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https://www.readbyqxmd.com/read/29332224/phosphatidylserine-exposing-blood-and-endothelial-cells-contribute-to-the-hypercoagulable-state-in-essential-thrombocythemia-patients
#1
Dongxia Tong, Muxin Yu, Li Guo, Tao Li, Jihe Li, Valerie A Novakovic, Zengxiang Dong, Ye Tian, Junjie Kou, Yayan Bi, Jinghua Wang, Jin Zhou, Jialan Shi
The mechanisms of thrombogenicity in essential thrombocythemia (ET) are complex and not well defined. Our objective was to explore whether phosphatidylserine (PS) exposure on blood cells and endothelial cells (ECs) can account for the increased thrombosis and distinct thrombotic risks among mutational subtypes in ET. Using flow cytometry and confocal microscopy, we found that the levels of PS-exposing erythrocytes, platelets, leukocytes, and serum-cultured ECs were significantly higher in each ET group [JAK2, CALR, and triple-negative (TN) (all P < 0...
January 13, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29323541/development-of-a-targeted-next-generation-sequencing-assay-to-detect-diagnostically-relevant-mutations-of-jak2-calr-and-mpl-in-myeloproliferative-neoplasms
#2
Thomas Frawley, Cathal P O'Brien, Eibhlin Conneally, Elisabeth Vandenberghe, Melanie Percy, Stephen E Langabeer, Karl Haslam
BACKGROUND: The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), consisting of polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a heterogeneous group of neoplasms that harbor driver mutations in the JAK2, CALR, and MPL genes. The detection of these mutations has been incorporated into the recent World Health Organization (WHO) diagnostic criteria for MPN. Given a pressing clinical need to screen for these mutations in a routine diagnostic setting, a targeted next-generation sequencing (NGS) assay for the detection of MPN-associated mutations located in JAK2 exon 14, JAK2 exon 12, CALR exon 9, and MPL exon 10 was developed to provide a single platform alternative to reflexive, stepwise diagnostic algorithms...
January 11, 2018: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/29321553/prediction-of-co-expression-genes-and-integrative-analysis-of-gene-microarray-and-proteomics-profile-of-keshan-disease
#3
Sen Wang, Rui Yan, Bin Wang, Peiru Du, Wuhong Tan, Mikko J Lammi, Xiong Guo
Keshan disease (KD) is a kind of endemic cardiomyopathy which has a high mortality. However, molecular mechanism in the pathogenesis of KD remains poorly understood. Serum samples were collected from 112 KD patients and 112 normal controls. Gene microarray was used to screen differently expressed genes. Genevestigator was applied to forecast co-expression genes of significant gene. iTRAQ proteomics analysis was used to verify significant genes and their co-expression genes. GO, COG, IPA and STRING were applied to undertake function categorization, pathway and network analysis separately...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29320819/molecular-and-biochemical-characterization-of-opisthorchis-viverrini-calreticulin
#4
Wanlapa Chaibangyang, Amornrat Geadkaew-Krenc, Suksiri Vichasri-Grams, Smarn Tesana, Rudi Grams
Calreticulin (CALR), a multifunctional protein thoroughly researched in mammals, comprises N-, P-, and C-domain and has roles in calcium homeostasis, chaperoning, clearance of apoptotic cells, cell adhesion, and also angiogenesis. In this study, the spatial and temporal expression patterns of the Opisthorchis viverrini CALR gene were analyzed, and calcium-binding and chaperoning properties of recombinant O. viverrini CALR (OvCALR) investigated. OvCALR mRNA was detected from the newly excysted juvenile to the mature parasite by RT-PCR while specific antibodies showed a wide distribution of the protein...
December 2017: Korean Journal of Parasitology
https://www.readbyqxmd.com/read/29316719/calbindin-d28k-immunoreactivity-in-human-enteric-neurons
#5
Katharina Zetzmann, Johanna Strehl, Carol Geppert, Stefanie Kuerten, Samir Jabari, Axel Brehmer
Calbindin (CALB) is well established as immunohistochemical marker for intrinsic primary afferent neurons in the guinea pig gut. Its expression by numerous human enteric neurons has been demonstrated but little is known about particular types of neurons immunoreactive for CALB. Here we investigated small and large intestinal wholemount sets of 26 tumor patients in order to evaluate (1) the proportion of CALB⁺ neurons in the total neuron population, (2) the colocalization of CALB with calretinin (CALR), somatostatin (SOM) and vasoactive intestinal peptide (VIP) and (3) the morphology of CALB+ neurons...
January 8, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29306106/quantitative-assessment-of-jak2-v617f-and-calr-mutations-in-philadelphia-negative-myeloproliferative-neoplasms
#6
Ambrus Gángó, Réka Mózes, Zsófia Boha, Béla Kajtár, Botond Timár, Péter Attila Király, Richárd Kiss, Viktória Fésüs, Noémi Nagy, Judit Demeter, Gábor Körösmezey, Zita Borbényi, Imelda Marton, Anita Szőke, Tamás Masszi, Péter Farkas, Judit Várkonyi, Márk Plander, Éva Pósfai, Miklós Egyed, Katalin Pál, Gáspár Radványi, Aryan Hamed, Judit Csomor, András Matolcsy, Donát Alpár, Csaba Bödör
BACKGROUND: Philadelphia negative myeloproliferative neoplasms (MPNs) are characterized by frequent mutations of driver genes including JAK2, CALR and MPL. While the influence of JAK2 V617F mutant allele burden on the clinical phenotype of MPN patients is well-described, the impact of CALR mutant allele burden on clinical features needs further investigation. PATIENTS AND METHODS: Quantitative assessment of JAK2 and CALR mutations was performed on diagnostic DNA samples from 425 essential thrombocythemia (ET) and 227 primary myelofibrosis patients using real-time quantitative PCR and fragment length analysis...
January 2, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29296879/buccal-epithelial-cells-display-somatic-bone-marrow-derived-calr-mutation
#7
Scott R Gilles, Linda B Baughn, Matthew L Schomaker, Elizabeth L Courville, Andrew C Nelson, Zohar Sachs
Buccal epithelial cells harbor an MPN-associated CALR mutation in a patient with CALR-mutant essential thrombocytosis, Ph+ CML, and no germ line CALR mutation.
November 28, 2017: Blood Advances
https://www.readbyqxmd.com/read/29296819/impact-of-genomic-alterations-on-outcomes-in-myelofibrosis-patients-undergoing-jak1-2-inhibitor-therapy
#8
Jay Y Spiegel, Caroline McNamara, James A Kennedy, Tony Panzarella, Andrea Arruda, Tracy Stockley, Mahadeo Sukhai, Mariam Thomas, Justyna Bartoszko, Jenny Ho, Nancy Siddiq, Dawn Maze, Aaron Schimmer, Andre Schuh, Hassan Sibai, Karen Yee, Jamie Claudio, Rebecca Devlin, Mark D Minden, Suzanne Kamel-Reid, Vikas Gupta
In myelofibrosis (MF), driver mutations in JAK2, MPL, or CALR impact survival and progression to blast phase, with the greatest risk conferred by triple-negative status. Subclonal mutations, including mutations in high-molecular risk (HMR) genes, such as ASXL1, EZH2, IDH1/2, and SRSF2 have also been associated with inferior prognosis. However, data evaluating the impact of next-generation sequencing in MF patients treated with JAK1/2 inhibitors are lacking. Using a 54-gene myeloid panel, we performed targeted sequencing on 100 MF patients treated with ruxolitinib (n = 77) or momelotinib (n = 23) and correlated mutational profiles with treatment outcomes...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29288169/defining-the-requirements-for-the-pathogenic-interaction-between-mutant-calreticulin-and-mpl-in-mpn
#9
Shannon Elf, Nouran S Abdelfattah, April J Baral, Danielle Beeson, Jeanne F Rivera, Amy Ko, Natalie Florescu, Gabriel Birrane, Edwin Chen, Ann Mullally
Mutations in calreticulin (CALR) are phenotypic drivers in the pathogenesis of myeloproliferative neoplasms (MPN). Mechanistic studies have demonstrated that mutant CALR binds to the thrombopoietin receptor MPL, and that the positive electrostatic charge of the mutant CALR C-terminus is required for mutant CALR-mediated activation of JAK-STAT signaling. Here we demonstrate that although binding between mutant CALR and MPL is required for mutant CALR to transform hematopoietic cells, binding alone is insufficient for cytokine independent growth...
December 29, 2017: Blood
https://www.readbyqxmd.com/read/29282219/mutant-calreticulin-knock-in-mice-develop-thrombocytosis-and-myelofibrosis-without-a-stem-cell-self-renewal-advantage
#10
Juan Li, Daniel Prins, Hyun Jung Park, Jacob Grinfeld, Carlos Gonzalez-Arias, Stephen Loughran, Oliver M Dovey, Thorsten Klampfl, Cavan Bennett, Tina L Hamilton, Dean C Pask, Rachel Sneade, Matthew Williams, Juliet Aungier, Cedric Ghevaert, George S Vassiliou, David G Kent, Anthony R Green
Somatic mutations in the endoplasmic reticulum chaperone calreticulin (CALR) are detected in approximately 40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). Multiple different mutations have been reported, but all result in a +1bp frame shift and generate a novel protein C-terminus. In this study, we generated a conditional mouse knock-in model of the most common CALR mutation, a 52bp deletion. The mutant novel human C-terminal sequence is integrated into the otherwise intact mouse CALR gene and results in mutant CALR expression under the control of the endogenous mouse locus...
December 27, 2017: Blood
https://www.readbyqxmd.com/read/29277359/soho-state-of-the-art-update-and-next-questions-mpn
#11
REVIEW
Prithviraj Bose, Jason Gotlib, Claire N Harrison, Srdan Verstovsek
The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29258411/calreticulin-affects-hematopoietic-stem-progenitor-cell-fate-by-impacting-erythroid-and-megakaryocytic-differentiation
#12
Simona Salati, Zelia Prudente, Elena Genovese, Valentina Pennucci, Sebastiano Rontauroli, Niccolo' Bartalucci, Carmela Mannarelli, Samantha Ruberti, Roberta Zini, Chiara Rossi, Elisa Bianchi, Paola Guglielmelli, Enrico Tagliafico, Alessandro M Vannucchi, Rossella Manfredini
Calreticulin (CALR) is a chaperone protein that localizes primarily to the endoplasmic reticulum (ER) lumen where it is responsible for the control of proper folding of neo-synthesized glycoproteins and for the retention of calcium. Recently, mutations affecting exon 9 of the CALR gene have been described in approximately 40% of patients with myeloproliferative neoplasms (MPNs). Although the role of mutated CALR in the development of MPNs has begun to be clarified, there are still no data available on the function of wild-type (WT) CALR during physiological hematopoiesis...
December 19, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/29228584/combination-of-calr-and-pdia3-is-a-potential-prognostic-biomarker-for-non-small-cell-lung-cancer
#13
Ke Wang, Hao Li, Ruo Chen, Yang Zhang, Xiu-Xuan Sun, Wan Huang, Huijie Bian, Zhi-Nan Chen
Proteomic-based approaches for biomarker discovery are promising strategies used in cancer research. In this study, we performed quantitative proteomic analysis on 16 paired samples of non-small cell lung cancer (NSCLC) and adjacent non-tumor lung tissues using label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS) to identify differentially expressed proteins. A total of 91 proteins were differentially expressed in NSCLC compared with adjacent non-tumor lung tissues among 4047 identified proteins (fold change > 1...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29226763/mipss70-mutation-enhanced-international-prognostic-score-system-for-transplantation-age-patients-with-primary-myelofibrosis
#14
Paola Guglielmelli, Terra L Lasho, Giada Rotunno, Mythri Mudireddy, Carmela Mannarelli, Maura Nicolosi, Annalisa Pacilli, Animesh Pardanani, Elisa Rumi, Vittorio Rosti, Curtis A Hanson, Francesco Mannelli, Rhett P Ketterling, Naseema Gangat, Alessandro Rambaldi, Francesco Passamonti, Giovanni Barosi, Tiziano Barbui, Mario Cazzola, Alessandro M Vannucchi, Ayalew Tefferi
Purpose To develop a prognostic system for transplantation-age patients with primary myelofibrosis (PMF) that integrates clinical, cytogenetic, and mutation data. Patients and Methods The study included 805 patients with PMF age ≤ 70 years recruited from multiple Italian centers and the Mayo Clinic (Rochester, MN), forming two independent learning and validation cohorts. A Cox multivariable model was used to select from among a list of 22 variables those that were predictive of overall survival (OS). Integrated clinical and genetic prognostic models with (MIPSS70-plus) or without (MIPSS70) cytogenetic information were developed...
December 9, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29217833/calr-mutational-status-identifies-different-disease-subtypes-of-essential-thrombocythemia-showing-distinct-expression-profiles
#15
Roberta Zini, Paola Guglielmelli, Daniela Pietra, Elisa Rumi, Chiara Rossi, Sebastiano Rontauroli, Elena Genovese, Tiziana Fanelli, Laura Calabresi, Elisa Bianchi, Simona Salati, Mario Cazzola, Enrico Tagliafico, Alessandro M Vannucchi, Rossella Manfredini
Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia-negative myeloproliferative neoplasms (MPNs) characterized by erythrocytosis and thrombocytosis, respectively. Approximately 95% of PV and 50-70% of ET patients harbor the V617F mutation in the exon 14 of JAK2 gene, while about 20-30% of ET patients carry CALRins5 or CALRdel52 mutations. These ET CALR-mutated subjects show higher platelet count and lower thrombotic risk compared to JAK2-mutated patients. Here, we showed that CALR-mutated and JAK2V617F-positive CD34+ cells display different gene and miRNA expression profiles...
December 8, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/29214350/co-culture-of-human-fibroblasts-and-borrelia-burgdorferi-enhances-collagen-and-growth-factor-mrna
#16
Elisabeth Aberer, Milana Surtov-Pudar, Daniel Wilfinger, Alexander Deutsch, Gerd Leitinger, Helmut Schaider
Skin fibrosis has been reported in Borrelia burgdorferi infection in Europe, but has been questioned by several authors. The objective of the present study was to examine the interaction of skin fibroblasts with B. burgdorferi sensu stricto B31 (BB) and B. afzelii (BA) in vitro by electron microscopy. We also determined the expression of collagen type I, TGF-β, FGF-1, calreticulin (CALR), decorin (DCN), and PDGF-α at the mRNA level in Borrelia/fibroblast co-cultures. Intact Borrelia attach to and transmigrate fibroblasts, and undergo cystic transformation outside the fibroblasts...
December 6, 2017: Archives of Dermatological Research
https://www.readbyqxmd.com/read/29203554/the-clinical-and-prognostic-relevance-of-driver-mutations-in-203-taiwanese-patients-with-primary-myelofibrosis
#17
Ming-Chung Kuo, Tung-Huei Lin, Chien-Feng Sun, Tung-Liang Lin, Jin-Hou Wu, Po-Nan Wang, Ying-Jung Huang, Hung Chang, Ting-Yu Huang, Lee-Yung Shih
AIMS: We investigated the clinical and prognostic relevance of the mutational status of driver genes with allele burden and endogenous erythroid colony (EEC) growth in 203 Taiwanese patients with primary myelofibrosis (PMF). METHODS: Pyrosequencing was used to detect JAK2V617F mutational status and measure allele burden, while MPL (exon 10) mutations were analysed by PCR assay and then by direct sequencing. CALR exon 9 mutations were first screened for length changes by GeneScan followed by sequencing...
December 4, 2017: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29192651/myeloid-neoplasms-with-features-intermediate-between-primary-myelofibrosis-and-chronic-myelomonocytic-leukemia
#18
Jennifer Chapman, Julia T Geyer, Mahsa Khanlari, Adrienne Moul, Carmen Casas, Scot T Connor, Yao-Shan Fan, Justin M Watts, Ronan T Swords, Francisco Vega, Attilio Orazi
Monocytosis can develop during disease course in primary myelofibrosis simulating that seen in chronic myelomonocytic leukemia, and should not lead to disease reclassification. In contrast, at presentation, rare cases have clinical, morphologic, and molecular genetic features truly intermediate between primary myelofibrosis and chronic myelomonocytic leukemia. The taxonomy and natural history of these diseases are unclear. We identified cases which either: (1) fulfilled the 2008 World Health Organization criteria for primary myelofibrosis but had absolute monocytosis and, when available, chronic myelomonocytic leukemia-related mutations (ASXL1, SRSF2, TET2) or (2) fulfilled criteria of chronic myelomonocytic leukemia but had megakaryocytic proliferation and atypia, marrow fibrosis, and myeloproliferative-type driver mutations (JAK2, MPL, CALR)...
December 1, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/29164670/driver-mutations-and-prognosis-in-primary-myelofibrosis-mayo-careggi-mpn-alliance-study-of-1-095-patients
#19
Ayalew Tefferi, Maura Nicolosi, Mythri Mudireddy, Natasha Szuber, Christy M Finke, Terra L Lasho, Curtis A Hanson, Rhett P Ketterling, Animesh Pardanani, Naseema Gangat, Carmela Mannarelli, Tiziana Fanelli, Paola Guglielmelli, Alessandro M Vannucchi
The 2013 discovery of calreticulin (CALR) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple-negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2, 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple-negative...
November 22, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29147619/the-jak2v617f-and-calr-exon-9-mutations-are-shared-immunogenic-neoantigens-in-hematological-malignancy
#20
Morten Orebo Holmström, Hans Carl Hasselbalch, Mads Hald Andersen
Approximately 90% of patients with the hematological malignancies termed the chronic myeloproliferative neoplasms harbor either the JAK2V617F-mutation or CALR exon 9 mutation. Both of these are recognized by T-cells, which make the mutations ideal targets for cancer immune therapy as they are shared antigens.
2017: Oncoimmunology
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