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Driver mutation

Abbas Agaimy, Matthias Bieg, Michael Michal, Helene Geddert, Bruno Märkl, Jan Seitz, Evgeny A Moskalev, Matthias Schlesner, Markus Metzler, Arndt Hartmann, Stefan Wiemann, Michal Michal, Thomas Mentzel, Florian Haller
Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms...
October 21, 2016: American Journal of Surgical Pathology
Ankit Malik, Deepika Sharma, Qifan Zhu, Rajendra Karki, Clifford S Guy, Peter Vogel, Thirumala-Devi Kanneganti
Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we have shown that Il33-deficient mice are highly susceptible to colitis and CAC...
October 24, 2016: Journal of Clinical Investigation
Tatsuya Kaji, Osamu Yamasaki, Minoru Takata, Masaki Otsuka, Toshihisa Hamada, Shin Morizane, Kenji Asagoe, Hiroyuki Yanai, Yoji Hirai, Hiroshi Umemura, Keiji Iwatsuki
BACKGROUND: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared...
October 13, 2016: Journal of Dermatological Science
Michaël Duruisseaux, Anne McLeer-Florin, Martine Antoine, Sanaz Alavizadeh, Virginie Poulot, Roger Lacave, Nathalie Rabbe, Jacques Cadranel, Marie Wislez
Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28-87% of the cases. NRG1 fusions were recently discovered in KRAS-negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed...
October 21, 2016: Cancer Medicine
Daniel Nichol, Mark Robertson-Tessi, Peter Jeavons, Alexander R A Anderson
Non-genetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance in both bacterial infections and cancers. Here, we study how bet-hedging emerges in the genotype-phenotype mapping through a simple interaction model: a molecular switch. We use simple Chemical Reaction Networks to implement stochastic switches that map gene products to phenotypes and investigate the impact of structurally distinct mappings on the evolution of phenotypic heterogeneity. Bet-hedging naturally emerges within this model and is robust to evolutionary loss through mutations to both the expression of individual genes and to the network itself...
October 21, 2016: Genetics
Siying Ren, Yongfeng Luo, Hui Chen, David Warburton, Hilaire C Lam, Larry Wang, Ping Chen, Elizabeth P Henske, Wei Shi
The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mTORC1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver...
October 18, 2016: American Journal of Pathology
Sung-Hwan Cho, Sang-Min Park, Ho-Sung Lee, Hwang-Yeol Lee, Kwang-Hyun Cho
BACKGROUND: Colorectal cancer arises from the accumulation of genetic mutations that induce dysfunction of intracellular signaling. However, the underlying mechanism of colorectal tumorigenesis driven by genetic mutations remains yet to be elucidated. RESULTS: To investigate colorectal tumorigenesis at a system-level, we have reconstructed a large-scale Boolean network model of the human signaling network by integrating previous experimental results on canonical signaling pathways related to proliferation, metastasis, and apoptosis...
October 20, 2016: BMC Systems Biology
Yi Shi, Xian-Bin Su, Kun-Yan He, Bing-Hao Wu, Bo-Yu Zhang, Ze-Guang Han
Somatic mutations of many cancer genes tend to co-occur (termed co-mutations) in certain patterns during tumor initiation and progression. However, the genetic and epigenetic mechanisms that contribute to the co-mutations of these cancer genes have yet to be explored. Here, we systematically investigated the association between the somatic co-mutations of cancer genes and high-order chromatin conformation. Significantly, somatic point co-mutations in protein-coding genes were closely associated with high-order spatial chromatin folding...
October 20, 2016: Scientific Reports
Karol Cichewicz, Emma J Garren, Chika Adiele, Yoshinori Aso, Zhang Wang, Martin Wu, Serge Birman, Gerald M Rubin, Jay Hirsh
Dopamine (DA) is a neurotransmitter with conserved behavioral roles between invertebrate and vertebrate animals. In addition to its neural functions, in insects DA is a critical substrate for cuticle pigmentation and hardening. Drosophila tyrosine hydroxylase (DTH) is the rate limiting enzyme for DA biosynthesis. Viable brain DA deficient flies were previously generated using tissue selective GAL4-UAS binary expression rescue of a DTH null mutation and these flies show specific behavioral impairments. To circumvent the limitations of rescue via binary expression, here we achieve rescue utilizing genomically integrated mutant DTH...
October 19, 2016: Genes, Brain, and Behavior
Tongtong Zhang, Junling Li
BACKGROUND: It has been proven that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and KRAS are common driver genes in non-small cell lung cancer (NSCLC). Molecular targeted therapy increases the overall response rate and progression-free survival (PFS) of patients with EGFR-sensitive mutation or echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion. However, target and targeted drugs for lung squamous cell carcinoma to indicate clinical therapy remain to be confirmed...
October 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Kirby Rickel, Fang Fang, Jianning Tao
Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogs of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma...
October 16, 2016: Bone
Stuart G Tangye
Some autoimmune disorders are monogenetic diseases; however, clinical manifestations among individuals vary, despite the presence of identical mutations in the disease-causing gene. In this issue of the JCI, Massaad and colleagues characterized a seemingly monogenic autoimmune disorder in a family that was linked to homozygous loss-of-function mutations in the gene encoding the endonuclease Nei endonuclease VIII-like 3 (NEIL3), which has not been previously associated with autoimmunity. The identification of an unrelated healthy individual with the same homozygous mutation spurred more in-depth analysis of the data and revealed the presence of a second mutation in a known autoimmune-associated gene...
October 17, 2016: Journal of Clinical Investigation
Jenna K Zalewski, Joshua H Mo, Simone Heber, Annie Heroux, Richard G Gardner, Jeffrey D Hildebrand, Andrew P VanDemark
Shroom-mediated remodeling of the actomyosin cytoskeleton is a critical driver of cellular shape and tissue morphology that underlies the development of many tissues, including the neural tube, eye, intestines, and vasculature. Shroom uses a conserved SD2 domain to direct the subcellular localization of Rho-kinase (Rock) which in turn drives changes in the cytoskeleton and cellular morphology through its ability to phosphorylate and activate non-muscle myosin II. Here, we present the structure of the human Shroom-Rock binding module, revealing an unexpected stoichiometry for Shrm in which two Shrm SD2 domains bind independent surfaces on Rock...
October 10, 2016: Journal of Biological Chemistry
Saroor A Patel, Sakari Vanharanta
Genetic analyses of cancer progression in patient samples and model systems have thus far failed to identify specific mutational drivers of metastasis. Yet, at least in experimental systems, metastatic cancer clones display stable traits that can facilitate progression through the many steps of metastasis. How cancer cells establish and maintain the transcriptional programmes required for metastasis remains mostly unknown. Emerging evidence suggests that metastatic traits may arise from epigenetically altered transcriptional output of the oncogenic signals that drive tumour initiation and early progression...
October 8, 2016: Molecular Oncology
Mateusz Bujko, Marcin M Machnicki, Emilia Grecka, Natalia Rusetska, Ewa Matyja, Paulina Kober, Tomasz Mandat, Małgorzata Rydzanicz, Rafał Płoski, Romuald Krajewski, Wieslaw Bonicki, Tomasz Stokłosa, Janusz A Siedlecki
BACKGROUND: Rhabdoid meningioma is rare aggressive meningioma histological subtype, which develops predominantly through progression from less malignant tumors. Due to a low incidence the biological background is unknown. The aim of this study was to profile somatic mutations in four meningioma samples from the same patient, derived previously from four subsequent tumor resections. CASE DESCRIPTION: 58-year-old woman suffering from recurrent meningioma progressing from atypical to rhabdoid subtype...
October 15, 2016: World Neurosurgery
Salem H Alshemmari, Reshmi Rajaan, Ashkan Emadi
No abstract text is available yet for this article.
September 21, 2016: Medical Principles and Practice: International Journal of the Kuwait University, Health Science Centre
Kiyohiro Sakai, Masayuki Takeda, Hidetoshi Hayashi, Kaoru Tanaka, Takeshi Okuda, Amami Kato, Yasumasa Nishimura, Tetsuya Mitsudomi, Atsuko Koyama, Kazuhiko Nakagawa
INTRODUCTION: The concept of "oligometastasis" has emerged as a basis on which to identify patients with stage IV non-small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. PATIENTS AND METHODS: Consecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study...
September 12, 2016: Thoracic Cancer
Satoshi Umemura
Primary aldosteronism (PA) is a heterogeneous group of disorders including both sporadic and familial forms (familial hyperaldosteronism type I, II and III). PA is the most frequent endocrine cause of secondary hypertension and associated with a higher rate of cardiovascular complications, compared with essential hypertension.Here I review the recent progress in understanding of the genetic and molecular mechanisms leading to autonomous aldosterone production in PA.Systematic screening detects primary aldosteronism in 5 to 10% of all patients with hypertension and in approximately 20% of patients with resistant hypertension...
September 2016: Journal of Hypertension
Elena Trujillo-Arribas, Hada C Macher, Pilar Jiménez-Arriscado, Fernando de la Portilla, Patrocinio Molinero, Juan M Guerrero, Amalia Rubio
Genomic characterization of cell-free circulating tumour DNA (ctDNA) may offer an opportunity to assess clonal dynamics throughout the course of a patient's illness. The existence of KRAS driver mutations in colon cancer patients is determinant to decide their treatment and to predict their outcome. DNA is extracted automatically from 400 μL of serum using the MagNa Pure Compact with the Nucleic Acid Isolation Kit I. DNA amplification, COLD-PCR and HRM were performed in the same run in the Light Cycler 480...
2016: Advances in Experimental Medicine and Biology
Erina Takai, Yasushi Totoki, Hiromi Nakamura, Mamoru Kato, Tatsuhiro Shibata, Shinichi Yachida
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect molecular characteristics of tumors, supporting the concept of "liquid biopsy".We determined the mutational status of KRAS in plasma cfDNA using multiplex droplet digital PCR in 259 patients with PDAC, retrospectively...
2016: Advances in Experimental Medicine and Biology
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