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https://www.readbyqxmd.com/read/29880487/bmp-bone-morphogenetic-protein-9-alk1-activin-like-kinase-receptor-type-i-signaling-prevents-hyperglycemia-induced-vascular-permeability
#1
Naoufal Akla, Claire Viallard, Natalija Popovic, Cindy Lora Gil, Przemyslaw Sapieha, Bruno Larrivée
OBJECTIVE: Diabetic macular edema is a major cause of visual impairment in diabetic retinopathy. It is caused by blood-retinal barrier breakdown that leads to vascular hyperpermeability. Current therapeutic approaches consist of retinal photocoagulation or targeting VEGF (vascular endothelial growth factor) to limit vascular leakage. However, long-term intravitreal use of anti-VEGFs is associated with potential safety issue, and the identification of alternative regulators of vascular permeability may provide safer therapeutic options...
June 7, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29877921/alk-expression-in-angiomatoid-fibrous-histiocytoma-a-potential-diagnostic-pitfall
#2
Alison L Cheah, Youran Zou, Christopher Lanigan, Steven D Billings, Brian P Rubin, Jason L Hornick, John R Goldblum
We recently encountered a case of primary pulmonary angiomatoid fibrous histiocytoma (AFH), which was initially misdiagnosed as inflammatory myofibroblastic tumor (IMT) based in part on anaplastic lymphoma kinase (ALK) expression by immunohistochemistry (IHC). Prompted by this experience, we evaluated ALK expression in 11 AFH, 15 IMT, and 11 follicular dendritic cell sarcomas using 3 different antibody clones: D5F3, 5A4, and ALK1. ALK IHC positive cases were analyzed with fluorescence in situ hybridization (FISH) using dual color ALK break-apart probe kit...
June 5, 2018: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29843236/immunohistochemical-analysis-of-activin-receptor-like-kinase-1-acvrl1-alk1-expression-in-the-rat-and-human-hippocampus-decline-in-ca3-during-progression-of-alzheimer-s-disease
#3
Stephanie L Adams, Laurent Benayoun, Kathy Tilton, Tiffany J Mellott, Sudha Seshadri, Jan Krzysztof Blusztajn, Ivana Delalle
The pathophysiology of Alzheimer's disease (AD) includes signaling defects mediated by the transforming growth factor β-bone morphogenetic protein-growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields...
May 18, 2018: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/29794143/hereditary-hemorrhagic-telangiectasia-diagnosis-and-management-from-the-hematologist-s-perspective
#4
Athena Kritharis, Hanny Al-Samkari, David J Kuter
Hereditary Hemorrhagic Telangiectasia, also known as Osler-Weber-Rendu syndrome, is an autosomal dominant disorder that causes abnormal blood vessel formation. The diagnosis of hereditary hemorrhagic telangiectasia is clinical, based on the Curacao criteria. Genetic mutations that have been identified include ENG, ACVRL1/ALK1, and MADH4/SMAD4, among others. Patients with hereditary hemorrhagic telangiectasia may have telangiectasias and arteriovenous malformations in various organs and suffer from many complications including bleeding, anemia, iron deficiency, and high output heart failure...
May 24, 2018: Haematologica
https://www.readbyqxmd.com/read/29789425/a-heterodimer-formed-by-bone-morphogenetic-protein-9-bmp9-and-bmp10-provides-most-bmp-biological-activity-in-plasma
#5
Emmanuelle Tillet, Marie Ouarné, Agnès Desroches-Castan, Christine Mallet, Mariela Subileau, Robin Didier, Anna Lioutsko, Guillaume Belthier, Jean-Jacques Feige, Sabine Bailly
Bone morphogenetic protein 9 (BMP9) and BMP10 are the two high-affinity ligands for the endothelial receptor activin receptor-like kinase 1 (ALK1) and are key regulators of vascular remodeling. They are both present in the blood, but their respective biological activities are still a matter of debate. The aim of the present work was to characterize their circulating forms to better understand how their activities are regulated in vivo. First, by cotransfecting BMP9 and BMP10, we found that both can form a disulfide-bonded heterodimer in vitro and that this heterodimer is functional on endothelial cells via ALK1...
May 22, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29753378/microrna-140-suppresses-human-chondrocytes-hypertrophy-by-targeting-smad1-and-controlling-the-bone-morphogenetic-protein-pathway-in-osteoarthritis
#6
Canfeng Li, Qinshen Hu, Zhuo Chen, Bin Shen, Jing Yang, Pengde Kang, Zongke Zhou, Fuxing Pei
BACKGROUND: This study aimed to investigate the expression levels and relationship of bone morphogenetic proteins (BMPs) signaling molecules and microRNA-140 (miR-140) in human osteoarthritis (OA) chondrocytes. MATERIALS AND METHODS: Different stage chondrocytes (normal cartilage, mid-stage OA and advanced-stage OA) were isolated from cartilage samples according to Kellgren and Lawrence criteria. The effect of miR-140 on BMPs signaling was evaluated by transfecting miR-140 mimic or inhibitor into chondrocytes...
May 2018: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/29751820/physical-interaction-of-stat1-isoforms-with-tgf-%C3%AE-receptors-leads-to-functional-crosstalk-between-two-signaling-pathways-in-epithelial-ovarian-cancer
#7
Xiaoling Tian, Wencai Guan, Lingyun Zhang, Wenwen Sun, Daibing Zhou, Qunbo Lin, Weimin Ren, Lubna Nadeem, Guoxiong Xu
BACKGROUND: The signal transducer and activator of transcription (STAT) and transforming growth factor-β (TGF-β) signaling pathways play important roles in epithelial ovarian cancer (EOC). However, the mechanism of crosstalk between two pathways is not completely understood. METHODS: The expression of STAT1 protein was detected by tissue microarray and immunoblotting (IB). The interaction of STAT1 isoforms with TGF-β receptors was confirmed by immunoprecipitation and IB...
May 11, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29729706/tgf%C3%AE-1-mediated-pi3k-akt-and-p38-map-kinase-dependent-alternative-splicing-of-fibronectin-extra-domain-a-in-human-podocyte-culture
#8
Tarunkumar Hemraj Madne, Mark Edward Carl Dockrell
Alternative splicing is an important gene regulation process to distribute proteins in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin (Fn) protein, present in the extra cellular matrix (ECM) and a recognised marker of various pathologies. TGFβ1 has been shown to induce alternative splicing of EDA+Fn in many cell types. Podocytes are spectacular cell type and play a key role in filtration and synthesise ECM proteins in renal physiology and pathology...
April 30, 2018: Cellular and Molecular Biology
https://www.readbyqxmd.com/read/29671342/human-articular-chondrocytes-retain-their-phenotype-in-sustained-hypoxia-while-normoxia-promotes-their-immunomodulatory-potential
#9
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
#10
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...
May 23, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29593101/thalidomide-reduces-hemorrhage-of-brain-arteriovenous-malformations-in-a-mouse-model
#11
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...
May 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
#12
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
#13
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
#14
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
#15
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...
May 2018: Angiogenesis
https://www.readbyqxmd.com/read/29460088/vascular-deficiency-of-smad4-causes-arteriovenous-malformations-a-mouse-model-of-hereditary-hemorrhagic-telangiectasia
#16
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...
May 2018: Angiogenesis
https://www.readbyqxmd.com/read/29449337/alk1-loss-results-in-vascular-hyperplasia-in-mice-and-humans-through-pi3k-activation
#17
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...
May 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29438260/endothelial-cell-biology-of-endoglin-in-hereditary-hemorrhagic-telangiectasia
#18
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...
May 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
#19
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
#20
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
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