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von hippel lindau

Shu-Ching Huang, Anyu Zhou, Dan T Nguyen, Henry S Zhang, Edward J Benz
Protein 4.1R (4.1R) isoforms are expressed in both cardiac and skeletal muscle. 4.1R is a component of the contractile apparatus. It is also associated with dystrophin at the sarcolemma in skeletal myofibers. However, the expression and function of 4.1R during myogenesis have not been characterized. We now report that 4.1R expression increases during C2C12 myoblast differentiation into myotubes. Depletion of 4.1R impairs skeletal muscle differentiation, and is accompanied by a decrease in the levels of myosin heavy and light chains and caveolin-3...
October 25, 2016: Journal of Biological Chemistry
Xing Liu, Xiaolian Cai, Bo Hu, Zhichao Mei, Dawei Zhang, Gang Ouyang, Jing Wang, Wei Zhang, Wuhan Xiao
FOXO3a, a member of the forkhead homeobox type O (FOXO) family of transcriptional factors, regulates cell survival in response to DNA damage, caloric restriction, and oxidative stress. The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of the E3 ubiquitin ligase complex that mediates hypoxia-inducible factor-α (HIF-α) degradation under aerobic conditions, thus acting as one of the key regulators of hypoxia signaling. However, whether FOXO3a impacts cellular hypoxia stress remains unknown...
October 24, 2016: Journal of Biological Chemistry
Steffen Grampp, James L Platt, Victoria Lauer, Rafik Salama, Franziska Kranz, Viviana K Neumann, Sven Wach, Christine Stöhr, Arndt Hartmann, Kai-Uwe Eckardt, Peter J Ratcliffe, David R Mole, Johannes Schödel
Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel-Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins...
October 24, 2016: Nature Communications
Brian Reed Curtis, Eric E Curtis
No abstract text is available yet for this article.
October 21, 2016: Internal and Emergency Medicine
Stefan J Lang, Bertan Cakir, Charlotte Evers, Franziska Ludwig, Clemens A K Lange, Hansjürgen T Agostini
BACKGROUND AND OBJECTIVE: The introduction of optical coherence tomography angiography (OCTA) provides new insights into the retinal vasculature. The aim of this study was to explore the value of OCTA in imaging retinal hemangioblastomas and monitoring laser treatment in patients with von Hippel-Lindau (VHL) disease. PATIENTS AND METHODS: Ten eyes of 10 patients with VHL disease were included in this retrospective case series. All patients underwent complete ophthalmological work-up including OCTA for retinal and optic nerve head hemangioblastoma...
October 1, 2016: Ophthalmic Surgery, Lasers & Imaging Retina
Georgios Z Papadakis, Corina Millo, Samira M Sadowski, Ulas Bagci, Nicholas J Patronas
Renal and pancreatic cysts and tumors are the most common visceral manifestations of von Hippel-Lindau (VHL) disease, a heritable multisystem cancer syndrome characterized by development of a variety of malignant and benign tumors. We report a case of a VHL patient with multiple renal cystic and complex cystic/solid lesions. The patient underwent Ga-DOTA-TATE-PET/CT showing intensely increased activity by a solid lesion which demonstrated enhancement on both CT and MRI scans, raising high suspicion for malignancy...
October 5, 2016: Clinical Nuclear Medicine
Michael J Feldman, Saman Sizdahkhani, Nancy A Edwards, Marsha J Merrill, Abhik Ray-Chaudhury, Zhengping Zhuang, Russell R Lonser, Edward H Oldfield, Prashant Chittiboina
von Hippel-Lindau (VHL) patients develop multiple central nervous system hemangioblastomas (HB). Some HBs become symptomatic with exponential growth or cyst formation following long periods of quiescence. Understanding the factors underlying growth in hemangioblastoma may lead to better strategies to arrest or prevent tumor growth. In 5 VHL patients, we resected quiescent hemangioblastomas (Q-HB) that were en-route during surgical access to symptomatic hemangioblastomas (S-HB), for matched tumor analysis. Quantitative reverse transcriptase analysis demonstrated a 2-fold increase in EPO expression in all S-HB, while 4/5 showed either Hypoxia Inducible Factor-1α or 2α upregulation...
October 17, 2016: Scientific Reports
Christos Panayi, Nagui Antoun, Richard Sandford
A 44-year-old woman with a history of von Hippel-Lindau (VHL) disease, a rare inherited neoplasia syndrome, presented acutely to hospital with a productive cough, symptoms of respiratory tract infection and odynophagia (painful swallowing). A chest X-ray confirmed right-sided pneumonia. Investigation of the persistent odynophagia using barium swallow revealed aspiration of the contrast into the lungs and suggested a neurological cause for her chest infection. Clinical assessment and speech and language therapy confirmed a pseudobulbar palsy...
October 13, 2016: BMJ Case Reports
Hannah L Bader, Tien Hsu
BACKGROUND: Mutations in the tumor suppressor gene von Hippel-Lindau (VHL) underlie a hereditary cancer syndrome-VHL disease-and are also frequently observed in sporadic renal cell carcinoma of the clear cell type (ccRCC). VHL disease is characterized by malignant and benign tumors in a few specific tissues, including ccRCC, hemangioblastoma and pheochromocytoma. The etiology of these tumors remains unresolved. METHODS: Conditional inactivation of the VHL gene in mouse (Vhlh) was generated to examine the pathophysiological role of the VHL gene function...
October 12, 2016: BMC Cancer
Sumanta K Pal, Harry A Drabkin, James A Reeves, John D Hainsworth, Susan E Hazel, Dario A Paggiarino, Jon Wojciak, Gary Woodnutt, Rupal S Bhatt
BACKGROUND: 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. METHODS: Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent...
October 11, 2016: Cancer
M Fähling, S Mathia, J Scheidl, R Abramovitch, Z Milman, A Paliege, H Peters, P B Persson, S N Heyman, C Rosenberger
AIM: Cyclosporin A (CsA) causes renal toxicity. The underlying mechanisms are incompletely understood, but may involve renal hypoxia and hypoxia-inducible factors (Hifs). We sought for hypoxia and Hif in mouse kidneys with CsA-induced toxicity, assessed their time course, Hif-mediated responses and the impact of interventional Hif upregulation. METHODS: Mice received CsA or its solvent cremophore for up to 6 weeks. Low salt diet (Na(+) ↓) was given in combination with CsA to enhance toxicity...
September 30, 2016: Acta Physiologica
Jung Hwa Lim, Hee Won Shin, Kyung-Sook Chung, Nam-Soon Kim, Ju Hee Kim, Hong-Ryul Jung, Dong-Soo Im, Cho-Rok Jung
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...
2016: PloS One
Andres A Urrutia, Aqeela Afzal, Jacob Nelson, Olena Davidoff, Kenneth W Gross, Volker H Haase
A classic response to systemic hypoxia is the increased production of red blood cells due to hypoxia-inducible factor (HIF)-mediated induction of erythropoietin (EPO). EPO is a glycoprotein hormone that is essential for normal erythropoiesis and is predominantly synthesized by peritubular renal interstitial fibroblast-like cells, which express cellular markers characteristic of neuronal cells and pericytes. To investigate whether the ability to synthesize EPO is a general functional feature of pericytes, we used conditional gene targeting to examine the von Hippel-Lindau (VHL) / prolyl-4-hydroxylase domain (PHD) / HIF axis in cell expressing neural glial antigen 2 (NG2), a known molecular marker of pericytes in multiple organs...
September 28, 2016: Blood
Suraj Peri, Elena Caretti, Rossella Tricarico, Karthik Devarajan, Mitchell Cheung, Eleonora Sementino, Craig W Menges, Emmanuelle Nicolas, Lisa A Vanderveer, Sharon Howard, Peggy Conrad, James A Crowell, Kerry S Campbell, Eric A Ross, Andrew K Godwin, Anthony T Yeung, Margie L Clapper, Robert G Uzzo, Elizabeth P Henske, Christopher J Ricketts, Cathy D Vocke, W Marston Linehan, Joseph R Testa, Alfonso Bellacosa, Levy Kopelovich, Alfred G Knudson
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)...
September 22, 2016: Oncotarget
Koen A van Overdam, Tom Missotten, Emine Kilic, Leigh H Spielberg
PURPOSE: To evaluate the clinical course after early surgical treatment with excision of retinal hemangioblastomas (RHs) before development of major complications. METHODS: 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...
September 29, 2016: Acta Ophthalmologica
Roland Darr, Joan Nambuba, Jaydira Del Rivero, Ingo Janssen, Maria Merino, Milena Todorovic, Bela Balint, Ivana Jochmanova, Josef T Prchal, Ronald Lechan, Arthur S Tischler, Vera Popovic, Dragana Miljic, Karen T Adams, F Ryan Prall, Alexander Ling, Meredith R Golomb, Michael Ferguson, Naris Nilubol, Clara Chen, Emily Chew, David Taieb, Constantine A Stratakis, Antonio Fojo, Chunzhang Yang, Electron Kebebew, Zhengping Zhuang, Karel Pacak
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...
September 27, 2016: Endocrine-related Cancer
K Santhirasegaram, K Wehrmann, N Feucht, C P Lohmann, M Maier
: The case report of a 35-year-old woman suffering from Hippel-Lindau syndrome (VHL) with retinal hemangiomas is presented. The patient developed macular edema with loss of vision and metamorphopsia. Laser treatment of hemangiomas improved the clinical picture. Hemangiomas were visualized using fluorescein angiography and optical coherence angiography. To our knowledge we describe retinal hemangiomas in VHL disease with the optical coherence tomographical angiography (OCTA) for the first time...
September 26, 2016: Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft
Giada Zurlo, Jianping Guo, Mamoru Takada, Wenyi Wei, Qing Zhang
Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, lysine, asparagine, aspartate and histidine. A classical example of this modification is hypoxia inducible factor alpha (HIF-α) prolyl hydroxylation, which affects HIF-α protein stability via the Von-Hippel Lindau (VHL) tumor suppressor pathway, a Cullin 2-based E3 ligase adaptor protein frequently mutated in kidney cancer...
September 20, 2016: Biochimica et Biophysica Acta
Kei Satoh, Samira M Sadowski, William Dieckmann, Martha Quezado, Naris Nilubol, Electron Kebebew, Dhaval Patel
BACKGROUND: Approximately 8-17 % of patients with von Hippel-Lindau (VHL) syndrome develop pancreatic neuroendocrine tumors (PNETs), with 11-20 % developing metastases. Tumor grade is predictive of prognosis. OBJECTIVE: The aim of this study was to determine if preoperative metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were associated with metastatic disease and tumor grade. METHODS: Sixty-two patients with VHL-associated PNETs prospectively underwent (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT)...
September 15, 2016: Annals of Surgical Oncology
Eli M Wallace, James P Rizzi, Guangzhou Han, Paul M Wehn, Zhaodan Cao, Xinlin Du, Tzuling Cheng, Robert M Czerwinski, Darryl D Dixon, Barry S Goggin, Jonas A Grina, Megan M Halfmann, Melissa A Maddie, Sarah R Olive, Stephen T Schlachter, Huiling Tan, Bin Wang, Keshi Wang, Shanhai Xie, Rui Xu, Hanbiao Yang, John A Josey
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...
September 15, 2016: Cancer Research
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