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https://www.readbyqxmd.com/read/28012237/sporadic-melanotic-schwannoma-with-overlapping-features-of-melanocytoma-bearing-a-gna11-mutation-in-an-adolescent-girl
#1
Christina Tatsi, Flora Bacopoulou, Charalampos Lyssikatos, Elena Belyavskaya, Fabio R Faucz, Constantine A Stratakis
Melanotic schwannoma (MS) is a soft tissue neoplasm that shares histologic features with melanocytic tumors and schwannomas. A type of MS, called psammomatous MS (PMS), is associated with Carney complex (CNC), which is caused by PRKAR1A mutations. Other pigmented neoplasms, such as uveal melanomas and melanocytomas (MCs), are associated with genetic defects in other genes including GNA11. We report an adolescent female with a large sporadic mesenteric MS with complex histologic findings reminiscent of both PMS and MC...
December 24, 2016: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28011461/antitumor-activity-of-rxdx-105-in-multiple-cancer-types-with-ret-rearrangements-or-mutations
#2
Gang G Li, Romel Somwar, James Joseph, Roger S Smith, Takuo Hayashi, Leenus Martin, Aleksandra Franovic, Annelie Schairer, Eric S Martin, Gregory J Riely, Jason Harris, Shunqi Yan, Ge Wei, Jennifer Oliver, Rupal Patel, Pratik Multani, Marc Ladanyi, Alexander Drilon
PURPOSE: While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations...
December 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27995993/prkar1a-is-a-functional-tumor-suppressor-inhibiting-erk-snail-e-cadherin-pathway-in-lung-adenocarcinoma
#3
Shaoqiang Wang, Yuanda Cheng, Yingying Zheng, Zhiwei He, Wei Chen, Wolong Zhou, Chaojun Duan, Chunfang Zhang
Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma...
December 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27943004/carney-complex-a-familial-lentiginosis-predisposing-to-a-variety-of-tumors
#4
REVIEW
Constantine A Stratakis
Carney complex is a familial lentiginosis syndrome; these disorders cover a wide phenotypic spectrum ranging from a benign inherited predisposition to develop cutaneous spots not associated with systemic disease to associations with several syndromes. Carney complex is caused by PRKAR1A mutations and perturbations of the cyclic AMP-dependent protein kinase (PKA) signaling pathway. In addition to the cutaneous findings, the main tumors associated with Carney complex are endocrine: 1) primary pigmented nodular adrenocortical disease, a bilateral adrenal hyperplasia leading to Cushing syndrome; 2) growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia leading to acromegaly; 3) thyroid and gonadal tumors, including a predisposition to thyroid cancer...
September 2016: Reviews in Endocrine & Metabolic Disorders
https://www.readbyqxmd.com/read/27938411/butyrate-attenuates-lipolysis-in-adipocytes-co-cultured-with-macrophages-through-non-prostaglandin-e2-mediated-and-prostaglandin-e2-mediated-pathways
#5
Hideo Ohira, Wao Tsutsui, Rie Mamoto, Sayaka Yamaguchi, Masako Nishida, Miki Ito, Yoshio Fujioka
BACKGROUND: Interactions between adipocytes and macrophages are associated with metabolic disorders. Production of pro-inflammatory mediators and the release of free fatty acids (FFAs) increase when these cells are co-cultured; butyrate significantly diminishes these effects by suppressing both the macrophage inflammatory and adipocyte lipolysis pathways. Butyrate is known to up-regulate the expression of prostaglandin E2 (PGE2). Therefore, we hypothesized that PGE2 is associated with the suppression of lipolysis by butyrate in co-culture...
December 9, 2016: Lipids in Health and Disease
https://www.readbyqxmd.com/read/27910854/the-genetic-basis-and-fitness-consequences-of-sperm-midpiece-size-in-deer-mice
#6
Heidi S Fisher, Emily Jacobs-Palmer, Jean-Marc Lassance, Hopi E Hoekstra
An extensive array of reproductive traits varies among species, yet the genetic mechanisms that enable divergence, often over short evolutionary timescales, remain elusive. Here we examine two sister-species of Peromyscus mice with divergent mating systems. We find that the promiscuous species produces sperm with longer midpiece than the monogamous species, and midpiece size correlates positively with competitive ability and swimming performance. Using forward genetics, we identify a gene associated with midpiece length: Prkar1a, which encodes the R1α regulatory subunit of PKA...
December 2, 2016: Nature Communications
https://www.readbyqxmd.com/read/27825928/structure-of-a-pka-ri%C3%AE-recurrent-acrodysostosis-mutant-explains-defective-camp-dependent-activation
#7
Jessica Gh Bruystens, Jian Wu, Audrey Fortezzo, Jason Del Rio, Cole Nielsen, Donald K Blumenthal, Ruth Rock, Eduard Stefan, Susan S Taylor
Most disease-related mutations that impair cAMP protein kinase A (PKA) signaling are present within the regulatory (R) PKA RI alpha-subunit (RIα). Although mutations in the PRKAR1A gene are linked to Carney complex (CNC) disease and, more recently, to acrodysostosis-1 (ACRDYS1), the two diseases show contrasting phenotypes. While CNC mutations cause increased PKA activity, ACRDYS1 mutations result in decreased PKA activity and cAMP resistant holoenzymes. Mapping the ACRDYS1 disease mutations reveals their localization to the second of two tandem cAMP-binding (CNB) domains (CNB-B), and here, we characterize a recurrent deletion mutant where the last 14 residues are missing...
December 4, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27813477/-genes-in-the-camp-pathway-causing-skeletal-dysplasia-with-or-without-hormonal-resistance
#8
Caroline Silve
Acrodysostosis refers to a heterogeneous group of rare skeletal dysplasia that share characteristic features including severe brachydactyly, facial dysostosis and nasal hypoplasia. The literature describing acrodysostosis cases has been confusing because some reported patients may have had other phenotypically related diseases presenting Albright Hereditary Osteodystrophy (AHO) such as pseudohypoparathyroidism type 1a (PHP1a) or pseudopseudohypoparathyroidism (PPHP). A question has been whether patients display or not abnormal mineral metabolism associated with resistance to PTH and/or resistance to other hormones that bind G-protein coupled receptors (GPCR) linked to Gsa, as observed in PHP1a...
2016: Biologie Aujourd'hui
https://www.readbyqxmd.com/read/27803029/prkar1a-gene-knockout-in-the-pancreas-leads-to-neuroendocrine-tumorigenesis
#9
Emmanouil Saloustros, Paraskevi Salpea, Matthew Starost, Sissi Liu, Fabio R Faucz, Edra London, Eva Szarek, Woo-Jin Song, Mehboob Hussain, Constantine A Stratakis
Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by the inactivation of the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles of prkar1a in mouse cells expressing pdx1 (Δ-Prkar1a). We found that these mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4-5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes...
January 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/27801954/the-world-health-organization-2016-classification-of-testicular-non-germ-cell-tumours-a-review-and-update-from-the-international-society-of-urological-pathology-testis-consultation-panel
#10
REVIEW
Muhammad T Idrees, Thomas M Ulbright, Esther Oliva, Robert H Young, Rodolfo Montironi, Lars Egevad, Daniel Berney, John R Srigley, Jonathan I Epstein, Satish K Tickoo
The World Health Organization (WHO) released a new tumour classification for the genitourinary system in early 2016 after consensus by pathologists with expertise in these organs. It utilized the framework of the 2004 classification, and incorporated the most up-to-date information concerning these tumours. In testicular tumours, the majority of the changes occurred in the nomenclature and classification of germ cell tumours; however, several modifications were also made for non-germ cell tumours. Among sex cord-stromal tumours, sclerosing Sertoli cell tumour (SCT) is no longer recognized as a separate entity but as a morphological variant of SCT not otherwise specified (NOS), as CTNNB1 gene mutations have been noted in both neoplasms but not in the other forms of SCT...
November 1, 2016: Histopathology
https://www.readbyqxmd.com/read/27756606/screening-for-genetic-causes-of-growth-hormone-hypersecretion
#11
REVIEW
Liliya Rostomyan, Albert Beckers
Growth hormone (GH) secreting pituitary tumors may be caused by genetic abnormalities in a variety of genes including AIP, MEN1, CDKN1B, and PRKAR1A. These can lead to GH secreting pituitary adenomas as an isolated occurrence (e.g. as aggressive sporadic adenomas or in familial isolated pituitary adenomas (FIPA)) or as part of syndromic conditions such as MEN1 or Carney complex. These tumors have more aggressive features than sporadic acromegaly, including a younger age at disease onset and larger tumor size, and they can be challenging to manage...
October 2016: Growth Hormone & IGF Research
https://www.readbyqxmd.com/read/27699247/pka-regulatory-subunit-1a-inactivating-mutation-induces-serotonin-signaling-in-primary-pigmented-nodular-adrenal-disease
#12
Zakariae Bram, Estelle Louiset, Bruno Ragazzon, Sylvie Renouf, Julien Wils, Céline Duparc, Isabelle Boutelet, Marthe Rizk-Rabin, Rossella Libé, Jacques Young, Dennis Carson, Marie-Christine Vantyghem, Eva Szarek, Antoine Martinez, Constantine A Stratakis, Jérôme Bertherat, Hervé Lefebvre
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters...
September 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/27606678/steroidogenic-acute-regulatory-protein-overexpression-correlates-with-protein-kinase-a-activation-in-adrenocortical-adenoma
#13
Weiwei Zhou, Luming Wu, Jing Xie, Tingwei Su, Lei Jiang, Yiran Jiang, Yanan Cao, Jianmin Liu, Guang Ning, Weiqing Wang
The association of pathological features of cortisol-producing adrenocortical adenomas (ACAs) with somatic driver mutations and their molecular classification remain unclear. In this study, we explored the association between steroidogenic acute regulatory protein (StAR) expression and the driver mutations activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling to identify the pathological markers of ACAs. Immunohistochemical staining for StAR and mutations in the protein kinase cAMP-activated catalytic subunit alpha (PRKACA), protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) and guanine nucleotide binding protein, alpha stimulating (GNAS) genes were examined in 97 ACAs...
2016: PloS One
https://www.readbyqxmd.com/read/27589370/knock-in-of-the-recurrent-r368x-mutation-of-prkar1a-that-represses-camp-dependent-protein-kinase-a-activation-a-model-of-type-1-acrodysostosis
#14
Catherine Le Stunff, Francoise Tilotta, Jérémy Sadoine, Dominique Le Denmat, Claire Briet, Emmanuelle Motte, Eric Clauser, Pierre Bougnères, Catherine Chaussain, Caroline Silve
In humans, activating mutations in the PRKAR1A gene cause acrodysostosis 1 (ACRDYS1). These mutations result in a reduction in PKA activation caused by an impaired ability of cAMP to dissociate mutant PRKAR1A from catalytic PKA subunits. Two striking features of this rare developmental disease are renal resistance to PTH and chondrodysplasia resulting from the constitutive inhibition of PTHR1/Gsa/AC/cAMP/PKA signaling. We developed a knock-in of the recurrent ACRDYS1 R368X PRKAR1A mutation in the mouse. No litters were obtained from [R368X]/[+] females (thus no homozygous [R368X]/[R368X] mice)...
September 2, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/27580882/a-genetic-variation-associated-with-plasma-erythropoietin-and-a-non-coding-transcript-of-prkar1a-in-sickle-cell-disease
#15
Xu Zhang, Binal N Shah, Wei Zhang, Santosh L Saraf, Galina Miasnikova, Adelina Sergueeva, Tatiana Ammosova, Xiaomei Niu, Mehdi Nouraie, Sergei Nekhai, Oswaldo Castro, Mark T Gladwin, Josef T Prchal, Joe G N Garcia, Roberto F Machado, Victor R Gordeuk
Blood erythropoietin (EPO) increases primarily to hypoxia. In sickle cell anemia (homozygous HBB(E6V); HbSS), plasma EPO is elevated due to hemolytic anemia-related hypoxia. Hydroxyurea treatment reduces hemolysis and anemia by increasing fetal hemoglobin, which leads to lower hypoxic transcriptional responses in blood mononuclear cells but paradoxically further increases EPO. To investigate this apparent hypoxia-independent EPO regulation, we assessed two sickle cell disease (SCD) cohorts for genetic associations with plasma EPO, by prioritizing 237,079 quantitative trait loci for expression level and/or transcript isoform variations of 12,727 genes derived from SCD blood mononuclear cells...
August 30, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27580546/a-novel-mutation-in-the-type-i%C3%AE-regulatory-subunit-of-protein-kinase-a-prkar1a-in-a-cushing-s-syndrome-patient-with-primary-pigmented-nodular-adrenocortical-disease
#16
Ryohei Mineo, Sachiko Tamba, Yuya Yamada, Tomonori Okita, Yusuke Kawachi, Reiko Mori, Mitsuaki Kyo, Kenji Saisho, Yohei Kuroda, Koji Yamamoto, Akiko Furuya, Tokuo Mukai, Takashi Maekawa, Yasuhiro Nakamura, Hironobu Sasano, Yuji Matsuzawa
A 40-year-old man presented with Cushing's syndrome due to bilateral adrenal hyperplasia with multiple nodules. Computed tomography scan results were atypical demonstrating an enlargement of the bilateral adrenal glands harboring multiple small nodules, but the lesion was clinically diagnosed to be primary pigmented nodular adrenocortical disease (PPNAD) based on both endocrinological test results and his family history. We performed bilateral adrenalectomy and confirmed the diagnosis histologically. An analysis of the patient and his mother's genomic DNA identified a novel mutation in the type Iα regulatory subunit of protein kinase A (PRKAR1A) gene; p...
2016: Internal Medicine
https://www.readbyqxmd.com/read/27566888/timely-screening-for-carney-complex-and-prkar1a-gene-mutations
#17
Jun Feng
No abstract text is available yet for this article.
November 2016: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/27548314/recurrent-somatic-mutations-in-polr2a-define-a-distinct-subset-of-meningiomas
#18
Victoria E Clark, Akdes Serin Harmancı, Hanwen Bai, Mark W Youngblood, Tong Ihn Lee, Jacob F Baranoski, A Gulhan Ercan-Sencicek, Brian J Abraham, Abraham S Weintraub, Denes Hnisz, Matthias Simon, Boris Krischek, E Zeynep Erson-Omay, Octavian Henegariu, Geneive Carrión-Grant, Ketu Mishra-Gorur, Daniel Durán, Johanna E Goldmann, Johannes Schramm, Roland Goldbrunner, Joseph M Piepmeier, Alexander O Vortmeyer, Jennifer Moliterno Günel, Kaya Bilgüvar, Katsuhito Yasuno, Richard A Young, Murat Günel
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref...
October 2016: Nature Genetics
https://www.readbyqxmd.com/read/27535175/growth-hormone-and-risk-for-cardiac-tumors-in-carney-complex
#19
W Patricia Bandettini, Alexander S Karageorgiadis, Ninet Sinaii, Douglas R Rosing, Vandana Sachdev, Marie Helene Schernthaner-Reiter, Evgenia Gourgari, Georgios Z Papadakis, Meg F Keil, Charalampos Lyssikatos, J Aidan Carney, Andrew E Arai, Maya Lodish, Constantine A Stratakis
Carney complex (CNC) is a multiple neoplasia syndrome that is caused mostly by PRKAR1A mutations. Cardiac myxomas are the leading cause of mortality in CNC patients who, in addition, often develop growth hormone (GH) excess. We studied patients with CNC, who were observed for over a period of 20 years (1995-2015) for the development of both GH excess and cardiac myxomas. GH secretion was evaluated by standard testing; dedicated cardiovascular imaging was used to detect cardiac abnormalities. Four excised cardiac myxomas were tested for the expression of insulin-like growth factor-1 (IGF-1)...
September 2016: Endocrine-related Cancer
https://www.readbyqxmd.com/read/27498419/celecoxib-treatment-of-fibrous-dysplasia-fd-in-a-human-fd-cell-line-and-fd-like-lesions-in-mice-with-protein-kinase-a-pka-defects
#20
Emmanouil Saloustros, Sisi Liu, Edward L Mertz, Nisan Bhattacharyya, Matthew F Starost, Paraskevi Salpea, Maria Nesterova, Michael Collins, Sergey Leikin, Constantine A Stratakis
Osteochondromyxomas (OMX) in the context of Carney complex (CNC) and fibrous dysplasia (FD)-like lesions (FDLL) in mice, as well as isolated myxomas in humans may be caused by inactivation of PRKAR1A, the gene coding for the type 1a regulatory subunit (R1α) of cAMP-dependent protein kinase (PKA). OMXs and FDLL in mice lacking Prkar1a grow from abnormal proliferation of adult bone stromal cells (aBSCs). Prkar1a and Prkaca (coding for Cα) haploinsufficiency leads to COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of aBSCs...
January 5, 2017: Molecular and Cellular Endocrinology
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