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https://www.readbyqxmd.com/read/29671342/human-articular-chondrocytes-retain-their-phenotype-in-sustained-hypoxia-while-normoxia-promotes-their-immunomodulatory-potential
#1
Claire Mennan, John Garcia, Helen McCarthy, Sharon Owen, Jade Perry, Karina Wright, Robin Banerjee, James B Richardson, Sally Roberts
Objective To assess the phenotype of human articular chondrocytes cultured in normoxia (21% O2 ) or continuous hypoxia (2% O2 ). Design Chondrocytes were extracted from patients undergoing total knee replacement ( n = 5) and cultured in ~21% (normoxic chondrocytes, NC) and 2% (hypoxic chondrocytes, HC) oxygen in both monolayer and 3-dimensional (3D) pellet culture and compared with freshly isolated chondrocytes (FC). Cells were assessed by flow cytometry for markers indicative of mesenchymal stromal cells (MSCs), chondrogenic-potency and dedifferentiation...
April 1, 2018: Cartilage
https://www.readbyqxmd.com/read/29621549/osh6p-a-homologue-of-the-oxysterol-binding-protein-is-involved-in-production-of-functional-cytochrome-p450-belonging-to-cyp52-family-in-n-alkane-assimilating-yeast-yarrowia-lipolytica
#2
Ryo Iwama, Mariho Hara, Aya Mizuike, Hiroyuki Horiuchi, Ryouichi Fukuda
In this study, we investigated the role of OSH6, which encodes a homolog of the oxysterol-binding protein, in the assimilation of n-alkanes in the yeast Yarrowia lipolytica. The deletion mutant of OSH6 showed growth defects on n-alkanes of 10-16 carbons. In the deletion mutant, production of the functional cytochrome P450 was not observed. However, transcription of ALK1, encoding a major P450 belonging to the CYP52 family that plays a critical role in n-alkane hydroxylation, and further translation of its transcript were noted in the deletion mutant as well as in the wild-type strain...
April 2, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29593101/thalidomide-reduces-hemorrhage-of-brain-arteriovenous-malformations-in-a-mouse-model
#3
Wan Zhu, Wanqiu Chen, Dingquan Zou, Liang Wang, Chen Bao, Lei Zhan, Daniel Saw, Sen Wang, Ethan Winkler, Zhengxi Li, Meng Zhang, Fanxia Shen, Sonali Shaligram, Michael Lawton, Hua Su
BACKGROUND AND PURPOSE: Brain arteriovenous malformation (bAVM) is an important risk factor for intracranial hemorrhage. Current treatments for bAVM are all associated with considerable risks. There is no safe method to prevent bAVM hemorrhage. Thalidomide reduces nose bleeding in patients with hereditary hemorrhagic telangiectasia, an inherited disorder characterized by vascular malformations. In this study, we tested whether thalidomide and its less toxic analog, lenalidomide, reduce bAVM hemorrhage using a mouse model...
March 28, 2018: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/29580923/endoglin-pathway-genetic-variation-in-preeclampsia-a-validation-study-in-norwegian-and-latina-cohorts
#4
Mandy J Schmella, James M Roberts, Yvette P Conley, Dianxu Ren, Gro L Storvold, Sue A Ingles, Melissa L Wilson, Anne Catherine Staff, Carl A Hubel
OBJECTIVE: The purpose of this study was to validate our previous genetic association findings related to the endoglin (ENG) pathway from an American Caucasian preeclampsia cohort in independent preeclampsia cohorts. We also sought to explore the ENG pathway for new genetic associations in these independent cohorts. STUDY DESIGN: We used a tagging single nucleotide (tSNP) approach to assess genetic variability across five ENG pathway genes (ENG, TGFβ1, TGFβR1, ALK1, and TGFβR2) in a Caucasian cohort from Norway (n = 77 preeclampsia cases & n = 63 normotensive controls) and a White Hispanic cohort from Southern California (n = 69 preeclampsia cases & n = 106 normotensive controls)...
November 15, 2017: Pregnancy Hypertension
https://www.readbyqxmd.com/read/29535220/inhibin-is-a-novel-paracrine-factor-for-tumor-angiogenesis-and-metastasis
#5
Priyanka Singh, Laura M Jenkins, Ben Horst, Victoria Alers, Shrikant Pradhan, Prabhjot Kaur, Tapasya Srivastava, Nadine Hempel, Balázs Győrffy, Eugenia V Broude, Nam Y Lee, Karthikeyan Mythreye
Inhibin is a heterodimeric TGF-β family ligand that is expressed in many cancers and is a selective biomarker for ovarian cancers, however its tumor-specific functions remain unknown. Here we demonstrate that the α subunit of Inhibin (INHA), which is critical for the functionality of dimeric Inhibin A/B, correlates with microvessel density (MVD) in human ovarian tissues and xenografts and is predictive of poor clinical outcomes in multiple cancers. We demonstrate that Inhibin regulated angiogenesis is necessary for metastasis...
March 13, 2018: Cancer Research
https://www.readbyqxmd.com/read/29514107/a-case-report-of-atypical-spitz-tumor-harboring-a-novel-mlph-alk-gene-fusion-with-discordant-alk-immunohistochemistry-results
#6
Masakazu Fujimoto, Yuki Togashi, Ibu Matsuzaki, Satoko Baba, Kengo Takeuchi, Yutaka Inaba, Masatoshi Jinnin, Shin-Ichi Murata
Frequent kinase fusions have been reported in spitzoid neoplasms, approximately 10% of which involve ALK rearrangements. Herein, we report a case of atypical Spitz tumour (AST) with a novel MLPH-ALK fusion, which has not been previously reported to contribute to cancer development. The tumour was detected in the right arm of a 40-year-old woman. The novel ALK fusion was identified by a 5'-rapid amplification of cDNA ends-based system optimised for formalin-fixed paraffin-embedded tissue. Initially, ALK expression was detected by immunohistochemistry (IHC) using 5A4 antibodies for both sensitive and conventional polymer detection method...
March 4, 2018: Human Pathology
https://www.readbyqxmd.com/read/29478089/serum-glucocorticoid-regulated-kinase-1-as-a-novel-transcriptional-target-of-bone-morphogenetic-protein-alk1-receptor-signaling-in-vascular-endothelial-cells
#7
Mutsumi Araki, Takashi Hisamitsu, Yumi Kinugasa-Katayama, Toru Tanaka, Yukihiro Harada, Shu Nakao, Sanshiro Hanada, Shuhei Ishii, Masahide Fujita, Teruhisa Kawamura, Yoshihiko Saito, Koichi Nishiyama, Yusuke Watanabe, Osamu Nakagawa
Bone morphogenetic protein 9 (BMP9)/BMP10-ALK1 receptor signaling is essential for endothelial differentiation and vascular morphogenesis. Mutations in ALK1/ACVRL1 and other signal-related genes are implicated in human vascular diseases, and the Alk1/Acvrl1 deletion in mice causes severe impairment of vascular formation and embryonic lethality. In the microarray screen to search for novel downstream genes of ALK1 signaling, we found that the mRNA and protein expression of serum/glucocorticoid-regulated kinase 1 (SGK1) was rapidly up-regulated by the BMP9 stimulation of cultured human endothelial cells...
February 24, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29460088/vascular-deficiency-of-smad4-causes-arteriovenous-malformations-a-mouse-model-of-hereditary-hemorrhagic-telangiectasia
#8
Angela M Crist, Amanda R Lee, Nehal R Patel, Dawn E Westhoff, Stryder M Meadows
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that leads to abnormal connections between arteries and veins termed arteriovenous malformations (AVM). Mutations in TGFβ pathway members ALK1, ENG and SMAD4 lead to HHT. However, a Smad4 mouse model of HHT does not currently exist. We aimed to create and characterize a Smad4 endothelial cell (EC)-specific, inducible knockout mouse (Smad4f/f ;Cdh5-CreERT2 ) that could be used to study AVM development in HHT. We found that postnatal ablation of Smad4 caused various vascular defects, including the formation of distinct AVMs in the neonate retina...
February 19, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29449337/alk1-activin-receptor-like-kinase-1-loss-results-in-vascular-hyperplasia-in-mice-and-humans-through-pi3k-phosphatidylinositol-3-kinase-activation
#9
Elisenda Alsina-Sanchís, Yaiza García-Ibáñez, Ana M Figueiredo, Carla Riera-Domingo, Agnès Figueras, Xavier Matias-Guiu, Oriol Casanovas, Luisa M Botella, Miquel A Pujana, Antoni Riera-Mestre, Mariona Graupera, Francesc Viñals
OBJECTIVE: ALK1 (activin-receptor like kinase 1) is an endothelial cell-restricted receptor with high affinity for BMP (bone morphogenetic protein) 9 TGF-β (transforming growth factor-β) family member. Loss-of-function mutations in ALK1 cause a subtype of hereditary hemorrhagic telangiectasia-a rare disease characterized by vasculature malformations. Therapeutic strategies are aimed at reducing potential complications because of vascular malformations, but currently, there is no curative treatment for hereditary hemorrhagic telangiectasia...
February 15, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29438260/endothelial-cell-biology-of-endoglin-in-hereditary-hemorrhagic-telangiectasia
#10
Wade W Sugden, Arndt F Siekmann
PURPOSE OF REVIEW: Mutations in the Endoglin (Eng) gene, an auxiliary receptor in the transforming growth factor beta (TGFβ)-superfamily signaling pathway, are responsible for the human vascular disorder hereditary hemorrhagic telangiectasia (HHT) type 1, characterized in part by blood vessel enlargement. A growing body of work has uncovered an autonomous role for Eng in endothelial cells. We will highlight the influence of Eng on distinct cellular behaviors, such as migration and shape control, which are ultimately important for the assignment of proper blood vessel diameters...
February 12, 2018: Current Opinion in Hematology
https://www.readbyqxmd.com/read/29367682/activation-of-activin-receptor-like-kinases-curbs-mucosal-inflammation-and-proliferation-in-chronic-rhinosinusitis-with-nasal-polyps
#11
Lotta Tengroth, Julia Arebro, Olivia Larsson, Claus Bachert, Susanna Kumlien Georén, Lars-Olaf Cardell
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a widespread disease causing obstruction of the nasal cavity. Its cause remains unclear. The transforming growth-factor beta (TGF-β) superfamily and their receptors, termed Activin receptor-like kinases (ALKs), have recently been suggested to play a role in local airway inflammation, but have so far not been evaluated in human nasal epithelial cells (HNECs) from CRSwNP patients. We demonstrated that ALK1-7 were expressed in the nasal polyp epithelium, and the expression of ALK1-6 was markedly elevated in polyps compared to nasal mucosa from healthy controls...
January 24, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29357852/admp-controls-the-size-of-spemann-s-organizer-through-a-network-of-self-regulating-expansion-restriction-signals
#12
Avi Leibovich, Hadas Kot-Leibovich, Danny Ben-Zvi, Abraham Fainsod
BACKGROUND: The bone morphogenetic protein (BMP) signaling gradient is central for dorsoventral patterning in amphibian embryos. This gradient is established through the interaction of several BMPs and BMP antagonists and modulators, some secreted by Spemann's organizer, a cluster of cells coordinating embryonic development. Anti-dorsalizing morphogenetic protein (ADMP), a BMP-like transforming growth factor beta ligand, negatively affects the formation of the organizer, although it is robustly expressed within the organizer itself...
January 22, 2018: BMC Biology
https://www.readbyqxmd.com/read/29350394/genetic-variants-in-the-polish-population-of-patients-with-pulmonary-arterial-hypertension-sequencing-of-bmpr2-alk1-and-eng-genes
#13
Barbara Uznańska-Loch, Kamil Wikło, Dominika Kulczycka-Wojdala, Bożena Szymańska, Łukasz Chrzanowski, Karina Wierzbowska-Drabik, Ewa Trzos, Jarosław Damian Kasprzak, Małgorzata Kurpesa
BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with a very serious prognosis. It seems that mutations in genes related to the transforming growth factor-beta signaling pathway are often related to the development of the disease. There was no study in Polish population that would cover this problem. AIM: To screen for genetic mutations in Polish cohort of patients with pulmonary hypertension, especially with idiopathic PAH, treated in a single hospital in Poland...
January 19, 2018: Kardiologia Polska
https://www.readbyqxmd.com/read/29305977/functional-analysis-of-a-novel-eng-variant-in-a-patient-with-hereditary-hemorrhagic-telangiectasia-hht-identifies-a-new-sp1-binding-site
#14
Sara Plumitallo, Lidia Ruiz-Llorente, Carmen Langa, Jacopo Morini, Gabriele Babini, Donata Cappelletti, Laura Scelsi, Alessandra Greco, Cesare Danesino, Carmelo Bernabeu, Carla Olivieri
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disease, with an autosomal dominant inheritance and a worldwide incidence of about 1: 5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG or ACVRL1, which code for ENDOGLIN and Activin A Receptor Type II-Like Kinase 1 (ALK1), belonging to the TGF-β/BMP signalling pathway. Typical HHT clinical features are mucocutaneous telangiectases, arteriovenous malformations, spontaneous and recurrent epistaxis, as well as gastrointestinal bleedings...
March 20, 2018: Gene
https://www.readbyqxmd.com/read/29259971/alk1fc-suppresses-the-human-prostate-cancer-growth-in-in-vitro-and-in-vivo-preclinical-models
#15
Letizia Astrologo, Eugenio Zoni, Sofia Karkampouna, Peter C Gray, Irena Klima, Joël Grosjean, Marie J Goumans, Lukas J A C Hawinkels, Gabri van der Pluijm, Martin Spahn, George N Thalmann, Peter Ten Dijke, Marianna Kruithof-de Julio
Prostate cancer is the second most common cancer in men and lethality is normally associated with the consequences of metastasis rather than the primary tumor. Therefore, targeting the molecular pathways that underlie dissemination of primary tumor cells and the formation of metastases has a great clinical value. Bone morphogenetic proteins (BMPs) play a critical role in tumor progression and this study focuses on the role of BMP9- A ctivin receptor- L ike K inase 1 and 2 (ALK1 and ALK2) axis in prostate cancer...
2017: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/28973643/tacrolimus-rescues-the-signaling-and-gene-expression-signature-of-endothelial-alk1-loss-of-function-and-improves-hht-vascular-pathology
#16
Santiago Ruiz, Pallavi Chandakkar, Haitian Zhao, Julien Papoin, Prodyot K Chatterjee, Erica Christen, Christine N Metz, Lionel Blanc, Fabien Campagne, Philippe Marambaud
Hereditary hemorrhagic telangiectasia (HHT) is a highly debilitating and life-threatening genetic vascular disorder arising from endothelial cell (EC) proliferation and hypervascularization, for which no cure exists. Because HHT is caused by loss-of-function mutations in bone morphogenetic protein 9 (BMP9)-ALK1-Smad1/5/8 signaling, interventions aimed at activating this pathway are of therapeutic value. We interrogated the whole-transcriptome in human umbilical vein ECs (HUVECs) and found that ALK1 signaling inhibition was associated with a specific pro-angiogenic gene expression signature, which included a significant elevation of DLL4 expression...
December 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28916158/pyrrolizines-design-synthesis-anticancer-evaluation-and-investigation-of-the-potential-mechanism-of-action
#17
Ahmed M Gouda, Ahmed H Abdelazeem, Hany A Omar, Ashraf N Abdalla, Mohammed A S Abourehab, Hamed I Ali
A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B cancer cell lines. Compound 10c was the most active against MCF-7 with IC50 value of 4.72µM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and apoptosis induction were suggested as potential molecular mechanisms for the anticancer activity of the novel pyrrolizines based on their structural features...
August 24, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28910869/-lymphomatoid-papulosis-a-clinicopathologic-analysis-and-whole-exome-sequencing
#18
T T Wang, Y Xie, L Li, L Wang
Objective: To study the clinicopathologic characteristics and immunophenotype of lymphomatoid papulosis(LyP), followed by exon mutation analysis with focus on gene mutations involved in apoptosis pathway and other possible pathogenic genes. Methods: Clinical data analysis and immunohistochemical staining were carried out in 20 cases of LyP. Whole exome sequencing technology was employed in 2 cases of type C of LyP. Results: Of the 20 cases, there were 9 males and 11 females with a median age of 28.6 years. Nineteen patients presented with multiple papules and nodules, and one case presented with only one tumor nodule...
September 8, 2017: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/28871312/alk1-signaling-in-development-and-disease-new-paradigms
#19
REVIEW
Beth L Roman, Andrew P Hinck
Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels...
December 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28820968/reduced-activin-receptor-like-kinase-1-activity-promotes-cardiac-fibrosis-in-heart-failure
#20
Kevin J Morine, Xiaoying Qiao, Vikram Paruchuri, Mark J Aronovitz, Emily E Mackey, Lyanne Buiten, Jonathan Levine, Keshan Ughreja, Prerna Nepali, Robert M Blanton, S Paul Oh, Richard H Karas, Navin K Kapur
INTRODUCTION: Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. HYPOTHESIS: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. METHODS AND RESULTS: In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure...
July 18, 2017: Cardiovascular Pathology: the Official Journal of the Society for Cardiovascular Pathology
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