1928 he was president of the 8th meeting held in the German capital Berlin. His Handbook of Urology, released by Ferdinand Springer publishing house, was a trendsetter in establishing urology as a specialty in Germany and bringing together the whole wisdom of all aspects of urology. He was the founder of the famous Maximilian Nitze Award of the DGU. As a Jew he-like many others-was forced to leave Nazi Germany after 1933. Even in Hungary, his native country, he again had to resist anti-Semitic hostility. Later on he lived in Mexico. Alexander von Lichtenberg has to be remembered with special focus on the exodus of German Jewish scientists during the Nazi time.

  2. Prenatal stress-induced increases in hippocampal von Willebrand factor expression are prevented by concurrent prenatal escitalopram

    PubMed Central

    Neigh, Gretchen N.; Nemeth, Christina L; Kelly, Sean D.; Hardy, Emily E.; Bourke, Chase; Stowe, Zachary N.; Owens, Michael J.

    2016-01-01

    Prenatal stress has been linked to deficits in neurological function including deficient social behavior, alterations in learning and memory, impaired stress regulation, and susceptibility to adult disease. In addition, prenatal environment is known to alter cardiovascular health; however, limited information is available regarding the cerebrovascular consequences of prenatal stress exposure. Vascular disturbances late in life may lead to cerebral hypoperfusion which is linked to a variety of neurodegenerative and psychiatric diseases. The known impact of cerebrovascular compromise on neuronal function and behavior highlights the importance of characterizing the impact of stress on not just neurons and glia, but also cerebrovasculature. Von Willebrand factor has previously been shown to be impacted by prenatal stress and is predictive of cerebrovascular health. Here we assess the impact of prenatal stress on von Willebrand factor and related angiogenic factors. Furthermore, we assess the potential protective effects of concurrent anti-depressant treatment during in utero stress exposure on the assessed cerebrovascular endpoints. Prenatal stress augmented expression of von Willebrand factor which was prevented by concurrent in utero escitalopram treatment. The functional implications of this increase in von Willebrand factor remain elusive, but the presented data demonstrate that although prenatal stress did not independently impact total vascularization, exposure to chronic stress in adulthood decreased blood vessel length. In addition, the current study demonstrates that production of reactive oxygen species in the hippocampus is decreased by prenatal exposure to escitalopram. Collectively, these findings demonstrate that the prenatal experience can cause complex changes in adult cerebral vascular structure and function. PMID:27422674

  3. Determining the von Mises stress power spectral density for frequency domain fatigue analysis including out-of-phase stress components

    NASA Astrophysics Data System (ADS)

    Bonte, M. H. A.; de Boer, A.; Liebregts, R.

    2007-04-01

    This paper provides a new formula to take into account phase differences in the determination of an equivalent von Mises stress power spectral density (PSD) from multiple random inputs. The obtained von Mises PSD can subsequently be used for fatigue analysis. The formula was derived for use in the commercial vehicle business and was implemented in combination with Finite Element software to predict and analyse fatigue failure in the frequency domain.

  4. Platelet von Willebrand factor in Hermansky-Pudlak syndrome.

    PubMed

    McKeown, L P; Hansmann, K E; Wilson, O; Gahl, W; Gralnick, H R; Rosenfeld, K E; Rosenfeld, S J; Horne, M K; Rick, M E

    1998-10-01

    The Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive inherited disorder characterized by oculocutaneous albinism, tissue accumulation of ceroid pigment, and a mild to moderate bleeding diathesis attributed to storage-pool deficient (SPD) platlets. Patients have platelet aggregation and release abnormalities. In addition, low levels of plasma von Willebrand factor (vWF) antigen in some HPS patients have been associated with a greater bleeding tendency than would be predicted from either condition alone. Other HPS patients have severe bleeding despite normal levels of plasma vWF, suggesting that at least one additional factor is responsible for their bleeding diathesis. Because platelet vWF levels have been well correlated with clinical bleeding times in patients with von Willebrand's disease, we have measured the platelet vWF activity and antigen levels in 30 HPS patients and have attempted to correlate their clinical bleeding with these values. The platelet vWF activity levels in patients was significantly lower than that of normal subjects (P < 0.0001). The patients as a group also had slightly lower values of plasma vWF activity when compared with normals (P-0.03). In 11 of the HPS patients, the multimeric structure of plasma vWF showed a decrease in the high molecular weight multimers and an increase in the low molecular weight multimers. In correlating the platelet and plasma vWF values with the bleeding histories, we were not able to show a predictable relationship in the majority of the patients.

  5. Expression of von Willebrand factor and caldesmon in the placental tissues of pregnancies complicated with intrauterine growth restriction.

    PubMed

    Göksever Çelik, Hale; Uhri, Mehmet; Yildirim, Gökhan

    2017-11-02

    The decreased placental perfusion is the underlying reason for intrauterine growth restriction that in turn leads to reduced placental perfusion and ischemia. However, there are several issues to be understood in the pathophysiology of intrauterine growth restriction. We aimed to study whether any compensatory response in placental vascular bed occur in pregnancies complicated with intrauterine growth restriction by the immunohistochemical staining of von Willebrand factor and caldesmon in placental tissues. A total of 103 pregnant women was enrolled in the study including 50 patients who were complicated with IUGR and 50 uncomplicated control patients. The study was designed in a prospective manner. All placentas were also stained with von Willebrand factor and caldesmon monoclonal kits. The immunohistochemical staining of von Willebrand factor and caldesmon expressions in placental tissues were different between normal and intrauterine growth restriction group. The percentages of 2+ and 3+ von Willebrand factor expression were higher in the intrauterine growth restriction group comparing with the normal group, although the difference was not statistically significant. The intensity of caldesmon expression was significantly lower in the intrauterine growth restriction group in comparison with the normal group (p < .001). Angiogenesis occurs as a placental response to intrauterine growth restriction which is a hypoxic condition. But newly formed vessels are immature and not strong enough. Our study is important to clarify the pathophysiology and placental compensatory responses in intrauterine growth restriction.

  6. Platelet Dysfunction and a High Bone Mass Phenotype in a Murine Model of Platelet-Type von Willebrand Disease

    PubMed Central

    Suva, Larry J.; Hartman, Eric; Dilley, Joshua D.; Russell, Susan; Akel, Nisreen S.; Skinner, Robert A.; Hogue, William R.; Budde, Ulrich; Varughese, Kottayil I.; Kanaji, Taisuke; Ware, Jerry

    2008-01-01

    The platelet glycoprotein Ib-IX receptor binds surface-bound von Willebrand factor and supports platelet adhesion to damaged vascular surfaces. A limited number of mutations within the glycoprotein Ib-IX complex have been described that permit a structurally altered receptor to interact with soluble von Willebrand factor, and this is the molecular basis of platelet-type von Willebrand disease. We have developed and characterized a mouse model of platelet-type von Willebrand disease (G233V) and have confirmed a platelet phenotype mimicking the human disorder. The mice have a dramatic increase in splenic megakaryocytes and splenomegaly. Recent studies have demonstrated that hematopoetic cells can influence the differentiation of osteogenic cells. Thus, we examined the skeletal phenotype of mice expressing the G233V variant complex. At 6 months of age, G233V mice exhibit a high bone mass phenotype with an approximate doubling of trabecular bone volume in both the tibia and femur. Serum measures of bone resorption were significantly decreased in G233V animals. With decreased bone resorption, cortical thickness was increased, medullary area decreased, and consequently, the mechanical strength of the femur was significantly increased. Using ex vivo bone marrow cultures, osteoclast-specific staining in the G233V mutant marrow was diminished, whereas osteoblastogenesis was unaffected. These studies provide new insights into the relationship between the regulation of megakaryocytopoiesis and bone mass. PMID:18187573

  7. MSFC Director welcomes attendees to the 10th Annual Wernher von

    NASA Image and Video Library

    2017-10-26

    Marshall Space Flight Center director Todd May welcomes attendees to the 10th annual Dr. Wernher von Braun Memorial Symposium held at the University of Alabama, Huntsville, Alabama. The three-day symposium brought together experts for discussion panels on science, engineering and technology under the theme “Gateways in Space: Exploration, Security, and Commerce.”

  8. Einheit von Forschung und Lehre: Implications for State Funding of Universities

    ERIC Educational Resources Information Center

    Frolich, Nicoline; Coate, Kelly; Mignot-Gerard, Stephanie; Knill, Christoph

    2010-01-01

    The Humboldtian educational ideal is based on the idea of the unity of teaching and research in universities ("Einheit von Forschung und Lehre"). The role of the state, according to Humboldt, was to fund universities in such a way that their autonomy was maintained. Much has changed in the funding mechanisms of higher education systems…

  9. Incidence and Prognosis of Spinal Hemangioblastoma: A Surveillance Epidemiology and End Results Study.

    PubMed

    Westwick, Harrison J; Giguère, Jean-François; Shamji, Mohammed F

    2016-01-01

    Intradural spinal hemangioblastoma are infrequent, vascular, pathologically benign tumors occurring either sporadically or in association with von Hippel-Lindau disease along the neural axis. Described in fewer than 1,000 cases, literature is variable with respect to epidemiological factors associated with spinal hemangioblastoma and their treatment. The objective of this study was to evaluate the epidemiology of intradural spinal hemangioblastoma with the Surveillance, Epidemiology and End Results (SEER) database while also presenting an illustrative case. The SEER database was queried for cases of spinal hemangioblastoma between 2000 and 2010 with the use of SEER*Stat software. Incidence was evaluated as a function of age, sex and race. Survival was evaluated with the Cox proportionate hazards ratio using IBM SPSS software evaluating age, sex, location, treatment modality, pathology and number of primaries (p = 0.05). Descriptive statistics of the same factors were also calculated. The case of a 43-year-old patient with a surgical upper cervical intramedullary hemangioblastoma is also presented. In the data set between 2000 and 2010, there were 133 cases with an age-adjusted incidence of 0.014 (0.012-0.017) per 100,000 to the standard USA population. Hemangioblastoma was the tenth most common intradural spinal tumor type representing 2.1% (133 of 6,156) of all spinal tumors. There was no difference in incidence between men and women with an female:male rate ratio of 1.05 (0.73-1.50) with p = 0.86. The average age of patients was 48.0 (45.2-50.9) years, and a lower incidence was noted in patients <15 years compared to all other age groups (p < 0.05). There was no difference in incidence amongst the different races. Treatment included surgical resection in 106 (79.7%) cases, radiation with surgery in 7 (5.3%) cases, and radiation alone was used in only 1 (0.8%) case, and no treatment was performed in 17 (12.8%) cases. Mortality was noted in 12 (9%) cases, and

  10. L'atteinte vésicale au cours de la neurofibromatose de Von Recklinghausen

    PubMed Central

    Benazzouz, Mohamed Hicham; Hajjad, Tilila; Essatara, Younes; El Sayegh, Hachem; Iken, Ali; Benslimane, Lounis; Nouini, Yassine

    2014-01-01

    La neurofibromatose de type 1 ou maladie de Von Recklinghausen est une maladie génétique autosomique dominante en rapport avec des mutations dans le gène suppresseur de tumeur NF1. L'atteinte uro-génitale au cours de cette maladie est rare et moins de 80 cas ont été rapportés à ce jour dans la littérature mondiale. Les auteurs rapportent un nouveau cas d'atteinte vésicale découverte fortuitement au cours du suivi d'une patiente atteinte de la maladie de Von Recklinghausen. A travers cette observation et une revue de la littérature les auteurs discutent également les difficultés diagnostiques, thérapeutiques ainsi que les modalités de suivi dans cette maladie. PMID:25328590

  11. Galerkin analysis of kinematic dynamos in the von Kármán geometry

    NASA Astrophysics Data System (ADS)

    Marié, L.; Normand, C.; Daviaud, F.

    2006-01-01

    We investigate dynamo action by solving the kinematic dynamo problem for velocity fields of the von Kármán type between two coaxial counter-rotating propellers in a cylinder. A Galerkin method is implemented that takes advantage of the symmetries of the flow and their subsequent influence on the nature of the magnetic field at the dynamo threshold. Distinct modes of instability have been identified that differ by their spatial and temporal behaviors. Our calculations give the result that a stationary and antisymmetric mode prevails at the dynamo threshold. We then present a quantitative analysis of the results based on the parametric study of four interaction coefficients obtained by reduction of our initially large eigenvalue problem. We propose these coefficients to measure the relative importance of the different mechanisms at play in the von Kármán kinematic dynamo.

  12. Quantitative conditions for time evolution in terms of the von Neumann equation

    NASA Astrophysics Data System (ADS)

    Wang, WenHua; Cao, HuaiXin; Chen, ZhengLi; Wang, Lie

    2018-07-01

    The adiabatic theorem describes the time evolution of the pure state and gives an adiabatic approximate solution to the Schödinger equation by choosing a single eigenstate of the Hamiltonian as the initial state. In quantum systems, states are divided into pure states (unite vectors) and mixed states (density matrices, i.e., positive operators with trace one). Accordingly, mixed states have their own corresponding time evolution, which is described by the von Neumann equation. In this paper, we discuss the quantitative conditions for the time evolution of mixed states in terms of the von Neumann equation. First, we introduce the definitions for uniformly slowly evolving and δ-uniformly slowly evolving with respect to mixed states, then we present a necessary and sufficient condition for the Hamiltonian of the system to be uniformly slowly evolving and we obtain some upper bounds for the adiabatic approximate error. Lastly, we illustrate our results in an example.

  13. Estimating age at a specified length from the von Bertalanffy growth function

    USGS Publications Warehouse

    Ogle, Derek H.; Isermann, Daniel A.

    2017-01-01

    Estimating the time required (i.e., age) for fish in a population to reach a specific length (e.g., legal harvest length) is useful for understanding population dynamics and simulating the potential effects of length-based harvest regulations. The age at which a population reaches a specific mean length is typically estimated by fitting a von Bertalanffy growth function to length-at-age data and then rearranging the best-fit equation to solve for age at the specified length. This process precludes the use of standard frequentist methods to compute confidence intervals and compare estimates of age at the specified length among populations. We provide a parameterization of the von Bertalanffy growth function that has age at a specified length as a parameter. With this parameterization, age at a specified length is directly estimated, and standard methods can be used to construct confidence intervals and make among-group comparisons for this parameter. We demonstrate use of the new parameterization with two data sets.

  14. von Neumann's Law: Theoretical and Microgravity Experimental Comparison for Coarsening Diffusion in Bubble Lattices

    NASA Technical Reports Server (NTRS)

    Noever, David A.

    2000-01-01

    The effects of gravity in influencing the theoretical limit for bubble lattice coarsening and aging behavior, otherwise called von Neumann's law, is examined theoretically and experimentally. Preliminary microgravity results will be discussed.

  15. Detailed von Willebrand factor multimer analysis in patients with von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease (MCMDM-1VWD).

    PubMed

    Budde, U; Schneppenheim, R; Eikenboom, J; Goodeve, A; Will, K; Drewke, E; Castaman, G; Rodeghiero, F; Federici, A B; Batlle, J; Pérez, A; Meyer, D; Mazurier, C; Goudemand, J; Ingerslev, J; Habart, D; Vorlova, Z; Holmberg, L; Lethagen, S; Pasi, J; Hill, F; Peake, I

    2008-05-01

    Type 1 von Willebrand disease (VWD) is a congenital bleeding disorder characterized by a partial quantitative deficiency of plasma von Willebrand factor (VWF) in the absence of structural and/or functional VWF defects. Accurate assessment of the quantity and quality of plasma VWF is difficult but is a prerequisite for correct classification. To evaluate the proportion of misclassification of patients historically diagnosed with type 1 VWD using detailed analysis of the VWF multimer structure. Previously diagnosed type 1 VWD families and healthy controls were recruited by 12 expert centers in nine European countries. Phenotypic characterization comprised plasma VWF parameters and multimer analysis using low- and intermediate-resolution gels combined with an optimized visualization system. VWF genotyping was performed in all index cases (ICs). Abnormal multimers were present in 57 out of 150 ICs; however, only 29 out of these 57 (51%) had VWF ristocetin cofactor to antigen ratio below 0.7. In most cases multimer abnormalities were subtle, and only two cases had a significant loss of the largest multimers. Of the cases previously diagnosed as type 1 VWD, 38% showed abnormal multimers. Depending on the classification criteria used, 22 out of these 57 cases (15% of the total cohort) may be reclassified as type 2, emphasizing the requirement for multimer analysis compared with a mere ratio of VWF functional parameters and VWF:Ag. This is further supported by the finding that even slightly aberrant multimers are highly predictive for the presence of VWF mutations.

  16. Analysis of nuclear accumulation of influenza NP antigen in von Magnus virus-infected cells.

    PubMed

    Maeno, K; Aoki, H; Hamaguchi, M; Iinuma, M; Nagai, Y; Matsumoto, T; Takeura, S; Shibata, M

    1981-01-01

    When 1-5C-4 cells were infected with von Magnus virus derived from influenza A/RI/5+ virus by successive undiluted passages in chick embryos, virus-specific proteins were synthesized but production of infectious virus was inhibited. In these cells the synthesis of viral RNA was suppressed and the nucleoprotein (NP) antigen was found predominantly in the nucleus in contrast to standard virus-infected cells in which the antigen was distributed throughout the whole cell. The intracellular location and migration of NP were determined by isotope labeling and sucrose gradient centrifugation of subcellular fractions. In standard virus-infected cell NP polypeptide was present predominantly in the cytoplasm in the form of viral ribonucleoprotein (RNP) and intranuclear RNP was detected in reduced amounts. In contrast, in von Magnus virus-infected cells NP polypeptide was present predominantly in the nucleus in a nonassembled, soluble from and the amount of cytoplasmic RNP was considerably reduced. After short-pulse labeling NP was detected exclusively in the cytoplasm in a soluble form and after a chase a large proportion of such soluble NP was seen in the nucleus. It is suggested that a large proportion of the NP synthesized in von Magnus virus-infected cells in not assembled into cytoplasmic RNP because of the lack of available RNA and the NP migrated into the nucleus and remained there.

  17. How Alexander von Humboldt's life story can inspire innovative soil research in developing countries

    NASA Astrophysics Data System (ADS)

    Bouma, Johan

    2017-09-01

    The pioneering vision of Alexander von Humboldt of science and society of the early 1800s is still highly relevant today. His open mind and urge to make many measurements characterizing the interconnected web of life are crucial ingredients as we now face the worldwide challenge of the UN Sustainable Development Goals. Case studies in the Philippines, Vietnam, Kenya, Niger, and Costa Rica demonstrate, in Alexander's spirit, interaction with stakeholders and attention to unique local conditions, applying modern measurement and modeling methods and allowing inter- and transdisciplinary research approaches. But relations between science and society are increasingly problematic, partly as a result of the information revolution and post-truth, fact-free thinking. Overly regulated and financially restricted scientific communities in so-called developed countries may stifle intellectual creativity. Researchers in developing countries are urged to leapfrog these problems in the spirit of Alexander von Humboldt as they further develop their scientific communities. Six suggestions to the science community are made with particular attention to soil science. (The Humboldt lecture, presented by the 2017 recipient of the Alexander von Humboldt lecture, Johan Bouma, can be accessed at http://client.cntv.at/egu2017/ml1.)

  18. Critical assessment of von Mises distribution and an infinite series ansatz for self-propelled particles

    NASA Astrophysics Data System (ADS)

    Kürsten, Rüdiger; Ihle, Thomas

    2017-03-01

    We consider a Vicsek model of self-propelled particles with bounded confidence, where each particle interacts only with neighbors that have a similar direction. Depending on parameters, the system exhibits a continuous or discontinuous polar phase transition from the isotropic phase to a phase with a preferred direction. In a recent paper (Lam, Schindler and Dauchot 2015 J. Stat. Mech. P10017) the von Mises distribution was proposed as an ansatz for polar ordering. In the present system the time evolution of the angular distribution can be solved in Fourier space. We compare the results of the Fourier analysis with the ones obtained by using the von Mises distribution ansatz. In the latter case the qualitative behavior of the system is recovered correctly. However, quantitatively there are serious deviations. We introduce an extended von Mises distribution ansatz such that a second term takes care of the next two Fourier modes. With the extended ansatz we find much better quantitative agreement. As an alternative approach we also use a Gaussian and a geometric series ansatz in Fourier space. The geometric series ansatz is analytically handable but fails for very weak noise, the Gaussian ansatz yields better results but it is not analytically treatable.

  19. Prognostischer Wert der Fläche und Dichte von Lymphgefäßen bei kutanem Plattenepithelkarzinom.

    PubMed

    Krediet, Jorien Tannette; Kanitakis, Jean; Bob, Adrienne; Schmitter, Julia; Carine Krediet, Annelot; Röwert, Joachim; Stockfleth, Eggert; Painsi, Clemens; Hügel, Rainer; Terhorst, Dorothea; Lange-Asschenfeldt, Bernhard

    2016-11-01

    Kutane Plattenepithelkarzinome (SCC) sind bekannt für ihre Fähigkeit, über Lymphgefäße zu metastasieren. In neueren Studien wird das Ausmaß der Lymphangiogenese als möglicher prognostischer Faktor bei einigen Hauttumoren genannt. Ziel dieser Studie war die Quantifizierung der Lymphangiogenese bei SCC entweder durch computergestützte Bildanalyse oder mithilfe der Zählmethode nach Chalkley. Gefäßparameter wurden im Hinblick auf ihre Vorhersagekraft für die Bildung von Tumormetastasen beurteilt und verglichen. In dieser Fallkontrollstudie wurden die klinischen und histologischen Daten von jeweils 15 SCC-Patienten mit bzw. ohne Metastasen retrospektiv analysiert. In den SCC-Proben wurde der für das Lymphendothel spezifische Marker D2-40 und der pan-vaskuläre Marker CD31 immunhistochemisch angefärbt und durch computergestützte morphometrische Bildanalyse in Hotspots sowie mithilfe der digitalisierten Zählmethode nach Chalkley analysiert. Die Dichte von Lymphgefäßen, die relative Lymphgefäßfläche und die mit der Chalkley-Methode ermittelte Zahl an Lymphgefäßen (Chalkley-Count) waren bei metastasierten SCC signifikant erhöht. Die Tumordicke war bei metastasierten SCC signifikant höher und besaß die höchste Vorhersagekraft für eine Metastasierung. Die Tumordicke war ein signifikanter Prädiktor für Lymphangiogeneseparameter. Die Lymphangiogenese ist bei metastasierten SCC erhöht, doch ihr Ausmaß wird von der Tumordicke beeinflusst. Die Tumordicke bildet weiterhin den zuverlässigsten prädiktiven Faktor für die Metastasierung. © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

  20. A visit paid to Jung by Alwine von Keller.

    PubMed

    Bernardini, Riccardo; Quaglino, Gian Piero; Romano, Augusto

    2011-04-01

    In the winter of 1943-1944, Jung had suffered a coronary thrombosis which almost cost him his life. During his illness, Jung experienced a series of visions, described in his Memories, Dreams, Reflections, which were also to influence significantly the development of his theoretical thinking. On 27(th) September 1944, Alwine von Keller (1878-1965) paid a visit to Jung, while he was still convalescing, in Zurich and documented her meeting with him in a series of notes, recently discovered, which testify to the fact that, at the time of their meeting, Jung was engaged in writing the 'Salt' chapter of Mysterium coniunctionis and investigating the alchemistic symbolism of the 'sea'. This theme seems to testify to a continuity of interests on Jung's part with the seminar he held at Eranos the previous year on the cartographic art of Opicinus de Canistris (1296-c.1352). With its addition of many unpublished details, Alwine von Keller's notes supplement the report which Jung made of his visions experienced during his sickness in MDR. In particular, these attest to the fact that Jung had attributed the terrible experience which he had endured to the problem of the conjunctio, which was confronting him from the theoretical point of view in his writing of Mysterium coniunctionis. © 2011, The Society of Analytical Psychology.