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https://www.readbyqxmd.com/read/29352118/pi3k-mtor-inhibition-promotes-the-regression-of-experimental-vascular-malformations-driven-by-pik3ca-activating-mutations
#1
Laura di Blasio, Alberto Puliafito, Paolo Armando Gagliardi, Valentina Comunanza, Desiana Somale, Giulia Chiaverina, Federico Bussolino, Luca Primo
Somatic activating mutations within the PIK3CA gene have been recently detected in sporadic lymphatic and venous malformations, and in vascular malformations (VM) associated to overgrowth syndromes, such as CLOVES and Klippel-Trenaunay syndrome. Although VM are often limited to specific tissue areas and can be well treated, in extended or recurrent lesions novel therapeutic approaches are needed. We generated a mouse model of VM by local expression of PIK3CA-activating mutation in endothelial cells. PIK3CA-driven lesions are characterized by large areas of hemorrhage, hyperplastic vessels, infiltrates of inflammatory cells, and elevated endothelial cell density...
January 19, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29351395/macrophage-colony-stimulating-factor-increases-hepatic-macrophage-content-liver-growth-and-lipid-accumulation-in-neonatal-rats
#2
Clare Pridans, Kristin A Sauter, Katharine M Irvine, Gemma M Davis, Lucas Lefevre, Anna Raper, Rocio Rojo, Ajit J Nirmal, Philippa Beard, Michael Cheeseman, David A Hume
Signaling via the colony stimulating factor 1 receptor (CSF1R) controls the survival, differentiation and proliferation of macrophages. Mutations in CSF1, or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of CSF1-Fc as a therapy for low birth weight (LBW) at term, using a model based upon maternal dexamethasone treatment in rats. Neonatal CSF1-Fc treatment did not alter somatic growth, and did not increase the blood monocyte count. Instead, there was a substantial increase in the size of liver in both control and LBW rats, and the treatment greatly exacerbated the lipid droplet accumulation seen in the dexamethasone LBW model...
December 21, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/29349598/phase-ib-study-evaluating-safety-and-clinical-activity-of-the-anti-her3-antibody-lumretuzumab-combined-with-the-anti-her2-antibody-pertuzumab-and-paclitaxel-in-her3-positive-her2-low-metastatic-breast-cancer
#3
Andreas Schneeweiss, Tjoung-Won Park-Simon, Joan Albanell, Ulrik Lassen, Javier Cortés, Veronique Dieras, Marcus May, Christoph Schindler, Frederik Marmé, Juan Miguel Cejalvo, Maria Martinez-Garcia, Iria Gonzalez, Jose Lopez-Martin, Anja Welt, Christelle Levy, Florence Joly, Francesca Michielin, Wolfgang Jacob, Céline Adessi, Annie Moisan, Georgina Meneses-Lorente, Tomas Racek, Ian James, Maurizio Ceppi, Max Hasmann, Martin Weisser, Andrés Cervantes
Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts)...
January 19, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29348113/genetics-in-endocrinology-the-expanding-genetic-horizon-of-primary-aldosteronism
#4
Silvia Monticone, Fabrizio Buffolo, Martina Tetti, Franco Veglio, Barbara Pasini, Paolo Mulatero
Aldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA, and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified...
January 18, 2018: European Journal of Endocrinology
https://www.readbyqxmd.com/read/29347918/somatic-evolutionary-timings-of-driver-mutations
#5
Karen Gomez, Sayaka Miura, Louise A Huuki, Brianna S Spell, Jeffrey P Townsend, Sudhir Kumar
BACKGROUND: A unified analysis of DNA sequences from hundreds of tumors concluded that the driver mutations primarily occur in the earliest stages of cancer formation, with relatively few driver mutation events detected in the late-arising subclones. However, emerging evidence from the sequencing of multiple tumors and tumor regions per individual suggests that late-arising subclones with additional driver mutations are underestimated in single-sample analyses. METHODS: To test whether driver mutations generally map to early tumor development, we examined multi-regional tumor sequencing data from 101 individuals reported in 11 published studies...
January 18, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29346117/the-deubiquitinase-usp9x-regulates-fbw7-stability-and-suppresses-colorectal-cancer
#6
Omar M Khan, Joana Carvalho, Bradley Spencer-Dene, Richard Mitter, David Frith, Ambrosius P Snijders, Stephen A Wood, Axel Behrens
The tumor suppressor FBW7 targets oncoproteins such as c-MYC for ubiquitylation and is mutated in several human cancers. We noted that in a significant percentage of colon cancers, FBW7 protein is undetectable despite the presence of FBW7 mRNA. To understand the molecular mechanism of FBW7 regulation in these cancers, we employed proteomics and identified the deubiquitinase USP9X as an FBW7 interactor. USP9X antagonised FBW7 ubiquitylation, and Usp9x deletion caused Fbw7 destabilization. Mice lacking Usp9x in the gut showed reduced secretory cell differentiation and increased progenitor proliferation, phenocopying Fbw7 loss...
January 18, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29346025/linkage-of-metabolic-defects-to-activated-pik3ca-alleles-in-endothelial-cells-derived-from-lymphatic-malformation
#7
Kathryn Glaser, Peter Dickie, Derek Neilson, Alexander Osborn, Belinda Hsi Dickie
BACKGROUND: Lymphatic endothelial cells (LECs) derived from lymphatic malformations (LMs) bear activated PIK3CA alleles yet display an inflammatory gene expression profile. A basis for the inflammatory phenotype was sought by screening for coexisting somatic mutations. METHODS AND RESULTS: Fourteen independent LEC populations bearing activated PIK3CA alleles were isolated from LM. These were characterized by the expression of growth and inflammatory genes (VEGFC, IL-6, COX-2, IL-8, HO-1, E-SEL) by qRT-PCR...
January 18, 2018: Lymphatic Research and Biology
https://www.readbyqxmd.com/read/29345757/whole-genome-sequencing-analysis-for-cancer-genomics-and-precision-medicine
#8
REVIEW
Hidewaki Nakagawa, Masashi Fujita
Explosive advances of next-generation sequencer (NGS) and computational analyses have been exploring somatic protein-altered mutations in most cancer types and these coding mutation data are intensively accumulated. However, there is limited information on somatic mutations in non-coding regions including introns, regulatory elements, and non-coding RNAs, structural variants and pathogen in cancer genomes remain widely unexplored. Whole genome sequencing (WGS) approaches can comprehensively explore all types of genomic alterations in cancer and help us to better understand the whole landscape of driver mutations and mutational signature in cancer genomes and elucidate functional or clinical implications of these unexplored genomic regions and mutational signature...
January 18, 2018: Cancer Science
https://www.readbyqxmd.com/read/29345375/understanding-the-regulation-of-apobec3-expression-current-evidence-and-much-to-learn
#9
REVIEW
Daniela Angela Covino, Maria Cristina Gauzzi, Laura Fantuzzi
The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of cytosine deaminases plays crucial roles in innate immunity through the ability of restricting viral replication by deamination and mutation of viral genomes. The antiviral function of these proteins was first discovered when research in the field of HIV infection revealed that one member of the family, namely APOBEC3G, restricts HIV infection in T lymphocytes and that the viral infectivity factor protein drives the proteosomal degradation of this enzyme, thus overriding its antiviral function...
December 15, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/29343972/targeting-histone-methyltransferase-and-demethylase-in-acute-myeloid-leukemia-therapy
#10
REVIEW
Germana Castelli, Elvira Pelosi, Ugo Testa
Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29343685/the-protective-role-of-dot1l-in-uv-induced-melanomagenesis
#11
Bo Zhu, Shuyang Chen, Hongshen Wang, Chengqian Yin, Changpeng Han, Cong Peng, Zhaoqian Liu, Lixin Wan, Xiaoyang Zhang, Jie Zhang, Christine G Lian, Peilin Ma, Zhi-Xiang Xu, Sharon Prince, Tao Wang, Xiumei Gao, Yujiang Shi, Dali Liu, Min Liu, Wenyi Wei, Zhi Wei, Jingxuan Pan, Yongjun Wang, Zhenyu Xuan, Jay Hess, Nicholas K Hayward, Colin R Goding, Xiang Chen, Jun Zhou, Rutao Cui
The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29343499/a-population-phylogenetic-view-of-mitochondrial-heteroplasmy
#12
Peter R Wilton, Arslan Zaidi, Kateryna Makova, Rasmus Nielsen
The mitochondrion has recently emerged as an active player in a myriad of cellular processes. Additionally, it was recently shown that more than 200 diseases are known to be linked to variants in mitochondrial DNA or in nuclear genes interacting with mitochondria. This has reinvigorated interest in its biology and population genetics. Mitochondrial heteroplasmy, or genotypic variation of mitochondria within an individual, is now understood to be common in humans and important in human health. However, it is still not possible to make quantitative predictions about the inheritance of heteroplasmy and its proliferation within the body, partly due to the lack of an appropriate model...
January 17, 2018: Genetics
https://www.readbyqxmd.com/read/29343284/extensive-armc5-genetic-variance-in-primary-bilateral-macronodular-adrenal-hyperplasia-that-started-with-exophthalmos-a-case-report
#13
Ping Jin, Muhammad Usman Janjua, Qin Zhang, Chang-Sheng Dong, Youbo Yang, Zhao-Hui Mo
BACKGROUND: Primary bilateral macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome characterized by the presence of bilateral secretory adrenal nodules. Recent studies have shown that primary bilateral macronodular adrenal hyperplasia is caused by combined germline and somatic mutations of the ARMC5 gene. Exophthalmos is an underappreciated sign of Cushing's syndrome. CASE PRESENTATION: A 52-year-old Chinese woman with progressively worsening bilateral proptosis presented to our hospital...
January 18, 2018: Journal of Medical Case Reports
https://www.readbyqxmd.com/read/29341473/somatic-mosaic-deletions-involving-scn1a-cause-dravet-syndrome
#14
Tojo Nakayama, Atsushi Ishii, Takeshi Yoshida, Hirosato Nasu, Keiko Shimojima, Toshiyuki Yamamoto, Shigeo Kure, Shinichi Hirose
Somatic mosaicism in single nucleotide variants of SCN1A is known to occur in a subset of parents of children with Dravet syndrome (DS). Here, we report recurrent somatic mosaic microdeletions involving SCN1A in children diagnosed with DS. Through the evaluation of 237 affected individuals with DS who did not show SCN1A or PCHD19 mutations in prior sequencing analyzes, we identified two children with mosaic microdeletions covering the entire SCN1A region. The allele frequency of the mosaic deletions estimated by multiplex ligation-dependent probe amplification and array comparative genomic hybridization was 25-40%, which was comparable to the mosaic ratio in lymphocytes and buccal mucosa cells observed by fluorescence in situ hybridization analysis...
January 17, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29341334/incidence-and-prognostic-impact-of-cytogenetic-aberrations-in-patients-with-systemic-mastocytosis
#15
Nicole Naumann, Mohamad Jawhar, Juliana Schwaab, Sebastian Kluger, Johannes Lübke, Georgia Metzgeroth, Henning D Popp, Nada Khaled, Hans-Peter Horny, Karl Sotlar, Peter Valent, Claudia Haferlach, Gudrun Göhring, Brigitte Schlegelberger, Manja Meggendorfer, Wolf-Karsten Hofmann, Nicholas C P Cross, Andreas Reiter, Alice Fabarius
The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, e.g. in SRSF2, ASXL1 or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n=102, 94%) with indolent (ISM, n=26) and advanced SM (n=83) with (n=73, 88%) or without AHN...
January 17, 2018: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/29340115/hypermutation-and-microsatellite-instability-in-gastrointestinal-cancers
#16
REVIEW
Kizuki Yuza, Masayuki Nagahashi, Satoshi Watanabe, Kazuaki Takabe, Toshifumi Wakai
Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29340104/somatic-mutation-dynamics-in-mds-patients-treated-with-azacitidine-indicate-clonal-selection-in-patients-responders
#17
Kamila Polgarova, Karina Vargova, Vojtech Kulvait, Nina Dusilkova, Lubomir Minarik, Zuzana Zemanova, Michal Pesta, Anna Jonasova, Tomas Stopka
Azacitidine (AZA) for higher risk MDS patients is a standard therapy with limited durability. To monitor mutation dynamics during AZA therapy we utilized massive parallel sequencing of 54 genes previously associated with MDS/AML pathogenesis. Serial sampling before and during AZA therapy of 38 patients (reaching median overall survival 24 months (Mo) with 60% clinical responses) identified 116 somatic pathogenic variants with allele frequency (VAF) exceeding 5%. High accuracy of data was achieved via duplicate libraries from myeloid cells and T-cell controls...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29340043/clinical-significance-of-yap1-activation-in-head-and-neck-squamous-cell-carcinoma
#18
Young-Gyu Eun, Dongjin Lee, Young Chan Lee, Bo Hwa Sohn, Eui Hyun Kim, Sun Young Yim, Kee Hwan Kwon, Ju-Seog Lee
By analyzing the genomic data of head and neck squamous cell cancer (HNSCC), we investigated clinical significance of YAP1 activation. Copy number and mRNA expression of YAP1 were analyzed together to assess clinical relevance of YAP1 activation in HNSCC. The clinical significance of YAP1 activation was further validated in four independent test cohorts. We also assessed the correlation of YAP1 activation with genomic alterations such as copy number alteration, somatic mutation, and miRNA expression. The YAP1-activated (YA) subgroup showed worse prognosis for HNSCC as tested and validated in five cohorts...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29339978/increase-of-somatic-cell-mutations-in-oxidative-damage-sensitive-drosophila
#19
Ryota Koike, Tomoyo Uchiyama, Sakae Arimoto-Kobayashi, Keinosuke Okamoto, Tomoe Negishi
Background: Oxidative damage is an important genotoxic source for almost all organisms. To efficiently detect mutations induced by oxidative damage, we previously developed a urate-null Drosophila strain. Using this Drosophila strain, we showed the mutagenic activity of environmental cigarette smoke (ECS) and the herbicide paraquat, which are known to produce reactive oxygen species (ROS). In the present study, we examined the mutagenic activities of carcinogenic mutagens that are considered to cause mutations by adduct formation, alkylation, or crosslinking of cellular DNA in the oxidative damage-sensitive Drosophila to evaluate how the oxidative damage induced by these mutagens is involved in causing mutations...
2018: Genes and Environment: the Official Journal of the Japanese Environmental Mutagen Society
https://www.readbyqxmd.com/read/29339498/mafa-missense-mutation-causes-familial-insulinomatosis-and-diabetes-mellitus
#20
Donato Iacovazzo, Sarah E Flanagan, Emily Walker, Rosana Quezado, Fernando Antonio de Sousa Barros, Richard Caswell, Matthew B Johnson, Matthew Wakeling, Michael Brändle, Min Guo, Mary N Dang, Plamena Gabrovska, Bruno Niederle, Emanuel Christ, Stefan Jenni, Bence Sipos, Maike Nieser, Andrea Frilling, Ketan Dhatariya, Philippe Chanson, Wouter W de Herder, Björn Konukiewitz, Günter Klöppel, Roland Stein, Márta Korbonits, Sian Ellard
The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
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