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Met mutation

Kathleen M Aguilar, Katherine B Winfree, Catherine E Muehlenbein, Yajun Emily Zhu, Thomas Wilson, Stewart Wetmore, Eric S Nadler
INTRODUCTION: Targeted therapies, including tyrosine kinase inhibitors (TKIs) that target the sensitizing epidermal growth factor receptor (EGFR) gene are recommended for patients with non-small cell lung cancer (NSCLC). Most patients with NSCLC who test positive for the EGFR mutation and receive TKIs develop resistance to these drugs. Questions remain regarding which treatment sequence is optimal for patients with EGFR-mutant NSCLC, and few studies have evaluated patterns of TKI treatment use in NSCLC, irrespective of EGFR mutation status, in a real-world setting...
October 19, 2018: Advances in Therapy
Diego Kauffmann-Guerrero, Kathrin Kahnert, Jörg Kumbrink, Zulfiya Syunyaeva, Amanda Tufman, Rudolf M Huber
No abstract text is available yet for this article.
September 21, 2018: Clinical Lung Cancer
Jeffrey R Gehlhausen, Eric Hawley, Benjamin Mark Wahle, Yongzheng He, Donna Edwards, Steven D Rhodes, Jacquelyn D Lajiness, Karl Staser, Shi Chen, Xianlin Yang, Jin Yuan, Xiaohong Li, Li Jiang, Abbi Smith, Waylan Bessler, George Sandusky, Anat Stemmer-Rachamimov, Timothy J Stuhlmiller, Steven P Angus, Gary L Johnson, Grzegorz Nalepa, Charles W Yates, D Wade Clapp, Su-Jung Park
Schwannomas are common, highly morbid, and medically untreatable tumors that can arise in patients with germline as well as somatic mutations in NF2. These mutations most commonly result in the loss of function of the NF2 encoded protein, Merlin. Little is known about how Merlin functions endogenously as a tumor suppressor and how its loss leads to oncogenic transformation in Schwann cells. Here, we identify NF-κB-inducing kinase (NIK) as a potential drug target driving NF-κB signaling and Merlin-deficient schwannoma genesis...
October 17, 2018: Human Molecular Genetics
O V Kurushina, V V Myroshnikova, P S Krivonozhkina
The familial form of the Creutzfeldt-Jakob disease (ffCJD) refers to a group of rare and severe neurodegenerative diseases associated with pathologic prion protein accumulation. The cause of disease is genetically determined. The disease has a continuously progressive course leading to death in 100% of cases. The symptoms of dementia dominate in the clinical picture. The authors describe a clinical case of subacute dementia in a 32-year-old patient. The disease had a progressive course. A preliminary diagnosis of ffCJD was established after neurological, psychiatric, genetic examinations and dynamic observation...
2018: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Przemyslaw W Twardowski, Catherine M Tangen, Xiwei Wu, Melissa R Plets, Elizabeth R Plimack, Neeraj Agarwal, Nicholas J Vogelzang, Jinhui Wang, Shu Tao, Ian M Thompson, Primo Lara
Background: Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway. A randomized multicenter parallel two-stage phase II trial of MET inhibitor tivantinib alone or in combination with EGFR inhibitor erlotinib was conducted in patients with pRCC. Methods: Patients with advanced pRCC and 0-1 prior systemic therapy were randomly assigned to tivantinib 360 mg BID (Arm 1) or tivantinib 360 mg BID plus erlotinib 150 mg daily (Arm 2)...
November 27, 2017: Kidney cancer
Inmaculada C Rodríguez-Rojo, Pablo Cuesta, María Eugenia López, Jaisalmer de Frutos-Lucas, Ricardo Bruña, Ernesto Pereda, Ana Barabash, Pedro Montejo, Mercedes Montenegro-Peña, Alberto Marcos, Ramón López-Higes, Alberto Fernández, Fernando Maestú
The pathophysiological processes undermining brain functioning decades before the onset of the clinical symptoms associated with dementia are still not well understood. Several heritability studies have reported that the Brain Derived Neurotrophic Factor ( BDNF ) Val66Met genetic polymorphism could contribute to the acceleration of cognitive decline in aging. This mutation may affect brain functional connectivity (FC), especially in those who are carriers of the BDNF Met allele. The aim of this work was to explore the influence of the BDNF Val66Met polymorphism in whole brain eyes-closed, resting-state magnetoencephalography (MEG) FC in a sample of 36 cognitively intact (CI) older females...
2018: Frontiers in Neuroscience
David Van Mater, Eric Xu, Anupama Reddy, Leonor Añó, Mohit Sachdeva, Wesley Huang, Nerissa Williams, Yan Ma, Cassandra Love, Lanie Happ, Sandeep Dave, David G Kirsch
Cancer results from the accumulation of genetic mutations in a susceptible cell of origin. We and others have also shown that injury promotes sarcoma development, but how injury cooperates with genetic mutations at the earliest stages of tumor formation is not known. Here, we utilized dual recombinase technology to dissect the complex interplay of the timing of KrasG12D activation, p53 deletion, and muscle injury in sarcomagenesis using a primary mouse model of soft tissue sarcoma. When mutations in oncogenic Kras and p53 are separated by 3 weeks, few sarcomas develop without injury...
October 18, 2018: JCI Insight
Sunu Budhi Raharjo, Rido Maulana, Irma Maghfirah, Fatimah Alzahra, Agnes Dinar Putrinarita, Dicky A Hanafy, Yoga Yuniadi
Mutations in the gene encoding the main cardiac sodium channel (SCN5A) are the commonest genetic cause of Brugada syndrome (BrS). However, the effect of SCN5A mutations on the outcomes of ventricular fibrillation (VF) and syncope remains uncertain. To clarify this relationship, a meta-analysis was performed. A comprehensive search was conducted to identify all eligible studies from PubMed, MEDLINE, EBSCO, ProQuest, Science Direct, Clinical Key, and Cochrane database for cohort studies of BrS populations that had been systematically tested for SCN5A mutations...
October 2018: Journal of Arrhythmia
Huiyan Deng, Chang Liu, Guoliang Zhang, Xiaoling Wang, Yueping Liu
ALK and ROS1 are prognostic and predictive tumor markers in non-small cell lung carcinoma (NSCLC), which are more often found in lung adenocarcinomas as with other oncogenes such as EGFR, KRAS, or C-MET. Their positivity is 2.6% and 1.3%, respectively, and patients who have mutations in both genes are extremely rare. Here, we report a 61-year-old male diagnosed with acinar adenocarcinoma, who was shown to have both ALK and ROS1 rearrangements but was EGFR- and C-MET mutation-negative. He was treated surgically and received targeted therapy...
October 1, 2018: Pathology, Research and Practice
Charu Aggarwal, Jeffrey C Thompson, Taylor A Black, Sharyn I Katz, Ryan Fan, Stephanie S Yee, Austin L Chien, Tracey L Evans, Joshua M Bauml, Evan W Alley, Christine A Ciunci, Abigail T Berman, Roger B Cohen, David B Lieberman, Krishna S Majmundar, Samantha L Savitch, Jennifer J D Morrissette, Wei-Ting Hwang, Kojo S J Elenitoba-Johnson, Corey J Langer, Erica L Carpenter
Importance: The clinical implications of adding plasma-based circulating tumor DNA next-generation sequencing (NGS) to tissue NGS for targetable mutation detection in non-small cell lung cancer (NSCLC) have not been formally assessed. Objective: To determine whether plasma NGS testing was associated with improved mutation detection and enhanced delivery of personalized therapy in a real-world clinical setting. Design, Setting, and Participants: This prospective cohort study enrolled 323 patients with metastatic NSCLC who had plasma testing ordered as part of routine clinical management...
October 11, 2018: JAMA Oncology
Mohammad Hamid, Ebtesam Zargan Nezhad, Hamid Galehdari, Alihossein Saberi, Gholamreza Shariati, Alireza Sedaghat
Background: Hemoglobin (Hb) Alesha is a rare and very unstable Hb variant, resulting in disruption of the heme pocket and producing severe hemolysis in heterozygous statues. In this study, we describe the first report of this variant in an Iranian boy originated from south of Iran with severe hemolytic anemia and mild splenomegaly. Methods: A six-year-old boy from Khuzestan Province and his parents were studied. Gap-PCR and direct sequencing were performed to detect the a-globin gene deletions and β-globin gene mutations, respectively...
October 14, 2018: Iranian Biomedical Journal
Johanna S Ungerstedt
Myeloid hematological malignancies are clonal bone marrow neoplasms, comprising of acute myeloid leukemia (AML), the myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), the myeloproliferative neoplasms (MPN) and systemic mastocytosis (SM). The field of epigenetic regulation of normal and malignant hematopoiesis is rapidly growing. In recent years, heterozygous somatic mutations in genes encoding epigenetic regulators have been found in all subtypes of myeloid malignancies, supporting the rationale for treatment with epigenetic modifiers...
October 9, 2018: International Journal of Molecular Sciences
Maria Tsoli, Carol Wadham, Mark Pinese, Tim Failes, Swapna Joshi, Emily Mould, Julia X Yin, Velimir Gayevskiy, Amit Kumar, Warren Kaplan, Paul G Ekert, Federica Saletta, Laura Franshaw, Jie Liu, Andrew Gifford, Martin A Weber, Michael Rodriguez, Richard J Cohn, Greg Arndt, Vanessa Tyrrell, Michelle Haber, Toby Trahair, Glenn M Marshall, Kerrie McDonald, Mark J Cowley, David S Ziegler
Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic, in vitro and in vivo testing to identify actionable targets and treatment options...
October 9, 2018: Cancer Biology & Therapy
José Mario Ortega-Olvera, Robert Winkler, Betzabet Quitanilla-Vega, Mineko Shibayama, Bibiana Chávez-Munguía, Dolores Martín-Tapia, Lourdes Alarcón, Lorenza González-Mariscal
Methamidophos (MET) is an organophosphate (OP) pesticide widely used in agriculture in developing countries. MET causes adverse effects in male reproductive function in humans and experimental animals, but the underlying mechanisms remain largely unknown. We explored the effect of MET on mice testes (5 mg/kg/day/4 days), finding that this pesticide opens the blood-testis barrier and perturbs spermatogenesis, generating the appearance of immature germ cells in the epididymis. In the seminiferous tubules, MET treatment changed the level of expression or modified the stage-specific localization of tight junction (TJ) proteins ZO-1, ZO-2, occludin, and claudin-3...
October 3, 2018: Toxicology and Applied Pharmacology
Akihiro Yoshimura, Junji Uchino, Keiko Tanimura, Yusuke Chihara, Nobuyo Tamiya, Yoshiko Kaneko, Takayuki Takeda, Osamu Hiranuma, Isao Hasegawa, Yutaka Kubota, Shinsuke Shiotsu, Chieko Takumi, Noriya Hiraoka, Tadaaki Yamada, Koichi Takayama
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation show a high response to EGFR-tyrosine kinase inhibitor (EGFR-TKI). Clinically, EGFR-positive NSCLC acquires several resistance mechanisms during EGFR-TKI treatment, such as the emergence of a secondary mutation (T790M), MET gene amplification, and transformation to small cell lung cancer. However, the mechanism of resistance to afatinib, a second-generation EGFR-TKI, remains unclear. In this study, we prospectively investigate the mechanism of resistance to afatinib using proteomic analyses...
October 2018: Medicine (Baltimore)
Eiji Iwama, Kazuko Sakai, Koichi Azuma, Daijiro Harada, Kaname Nosaki, Katsuyuki Hotta, Makoto Nishio, Takayasu Kurata, Tatsuro Fukuhara, Hiroaki Akamatsu, Koichi Goto, Takayuki Shimose, Junji Kishimoto, Yoichi Nakanishi, Kazuto Nishio, Isamu Okamoto
Liquid biopsy offers a potential alternative to tissue biopsy for detection of genetic alterations in cancer, and it has been introduced into clinical practice to detect the tyrosine kinase inhibitor (TKI) resistance-conferring T790M mutation of EGFR in patients with non-small cell lung cancer (NSCLC). We prospectively collected tumor and plasma samples from 25 NSCLC patients who harbored activating mutations of EGFR and experienced failure of treatment with afatinib. The samples were analyzed by digital PCR (dPCR) and next-generation sequencing (NGS)...
October 5, 2018: Cancer Science
Ryan C Godwin, Lindsay M Macnamara, Rebecca W Alexander, Freddie R Salsbury
The fidelity of protein synthesis is largely dominated by the accurate recognition of transfer RNAs (tRNAs) by their cognate aminoacyl-tRNA synthetases. Aminoacylation of each tRNA with its cognate amino acid is necessary to maintain the accuracy of genetic code input. Aminoacylated tRNAMet functions in both initiation and elongation steps during protein synthesis. As a precursor to the investigation of a methionyl-tRNA synthetase-tRNAMet complex, presented here are the results of molecular dynamics (MD) for single nucleotide substitutions in the D-loop of tRNAMet (G15A, G18A, and G19A) probing structure/function relationships...
September 30, 2018: ACS Omega
Paul W Harms, Kelly L Harms, Patrick S Moore, James A DeCaprio, Paul Nghiem, Michael K K Wong, Isaac Brownell
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy...
October 4, 2018: Nature Reviews. Clinical Oncology
Ian W Flinn, Peter Hillmen, Marco Montillo, Zsolt Nagy, Árpád Illés, Gabriel Etienne, Julio Delgado, Bryone J Kuss, Constantine S Tam, Zoltán Gasztonyi, Fritz Offner, Scott Lunin, Francesco Bosch, Matthew S Davids, Nicole Lamanna, Ulrich Jaeger, Paolo Ghia, Florence Cymbalista, Craig A Portell, Alan P Skarbnik, Amanda F Cashen, David T Weaver, Virginia M Kelly, Barry Turnbull, Stephan Stilgenbauer
Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphoinositide 3-kinase (PI3K) δ and -γ being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B cell proliferation and survival in clonal B cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a Phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO™, a global Phase 3 randomized study of duvelisib versus ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL...
October 4, 2018: Blood
Hang Yang, Yanyun Ma, Mingyao Luo, Kun Zhao, Yinhui Zhang, Guoyan Zhu, Xiaogang Sun, Fanyan Luo, Lin Wang, Chang Shu, Zhou Zhou
BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutations in the FBN1 gene. Approximately 90% of classic MFS patients have a FBN1 mutation that can be identified by single-gene sequencing or gene-panel sequencing targeting FBN1. However, a small proportion of MFS patients carry a large genomic deletion in FBN1, which cannot be detected by routine sequencing. Here, we performed an MLPA (multiplex ligation-dependent probe amplification) test to detect large deletions and/or duplications in FBN1 and TGFBR2 in 115 unrelated Chinese patients with suspected MFS or early-onset aneurysm/dissection...
October 4, 2018: Human Genomics
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