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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 12, 2016: Growth Hormone & IGF Research
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
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
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
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
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
Jun Feng
No abstract text is available yet for this article.
November 2016: Journal of Thoracic and Cardiovascular Surgery
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
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
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 lead to COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of aBSCs...
August 4, 2016: Molecular and Cellular Endocrinology
Adam Alleemudder, Rajiv Pillai
We describe the case of a 7-year-old boy who presented with testicular pain but was found to have bilateral testicular lesions later confirmed as Sertoli cell tumors. Genetic testing confirmed a PRKAR1A gene mutation consistent with Carney complex, a rare genetic disorder characterized by skin lesions, myxomas, and multiple endocrine neoplasms. A review of the condition is made highlighting the association with testicular tumors, particularly of Sertoli cell origin.
July 2016: Urology Annals
Anli Tong, Guanghua Liu, Fen Wang, Jun Jiang, Zhaoli Yan, Dianxi Zhang, Yinsheng Zhang, Jun Cai
CONTEXT: To date, all the familial hyperaldosteronism type III (FH-III) patients reported presented with typical primary aldosteronism (PA), without showing other adrenal hormone abnormalities. OBJECTIVE: This study characterized a novel phenotype of FH-III, and explored the possible pathogenesis. PATIENTS AND METHODS: A male patient presented with severe hypertension and hypokalemia at the age of 2, and developed Cushing's syndrome at 20...
July 12, 2016: Journal of Clinical Endocrinology and Metabolism
Paulina Szyszka, Ashley B Grossman, Salvador Diaz-Cano, Krzysztof Sworczak, Dorota Dworakowska
Adrenocortical carcinoma is associated with a low cure rate and a high recurrence rate. The prognosis is poor, and at diagnosis 30-40% of cases are already metastatic. The current therapeutic options (surgical resection, followed by adjuvant mitotane treatment +/- chemotherapy) are limited, and the results remain unsatisfactory. Key molecular events that contribute to formation of adrenocortical cancer are IGF2 overexpression, TP53-inactivating mutations, and constitutive activation of the Wnt/b-catenin signalling pathway via activating mutations of the b-catenin gene...
2016: Endokrynologia Polska
Labrini Papanastasiou, Stelios Fountoulakis, Nikos Voulgaris, Theodora Kounadi, Theodosia Choreftaki, Akrivi Kostopoulou, George Zografos, Charalampos Lyssikatos, Constantine A Stratakis, George Piaditis
OBJECTIVE: Carney complex (CNC) is a rare autosomal dominant multiple neoplasia syndrome characterized by the presence of endocrine and non-endocrine tumors. More than 125 different germline mutations of the protein Kinase A type 1-α regulatory subunit (PRKAR1A) gene have been reported. We present a novel PRKAR1A gene germline mutation in a patient with severe osteoporosis and recurrent vertebral fractures. DESIGN: Clinical case report. CASE REPORT: A 53-year-old male with a medical history of surgically removed recurrent cardiac myxomas was evaluated for repeated low-pressure vertebral fractures and severe osteoporosis...
January 2016: Hormones: International Journal of Endocrinology and Metabolism
M A Aguileta, D Rojas-Rivera, V Goossens, Y Estornes, G Van Isterdael, P Vandenabeele, M J M Bertrand
The endoplasmic reticulum (ER) has a crucial role in the proper folding of proteins that are synthesized in the secretory pathway. Physiological and pathological conditions can induce accumulation of mis- or unfolded proteins in the ER lumen and thereby generate a state of cellular stress known as ER stress. The unfolded protein response aims at restoring protein-folding homeostasis, but turns into a toxic signal when ER stress is too severe or prolonged. ER stress-induced cellular dysfunction and death is associated with several human diseases, but the molecular mechanisms regulating death under unresolved ER stress are still unclear...
October 2016: Cell Death and Differentiation
Alessandro Del Gobbo, Erika Peverelli, Donatella Treppiedi, Andrea Lania, Giovanna Mantovani, Stefano Ferrero
In this review, we discuss the molecular mechanisms and prognostic implications of the protein kinase A (PKA) signaling pathway in human tumors, with special emphasis on the malignant thyroid. The PKA signaling pathway is differentially activated by the expression of regulatory subunits 1 (R1) and 2 (R2), whose levels change during development, differentiation, and neoplastic transformation. Following the identification of gene mutations within the PKA regulatory subunit R1A (PRKAR1A) that cause Carney complex-associated neoplasms, several investigators have studied PRKAR1A expression in sporadic thyroid tumors...
August 1, 2016: Experimental Cell Research
Siraj M Ali, Thomas Hensing, Alexa B Schrock, Justin Allen, Eric Sanford, Kyle Gowen, Atul Kulkarni, Jie He, James H Suh, Doron Lipson, Julia A Elvin, Roman Yelensky, Zachary Chalmers, Juliann Chmielecki, Nir Peled, Samuel J Klempner, Kashif Firozvi, Garrett M Frampton, Julian R Molina, Smitha Menon, Julie R Brahmer, Heber MacMahon, Jan Nowak, Sai-Hong Ignatius Ou, Marjorie Zauderer, Marc Ladanyi, Maureen Zakowski, Neil Fischbach, Jeffrey S Ross, Phil J Stephens, Vincent A Miller, Heather Wakelee, Shridar Ganesan, Ravi Salgia
INTRODUCTION: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate...
June 2016: Oncologist
Laura Massobrio, Sabina Nasti, Claudia Martinuzzi, Francesco Chiarella, Fabrizio Montecucco, Gian Marco Rosa, Alberto Valbusa
BACKGROUND: Intracardiac myxomas are frequent benign tumors of the heart and typically localize in the left atri- um and interatrial septum. When myxomas generate at other sites, they are designated as atypical. Mutations in the PRKAR1A gene (a tumor suppressor gene that encodes a protein kinase A [PKA] regulatory 1-alpha subunit) have been identified in both syndromic and non-syndromic cardiac atypical myxomas. METHODS: We report the case of a 33-year old woman suffering from night fever, weight loss, asthenia, and progressive dyspnea...
2016: Clinical Laboratory
Raitis Peculis, Inga Balcere, Vita Rovite, Kaspars Megnis, Andra Valtere, Janis Stukens, Ligita Arnicane, Liene Nikitina-Zake, Aivars Lejnieks, Valdis Pirags, Janis Klovins
OBJECTIVE: Although pituitary adenomas (PAs) affect a significant proportion of the population, only a fraction have the potential to become clinically relevant during an individual's lifetime, causing hormonal imbalance or complications due to mass effect. The overwhelming majority of cases are sporadic and without a clear familial history, and the genotype-phenotype correlation in PA patients is poorly understood. Our aim was to investigate the involvement of genes known for their role in familial cases on drug response and tumor suppression in the development and pathology of PAs in a patient group from Latvia...
August 2016: European Journal of Endocrinology
Siyuan Zheng, Andrew D Cherniack, Ninad Dewal, Richard A Moffitt, Ludmila Danilova, Bradley A Murray, Antonio M Lerario, Tobias Else, Theo A Knijnenburg, Giovanni Ciriello, Seungchan Kim, Guillaume Assie, Olena Morozova, Rehan Akbani, Juliann Shih, Katherine A Hoadley, Toni K Choueiri, Jens Waldmann, Ozgur Mete, A Gordon Robertson, Hsin-Ta Wu, Benjamin J Raphael, Lina Shao, Matthew Meyerson, Michael J Demeure, Felix Beuschlein, Anthony J Gill, Stan B Sidhu, Madson Q Almeida, Maria C B V Fragoso, Leslie M Cope, Electron Kebebew, Mouhammed A Habra, Timothy G Whitsett, Kimberly J Bussey, William E Rainey, Sylvia L Asa, Jérôme Bertherat, Martin Fassnacht, David A Wheeler, Gary D Hammer, Thomas J Giordano, Roel G W Verhaak
We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs...
May 9, 2016: Cancer Cell
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