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https://www.readbyqxmd.com/read/29784736/targeted-therapy-for-patients-with-metastatic-non-small-cell-lung-cancer
#1
Karen L Reckamp
Molecular testing is recommended for initial diagnosis in patients with non-small cell lung cancer (NSCLC), according to the updated NCCN Guidelines, because targeted therapies are available that can improve patient outcomes. Targeted therapies are currently approved for EGFR mutations, ALK and ROS1 gene rearrangements, and BRAF mutations, with the list of emerging "actionable" targets growing. The 2018 NCCN Guidelines for NSCLC incorporate new therapies, including the EGFR tyrosine kinase inhibitor osimertinib and the ALK inhibitor alectinib, as first-line preferences...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29777599/immense-random-colocalization-revealed-by-automated-high-content-image-cytometry-seriously-questions-fish-as-gold-standard-for-detecting-eml4-alk-fusion
#2
Gábor Smuk, Tamás Tornóczky, László Pajor, Ilse Chudoba, Béla Kajtár, Veronika Sárosi, Gábor Pajor
EML4-ALK gene fusion (inv2(p21p23)) of non-small cell lung cancer (NSCLC) predisposes to tyrosine kinase inhibitor treatment. One of the gold standard diagnostics is the dual color (DC) break-apart (BA) FISH technique, however, the unusual closeness of the involved genes has been suggested to raise likelihood of random co-localization (RCL) of signals. Although this is suspected to decrease sensitivity (often to as low as 40-70%), the exact level and effect of RCL has not been revealed thus far. Signal distances were analyzed to the 0...
May 19, 2018: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
https://www.readbyqxmd.com/read/29776956/integrin-%C3%AE-3-inhibition-enhances-the-antitumor-activity-of-alk-inhibitor-in-alk-rearranged-nsclc
#3
Ka-Won Noh, Insuk Sohn, Ji-Young Song, Hyun-Tae Shin, Yu Jin Kim, Kyungsoo Jung, Minjung Sung, Mingi Kim, Sungbin An, Joungho Han, Se-Hoon Lee, Mi-Sook Lee, Yoon-La Choi
BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive cancers are sensitive to small molecule ALK kinase inhibitors, but most cases experience failure following treatment. Hence, additional drug targets and combination therapeutic treatments are needed. We investigated gene expression that is regulated by the expression of ALK and explored its roles in cancer progression and therapeutic implication. PATIENTS AND METHODS: We screened ALK-rearranged non-small cell lung cancer (NSCLC) cases using immunohistochemistry and fluorescence in situ hybridization, and then conducted multiplex gene expression analysis...
May 18, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29775614/tumor-dependent-secretion-of-close-homolog-of-l1-results-in-elevation-of-its-circulating-level-in-mouse-model-for-human-lung-tumor
#4
Norihiro Kotani, Yui Ida, Takanari Nakano, Izumi Sato, Ryusuke Kuwahara, Arisa Yamaguchi, Masahiro Tomita, Koichi Honke, Takayuki Murakoshi
Close homolog of L1 (CHL1) and its truncated form mainly play crucial roles in mouse brain development and neural functions. Herein, we newly identified that truncated form of CHL1 is produced and released from lung tumor tissue in a mouse model expressing human EML4-ALK fusion gene. Both western blot and direct ELISA analysis revealed that mouse CHL1 level in serum (including serum extracellular vesicles) was significantly elevated in EML4-ALK transgenic mice. The correlation between the tumor size and the amount of CHL1 secretion could be examined in this study, and showed a significant positive correlation in a tumor size-dependent manner...
May 15, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29774128/systematic-review-and-meta-analysis-of-selected-toxicities-of-approved-alk-inhibitors-in-metastatic-non-small-cell-lung-cancer
#5
Rubens Barros Costa, Ricardo L B Costa, Sarah M Talamantes, Jason B Kaplan, Manali A Bhave, Alfred Rademaker, Corinne Miller, Benedito A Carneiro, Devalingam Mahalingam, Young Kwang Chae
Introduction: Anaplastic lymphoma kinase ( ALK ) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update. Materials and Methods: A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29774063/dual-target-gene-therapy-to-eml4-alk-nsclc-by-a-gold-nanoshell-based-system
#6
Siwen Li, Yuxi Liu, Yalan Rui, Liping Tang, Samuel Achilefu, Yueqing Gu
Although EML4-ALK transforming fusion gene is represented in only 8% of non-small cell lung cancer (NSCLC) cases, its expression is partly responsive for the failure of current NSCLC treatments. Preventing secondary mutation of the ALK protein through direct gene manipulation could overcome NSCLC drug resistance. Method: In this study, we developed a gold nanoshell (HAuNs) drug carrier for delivery and selective photo-thermal release of genes that target ALK and microRNA-301 in NSCLC. Additionally, the densely-coated nanoshell adsorbed high amounts of the positively-charged anticancer drug doxorubicin (DOX), generating an exciting multidimensional treatment strategy that includes gene-, thermal- and chemo- therapy...
2018: Theranostics
https://www.readbyqxmd.com/read/29768119/exploratory-analysis-of-brigatinib-activity-in-patients-with-anaplastic-lymphoma-kinase-positive-non-small-cell-lung-cancer-and-brain-metastases-in-two-clinical-trials
#7
D Ross Camidge, Dong-Wan Kim, Marcello Tiseo, Corey J Langer, Myung-Ju Ahn, Alice T Shaw, Rudolf M Huber, Maximilian J Hochmair, Dae Ho Lee, Lyudmila A Bazhenova, Kathryn A Gold, Sai-Hong Ignatius Ou, Howard L West, William Reichmann, Jeff Haney, Tim Clackson, David Kerstein, Scott N Gettinger
Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials...
May 16, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29764592/-analysis-of-the-first-diagnosis-symptom-and-its-influencing-factors-in-500-patients-with-lung-cancer
#8
Xin Zhang, Puyuan Xing, Xuezhi Hao, Junling Li
BACKGROUND: As the morbidity and mortality in lung cancer keep raising, we are here to discuss the effect of clinical features especially the initial symptomon on diagnosis and follow-up treatment of newly diagnosed lung cancer patients. METHODS: The clinical features of the 500 patients with lung cancer in our hospital from March, 2017 to May, 2017 were analyzed retrospectively, including the initial symptom, stage, biomarkers, pathology, etc. RESULTS: There were 266 famle (53...
May 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/29764505/xenograft-tumors-derived-from-malignant-pleural-effusion-of-the-patients-with-non-small-cell-lung-cancer-as-models-to-explore-drug-resistance
#9
Yunhua Xu, Feifei Zhang, Xiaoqing Pan, Guan Wang, Lei Zhu, Jie Zhang, Danyi Wen, Shun Lu
BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively...
May 9, 2018: Cancer communications
https://www.readbyqxmd.com/read/29762727/development-of-targeted-therapy-and-immunotherapy-for-treatment-of-small-cell-lung-cancer
#10
Motonobu Saito, Kouya Shiraishi, Akiteru Goto, Hiroyuki Suzuki, Takashi Kohno, Koji Kono
Targeted therapy against druggable genetic aberrations has shown a significantly positive response rate and longer survival in various cancers, including lung cancer. In lung adenocarcinoma (LADC), specific thyroxin kinase inhibitors against EGFR mutations and ALK fusions are used as a standard treatment regimen and show significant positive efficacy. On the other hand, targeted therapy against driver gene aberrations has not been adapted yet in small cell lung cancer (SCLC). This is because driver genes and druggable aberrations are rarely identified by next generation sequencing in SCLC...
May 14, 2018: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29760954/the-p53-activator-overcomes-resistance-to-alk-inhibitors-by-regulating-p53-target-selectivity-in-alk-driven-neuroblastomas
#11
Makoto Miyazaki, Ryo Otomo, Yuko Matsushima-Hibiya, Hidenobu Suzuki, Ayana Nakajima, Naomi Abe, Arata Tomiyama, Koichi Ichimura, Koichi Matsuda, Toshiki Watanabe, Takahiro Ochiya, Hitoshi Nakagama, Ryuichi Sakai, Masato Enari
Anaplastic lymphoma kinase (ALK) is an oncogenic receptor tyrosine kinase that is activated by gene amplification and mutation in neuroblastomas. ALK inhibitors can delay the progression of ALK-driven cancers, but are of limited use owing to ALK inhibitor resistance. Here, we show that resistance to ALK inhibitor in ALK-driven neuroblastomas can be attenuated by combination treatment with a p53 activator. Either ALK inhibition or p53 activator treatment induced cell cycle arrest, whereas combination treatment induced apoptosis, and prevented tumour relapse both in vitro and in vivo...
2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29758012/the-long-non-coding-rna-mir503hg-enhances-proliferation-of-human-alk-negative-anaplastic-large-cell-lymphoma
#12
Po-Shuan Huang, I-Hsiao Chung, Yang-Hsiang Lin, Tzu-Kang Lin, Wei-Jan Chen, Kwang-Huei Lin
Anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) is a rare type of highly malignant, non-Hodgkin lymphoma. Currently, only a few gene rearrangements have been linked to ALK-negative ALCL progression. However, the specific molecular mechanisms underlying the growth of ALK-negative ALCL tumors remain unclear. Here, we investigated aberrantly expressed, long non-coding RNAs (lncRNAs) in ALK-negative ALCL and assessed their potential biological function. MIR503HG ( miR-503 host gene) was highly expressed in ALK-negative cell lines and was significantly upregulated in tumors in mice formed from ALK-negative ALCL cell lines...
May 14, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29755689/a-subgroup-of-pleural-mesothelioma-expresses-alk-protein-and-may-be-targetable-by-combined-rapamycin-and-crizotinib-therapy
#13
Dina Mönch, Sabine Bode-Erdmann, Jörg Kalla, Jörn Sträter, Carsten Schwänen, Roger Falkenstern-Ge, Siegfried Klumpp, Godehard Friedel, German Ott, Claudia Kalla
Malignant pleural mesothelioma (MPM) is a neoplasm with inferior prognosis and notorious chemotherapeutic resistance. Targeting aberrantly overexpressed kinases to cure MPM is a promising therapeutic strategy. Here, we examined ALK, MET and mTOR as potential therapeutic targets and determined the combinatorial efficacy of ALK and mTOR targeting on tumor cell growth in vivo . First, ALK overexpression, rearrangement and mutation were studied in primary MPM by qRT-PCR, FISH, immunohistochemistry and sequence analysis; mTOR and MET expression by qRT-PCR and immunohistochemistry...
April 17, 2018: Oncotarget
https://www.readbyqxmd.com/read/29747676/epithelioid-cell-histiocytoma-with-sqstm1-alk-fusion-a-case-report
#14
Ryuko Nakayama, Yuki Togashi, Satoko Baba, Yo Kaku, Yuki Teramoto, Takaki Sakurai, Hironori Haga, Kengo Takeuchi
BACKGROUND: Epithelioid cell histiocytoma (ECH), which is also known as epithelioid benign fibrous histiocytoma, has been classified as a rare variant of fibrous histiocytoma (FH). However, the recent detection of ALK protein expression and/or ALK gene rearrangement in ECH suggests that it might be biologically different from conventional FH. CASE PRESENTATION: A 27-year-old male presented with nodule on his left foot, which had been present for 5 years. A macroscopic examination revealed an exophytic, hyperkeratotic nodule on the dorsum of the left foot...
May 10, 2018: Diagnostic Pathology
https://www.readbyqxmd.com/read/29746612/clinical-significance-of-complex-glandular-patterns-in-lung-adenocarcinoma-clinicopathologic-and-molecular-study-in-a-large-series-of-cases
#15
Muyu Kuang, Xuxia Shen, Chongze Yuan, Haichuan Hu, Yang Zhang, Yunjian Pan, Chao Cheng, Difan Zheng, Lei Cheng, Yue Zhao, Xiaoting Tao, Yuan Li, Haiquan Chen, Yihua Sun
Objectives: To explore whether complex glandular patterns (CGPs) have a potential role in the clinical management of patients with lung adenocarcinoma. Methods: We included 356 patients with lung adenocarcinoma with available clinicopathologic information, gene mutations, and clinical outcomes for analysis. Results: We identified 54 (15.2%) CGP-predominant cases. The CGPs were associated with ALK rearrangement and HER2 mutation. Survival analysis showed that the clinical outcome of CGP-predominant patients was worse than that for acinar-predominant patients (overall survival [OS], 66...
May 9, 2018: American Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29742496/ceritinib-enhances-the-efficacy-of-substrate-chemotherapeutic-agent-in-human-abcb1-overexpressing-leukemia-cells-in-vitro-in-vivo-and-ex-vivo
#16
Li Yang, Manjun Li, Fang Wang, Chen Zhen, Min Luo, Xiaona Fang, Hong Zhang, Jianye Zhang, Qingshan Li, Liwu Fu
BACKGROUND/AIMS: Multidrug resistance (MDR) triggered by ATP binding cassette (ABC) transporters, such as ABCB1, ABCC1, and ABCG2, is a key obstacle for successful cancer chemotherapy. There is currently no FDA-approved MDR modulator that can be used in clinic. Ceritinib, a selective ALK inhibitor, has been approved as the second-line treatment for ALK-positive non-small cell lung cancer. Here, we examined the role of ceritinib in leukemia associated MDR in therapy. METHODS: The cell proliferation was detected by MTT assay...
May 5, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29738763/3d-culture-system-containing-gellan-gum-restores-oncogene-dependence-in-ros1-rearrangements-non-small-cell-lung-cancer
#17
Bo Gong, Tomoko Oh-Hara, Naoya Fujita, Ryohei Katayama
The ROS1 fusion gene has been identified in approximately 1% of non-small cell lung cancer (NSCLC) cases. Several clinical studies have highlighted ROS1 as a promising therapeutic target because crizotinib, a multi-targeted drug against ROS1, ALK, and the MET proto-oncogene, has elicited remarkable responses in ROS1-rearrangements NSCLC. However, acquired resistance mediated by ROS1 kinase domain mutations has been identified and a system to assess ROS1 inhibitors for these resistant mutations is necessary for the promotion of drug development...
May 5, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29737033/clonally-related-primary-alk-rearranged-adenocarcinoma-and-associated-metastatic-lesions
#18
You-Cai Zhu, Yun-Te Deng, Wen-Xian Wang, Chun-Wei Xu, Wu Zhuang, Kai-Qi Du
ALK rearrangement is a driver gene in non-small cell lung cancer (NSCLC). ALK-positive tumors are sensitive to ALK-tyrosine kinase inhibitors (TKIs). The detection of key driver genes is crucial to enable personalized treatment. Different histomorphological patterns have different driver genes. Herein, we report the case of a 42-year-old male patient diagnosed with adenocarcinoma with different histomorphologies in the primary lung site (mucinous type) and lymph node metastasis (solid type), of the same genotype, both presenting with ALK rearrangement but negative for EGFR mutation...
May 8, 2018: Thoracic Cancer
https://www.readbyqxmd.com/read/29732009/non-invasive-tumor-genotyping-using-radiogenomic-biomarkers-a-systematic-review-and-oncology-wide-pathway-analysis
#19
REVIEW
Robin W Jansen, Paul van Amstel, Roland M Martens, Irsan E Kooi, Pieter Wesseling, Adrianus J de Langen, Catharina W Menke-Van der Houven van Oordt, Bernard H E Jansen, Annette C Moll, Josephine C Dorsman, Jonas A Castelijns, Pim de Graaf, Marcus C de Jong
With targeted treatments playing an increasing role in oncology, the need arises for fast non-invasive genotyping in clinical practice. Radiogenomics is a rapidly evolving field of research aimed at identifying imaging biomarkers useful for non-invasive genotyping. Radiogenomic genotyping has the advantage that it can capture tumor heterogeneity, can be performed repeatedly for treatment monitoring, and can be performed in malignancies for which biopsy is not available. In this systematic review of 187 included articles, we compiled a database of radiogenomic associations and unraveled networks of imaging groups and gene pathways oncology-wide...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29713646/mutational-profiling-of-non-small-cell-lung-cancer-resistant-to-osimertinib-using-next-generation-sequencing-in-chinese-patients
#20
Keke Nie, Haiping Jiang, Chunling Zhang, Chuanxin Geng, Xiajuan Xu, Ling Zhang, Hao Zhang, Zhongfa Zhang, Ketao Lan, Youxin Ji
Purpose: To identify the somatic mutated genes for optimal targets of non-small-cell lung cancer after resistance to osimertinib treatment. Patients and Methods: Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS)...
2018: BioMed Research International
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