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Cindy Hunt, Alicja Michalak, Elaine Johnston, Chrissy Lefkimmiatis, Leila Macumber, Tony Jocko, Donna Ouchterlony
OBJECTIVE: Hockey is a popular sport played by many First Nation youth. Concussion frequently goes unrecognized and unreported in youth hockey. Unintentional injuries among Indigenous youth occur at rates three to four times the national Canadian average. The study sought to examine knowledge, attitudes and sources of concussion information among First Nations people attending a provincial hockey tournament. METHODS: A cross-sectional survey was undertaken. The survey by Mzazik et al...
March 19, 2018: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
Hongyang Lu, Bo Chen, Jing Qin, Fajun Xie, Na Han, Zhiyu Huang
The present study describes the case of a 48-year-old man who was diagnosed with lung adenocarcinoma with an epidermal growth factor receptor (EGFR) 21 L858R mutation. The patient received surgery and adjuvant chemotherapy. When multiple lung metastases appeared, icotinib was administered. Following resistance to icotinib, biopsy by endobroncheal ultrasonography for a right lung hilar lymph node revealed transformation to a neuroendocrine morphology. Neuron-specific enolase (NSE) levels were elevated, accompanied with disease progression following transformation to the neuroendocrine morphology...
April 2018: Oncology Letters
Xuanxuan Wang, Yanjun Gu, Hai Liu, Liming Shi, Xiaonan Sun
Background: Radiotherapy and cisplatin-based chemotherapy are currently considered as standard treatments employed for advanced cervical cancer (CC). However, patients with local recurrence or distant metastasis continue to have poor outcomes. EGFR overexpression correlated with chemo/radioresistance, and disease failure has been well proved in the previous studies. Hence, the aim of this study was to explore the therapeutic efficacy and underlying mechanism of the sensitization to radiation or cisplatin of icotinib hydrochloride (IH), a high-selective EGFR tyrosine kinase inhibitor (TKI), in the Hela S3 human CC cell line...
2018: OncoTargets and Therapy
Şuayib Yalçın, Ramazan Yildiz, Faysal Dane, Aziz Karaoğlu, Berna Öksüzoğlu, Özgür Özyılkan, Alper Sevinç, Feyyaz Özdemir, Hande Turna, Rüçhan Uslu, Esat Ulay
Introduction: The introduction of targeted therapies in renal cell carcinoma has significantly improved its prognosis and treatment outcomes in recent years. Such treatment options are targeted therapies of the vascular endothelial growth factor (VEGF) pathway and the mammalian target of the rapamycin pathway. With the use of tyrosine kinase inhibitors (TKIs) and mammalian target of the rapamycin inhibitors, overall survival has increased up to 2 years. In Turkey, due to applicable reimbursement conditions for patients with metastatic renal cell carcinoma (mRCC), interferon use is mandated as a first-line treatment, thus providing information on the use of everolimus only after initial interferon and second-line VEGF-targeted treatments such as VEGF-TKI...
2018: OncoTargets and Therapy
Sandrine Girerd, Lucie Tosca, Olivier Herault, Christine Vignon, Denis Biard, Djamel Aggoune, Fatima Dkhissi, Marie Laure Bonnet, Nathalie Sorel, Christophe Desterke, Annelise Bennaceur-Griscelli, Gerard Tachdjian, François Guilhot, Joelle Guilhot, Jean-Claude Chomel, Ali G Turhan
Manganese Superoxide dismutase 2 (SOD2) plays a crucial role in antioxidant defense but there are no data suggesting its role in genetic instability in CML. We evaluated the effects of SOD2 silencing in human UT7 cell line expressing either non-mutated or T315I-mutated BCR-ABL. Array-CGH experiments detected in BCR-ABL-expressing cells silenced for SOD2 a major genetic instability within several chromosomal loci, especially in regions carrying the glypican family (duplicated) and β-defensin genes (deleted)...
March 16, 2018: Biochemical and Biophysical Research Communications
Spencer S Watson, Mark Dane, Koei Chin, Zuzana Tatarova, Moqing Liu, Tiera Liby, Wallace Thompson, Rebecca Smith, Michel Nederlof, Elmar Bucher, David Kilburn, Matthew Whitman, Damir Sudar, Gordon B Mills, Laura M Heiser, Oliver Jonas, Joe W Gray, James E Korkola
Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib...
February 21, 2018: Cell Systems
Xiaoyuan Wang, Hang Yin, Hongxia Zhang, Jing Hu, Hailing Lu, Chunhong Li, Mengru Cao, Shi Yan, Li Cai
Acquired resistance to epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical obstacle in the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). EHD1, a protein of the C-terminal Eps15 homology domain-containing (EHD) family, plays a role in regulating endocytic recycling, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we found that a lower EHD1 expression improved both EGFR-TKIs sensitivity, which is consistent with a lower CD133 expression, and progression-free survival in NSCLC patients...
March 16, 2018: Cell Death & Disease
Meng-Shih Weng, Jer-Hwa Chang, Wen-Yueh Hung, Yi-Chieh Yang, Ming-Hsien Chien
BACKGROUND: The epidermal growth factor receptor (EGFR) plays important roles in cell survival, growth, differentiation, and tumorigenesis. Dysregulation of the EGFR is a common mechanism in cancer progression especially in non-small cell lung cancer (NSCLC). MAIN BODY: Suppression of the EGFR-mediated signaling pathway is used in cancer treatment. Furthermore, reactive oxygen species (ROS)-induced oxidative stress from mitochondrial dysfunction or NADPH oxidase (NOX) overactivation and ectopic expression of antioxidative enzymes were also indicated to be involved in EGFR-mediated tumor progression (proliferation, differentiation, migration, and invasion) and drug resistance (EGFR tyrosine kinase inhibitor (TKI))...
March 16, 2018: Journal of Experimental & Clinical Cancer Research: CR
Yang Chen, Youyou Wang, Lujun Zhao, Ping Wang, Jifeng Sun, Rudi Bao, Chenghai Li, Ningbo Liu
Objective: To investigate the potential of HS-10182, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), as a radiosensitizer in non-small cell lung cancer (NSCLC). Methods: Two cell lines of NSCLCs, A549 that possesses wild-type (WT) EGFRs and H1975 that possesses EGFR L858R/T790M double mutations, were treated with HS-10182 at various concentrations, and cell viabilities were determined using the MTS assay. The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups...
February 2018: Cancer Biology & Medicine
Yuta Takashima, Jun Sakakibara-Konishi, Yutaka Hatanaka, Kanako C Hatanaka, Yoshihito Ohhara, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Yoshihiro Matsuno, Masaharu Nishimura
BACKGROUND: Approximately 20% to 30% of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC...
February 19, 2018: Clinical Lung Cancer
Bo Zhang, Shuyuan Wang, Jie Qian, Wenjia Yang, Fangfei Qian, Jun Lu, Yanwei Zhang, Rong Qiao, Baohui Han
BACKGROUND: Two or more different epidermal growth factor receptor (EGFR) mutations can be detected within a single tumor sample, which represents complex mutations. However, the frequency and efficacy of tyrosine kinase inhibitor (TKI) treatments for patients harboring these mutations are unknown. METHODS: From January 2011 to January 2017, patients diagnosed with EGFR mutations were screened. The effectiveness of TKIs in patients with complex mutations was retrospectively analyzed...
March 15, 2018: Cancer
Maudy Walraven, Marjolein Y V Homs, Astrid A M van der Veldt, Henk Dekker, Jose Koldenhof, Richard Honeywell, Arjan Barendrecht, Silvie A E Sebastian, Naomi Parr, Arnold C Koekman, Emile E Voest, Mark Roest, Suzanne J A Korporaal, Henk M W Verheul
INTRODUCTION: At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings...
March 12, 2018: Angiogenesis
Ching-Yuan Kuo, Po-Nan Wang, Wen-Li Hwang, Cheng-Hwai Tzeng, Li-Yaun Bai, Jih-Luh Tang, Ming-Chih Chang, Sheng-Fung Lin, Tsai-Yun Chen, Yeu-Chin Chen, Tran-Der Tan, Chih-Yi Hsieh, Chinjune Lin, Clinton Lai, Darko Miljkovic, Cheng-Shyong Chang
Background: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), is approved for the treatment of patients with chronic myeloid leukemia (CML) in many countries, including Taiwan. Though a number of controlled clinical trials have demonstrated the safety and efficacy of nilotinib, studies assessing the safety and efficacy of nilotinib in routine clinical practice are limited. Methods: The current study was an open-label, single-arm study conducted across 12 centers in Taiwan in adult patients with CML in chronic or accelerated phase with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to one or more previous TKIs...
March 2018: Therapeutic Advances in Hematology
Helena Yu, Ken Suzawa, Emmet J Jordan, Ahmet Zehir, Andy Ni, Hyunjae Ryan Kim, Mark G Kris, Matthew D Hellmann, Bob T Li, Romel Somwar, David B Solit, Michael F Berger, Maria E Arcila, Gregory J Riely, Marc Ladanyi
PURPOSE: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing.      Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR mutant lung cancer. Clinical data were collected and correlated with somatic mutation data...
March 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yongchang Lai, Zhijian Zhao, Tao Zeng, Xiongfa Liang, Dong Chen, Xiaolu Duan, Guohua Zeng, Wenqi Wu
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC), and is frequently accompanied by the genetic features of von Hippel-Lindau (VHL) loss. VHL loss increases the expression of hypoxia-inducible factors (HIFs) and their targets, including epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF). The primary treatment for metastatic RCC (mRCC) is molecular-targeted therapy, especially anti-angiogenic therapy...
2018: Cancer Cell International
Xiang Cao, Yi Zhou, Hongfang Sun, Miao Xu, Xiaowen Bi, Zhihui Zhao, Binghui Shen, Fengyi Wan, Zhuan Hong, Lei Lan, Lan Luo, Zhigang Guo, Zhimin Yin
Non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations initially respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and have shown favorable outcomes. However, acquired drug resistance to EGFR-TKIs develops in almost all patients mainly due to the EGFR T790 M mutation. Here, we show that treatment with low-dose EGFR-TKI results in the emergence of the EGFR T790 M mutation and in the reduction of HSP70 protein levels in HCC827 cells. Erlotinib treatment inhibits HSP70 phosphorylation at tyrosine 41 and increases HSP70 ubiquitination, resulting in HSP70 degradation...
March 7, 2018: Cancer Letters
Weihua Li, Tian Qiu, Lei Guo, Yun Ling, Yibo Gao, Jianming Ying, Jie He
Primary EGFR T790M mutation is occasionally identified by routine mutation testing in tyrosine kinase inhibitor (TKI)-naive patients with non-small cell lung cancer (NSCLC). We herein aimed to compare the characteristics of primary and acquired T790M mutations in NSCLC patients, and their response to osimertinib. Using amplification refractory mutation system (ARMS) detection, primary T790M was identified in 0.5% (46/8723) of TKI-naive patients, whereas acquired T790M was detected in 49.7% (71/143) of TKI-relapsed patients...
March 7, 2018: Cancer Letters
Fulvio Massaro, Gioia Colafigli, Matteo Molica, Massimo Breccia
Chronic myeloid leukemia (CML) is characterized by a pathognomonic chromosomal translocation, which leads to the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus 1 (ABL1) genes, generating an oncoprotein with deregulated tyrosine kinase activity. Areas covered: In the last two decades, BCR/ABL1 kinase has become the molecular target for tyrosine kinase inhibitors (TKIs), a class of drugs that impressively improved overall survival. Despite these results, a proportion of patients experiences resistance to TKIs and need to change treatment...
March 9, 2018: Expert Review of Hematology
Małgorzata Janeczko-Czarnecka, Maryna Krawczuk-Rybak, Irena Karpińska-Derda, Maciej Niedźwiecki, Katarzyna Musioł, Magdalena Ćwiklińska, Katarzyna Drabko, Katarzyna Mycko, Tomasz Ociepa, Katarzyna Pawelec, Danuta Januszkiewicz-Lewandowska, Marek Ussowicz, Blanka Rybka, Renata Ryczan-Krawczyk, Andrzej Kołtan, Grażyna Karolczyk, Agnieszka Zaucha-Prażmo, Wanda Badowska, Krzysztof Kałwak
BACKGROUND: Chronic myeloid leukemia (CML) constitutes only 2-3% of all leukemias in pediatric patients. Philapelphia chromosome and BCR-ABL fusion are genetic hallmarks of CML, and their presence is crucial for targeted molecular therapy with tyrosine kinase inhibitors (TKIs), which replaced hematopoietic stem cell transplantation (HSCT) as a standard first-line therapy. The disease in pediatric population is rare, and despite molecular and clinical similarities to CML in adults, different approach is needed, due to the long lifetime expectancy and distinct developmental characteristics of affected children...
January 2018: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
Pierre Laneuville
Strict criteria for when to stop tyrosine kinase inhibitor (TKI) therapy in clinical practice are not easily defined without an agreement on what probability of achieving a treatment-free remission (TFR) constitutes a medically acceptable standard and consideration of the potential medical risks of continued TKI therapy and/or patient preferences. Patients in sustained deep molecular response (DMR) have no significant chronic myelogenous leukemia-related risk of progression and death, and thus, safety is of paramount importance...
March 8, 2018: Current Treatment Options in Oncology
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