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Tyrosine kinases

Wen-Jun Wang, Chao-Feng Zheng, Zhuang Liu, Yan-Hong Tan, Xiu-Hua Chen, Bin-Liang Zhao, Guo-Xia Li, Zhi-Fang Xu, Fang-Gang Ren, Yao-Fang Zhang, Jian-Mei Chang, Hong-Wei Wang
OBJECTIVE: The present study intended to establish a droplet digital PCR (dd-PCR) for monitoring minimal residual disease (MRD) in patients with BCR/ABL (P210)-positive CML, thereby achieving deep-level monitoring of tumor load and determining the efficacy for guided clinically individualized treatment. METHODS: Using dd-PCR and RT-qPCR, two cell suspensions were obtained from K562 cells and normal peripheral blood mononuclear cells by gradient dilution and were measured at the cellular level...
April 25, 2018: European Journal of Haematology
Lindsey B Crawford, Jung Heon Kim, Donna Collins-McMillen, Byeong-Jae Lee, Igor Landais, Christine Held, Jay A Nelson, Andrew D Yurochko, Patrizia Caposio
The ability of human cytomegalovirus (HCMV) to reactivate from latent infection of hematopoietic progenitor cells (HPCs) is intimately linked to cellular differentiation. HCMV encodes UL7 that our group has shown is secreted from infected cells and induces angiogenesis. In this study, we show that UL7 is a ligand for Fms-like tyrosine kinase 3 receptor (Flt-3R), a well-known critical factor in HPC differentiation. We observed that UL7 directly binds Flt-3R and induces downstream signaling cascades, including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways...
April 24, 2018: MBio
Uday P Pratap, Hannah P Priyanka, Karthik R Ramanathan, Vishak Raman, Lalgi Hima, Srinivasan Thyagarajan
OBJECTIVE: Aging is associated with the development of diseases because of immunosuppression and altered functioning of the neuroendocrine system. The medicinal properties of Morinda citrifolia L. have been widely exploited for the treatment of age-associated diseases. This study aims to investigate the in vitro and in vivo effects of noni (M. citrifolia) fruit juice (NFJ) on neuro-immunomodulation in the lymph node lymphocytes of F344 rats. METHODS: Lymphocytes isolated from axillary and inguinal lymph nodes of young (3-4 months) and old (18-21 months) rats were treated in vitro with different concentrations (0...
April 12, 2018: Journal of Integrative Medicine
H Zhang, F Yang, A F Wang, P Jia, X Wang, Y Yuan, P Zhang, Y J Xu
Objective: To investigate the effects of hepcidin on iron, osteoclasts and bone mass in iron accumulation mice. Methods: Eight-week old C57/BL6 male mice were divided into control group (CTR group), high iron group (Fe group) and iron reduction group (Hepc group). CTR group and Fe group were wild-type mice, Hepc group were hepcidin gene overexpression mice.Fe group and Hepc group were injected intraperitoneally with iron, and the mice in the CTR group were injected intraperitoneally with the same amount of saline...
April 17, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Chloe J Peach, Viviane W Mignone, Maria Augusta Arruda, Diana C Alcobia, Stephen J Hill, Laura E Kilpatrick, Jeanette Woolard
Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGFxxx a or VEGFxxx b isoforms. Alternative splicing events at exons 5⁻7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1...
April 23, 2018: International Journal of Molecular Sciences
Ryohei Kozaki, Meike Vogler, Harriet S Walter, Sandrine Jayne, David Dinsdale, Reiner Siebert, Martin J S Dyer, Toshio Yoshizawa
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines...
April 23, 2018: Cancers
Anna Tankiewicz-Kwedlo, Justyna Magdalena Hermanowicz, Krystyna Pawlak, Robert Czarnomysy, Krzysztof Bielawski, Izabela Prokop, Dariusz Pawlak
The Bruton’s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as an antileukemic agent, but applications in solid cancer have been found recently. The compound promotes apoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs. We decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal transduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by Epo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial membrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein BCL-2 in colon adenocarcinoma cells...
April 23, 2018: International Journal of Molecular Sciences
Yuji Eso, Hiroyuki Marusawa
Systemic chemotherapy using a multi-targeted tyrosine kinase inhibitor is an established treatment for advanced-stage tumors in various organs. Comprehensive genomic analyses using next-generation sequencing technology revealed the intra- and inter-tumor heterogeneity of human hepatocellular carcinomas (HCCs), and provided evidence for the use of therapeutic agents effective against multiple targets in tumor cells. Recently, the efficacy and safety of a multi-targeted tyrosine kinase inhibitor, lenvatinib, was confirmed by a randomized global phase III trial and thus lenvatinib was approved as first-line therapy for HCC, providing a new therapeutic option for patients in an advanced stage...
April 24, 2018: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Karoline Mayer-Pickel, Christina Stern, Katharina Eberhard, Uwe Lang, Barbara Obermayer-Pietsch, Mila Cervar-Zivkovic
OBJECTIVES: An imbalance of angiogenic placental factors such as endoglin, soluble fms-like tyrosine kinase 1(sFlt-1) and placental growth factor (PlGF) has been implicated in the pathophysiology of preeclampsia. This study aimed to evaluate serum levels of sFlt-1, PlGF and endoglin in women with primary and secondary antiphospholipid Syndrome (APS) and systemic lupus erythematosus (SLE) longitudinally through pregnancy. MATERIAL AND METHODS: Serum levels of sFlt-1, PlGF and endoglin were measured prospectively at 4-week intervals (from gestational weeks 12-36) in 17 women with primary APS (PAPS), 18 women with secondary APS (SAPS), and 23 women with SLE...
April 18, 2018: Journal of Reproductive Immunology
Alessandra Bisagni, Maria Pagano, Sally Maramotti, Francesca Zanelli, Martina Bonacini, Elena Tagliavini, Luca Braglia, Massimiliano Paci, Andrea Mozzarelli, Stefania Croci
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (gefitinib, erlotinib and afatinib) are indicated as first-line therapy in patients with non-small cell lung cancer (NSCLC) whose tumors harbor activating mutations in the EGFR gene. Erlotinib is also used in second and third-line therapy for patients whose tumors have wild type EGFR but to date there are no validated biomarkers useful to identify which patients may benefit from this treatment. The expression level of four miRNAs: miR-133b, -146a, -7 and -21 which target EGFR was investigated by real-time PCR in tumor specimens from NSCLC patients treated with erlotinib administered as the second or third line...
2018: PloS One
James A Kennedy, Gabriela Hobbs
PURPOSE OF REVIEW: Over the past two decades, the introduction of tyrosine kinase inhibitors (TKIs) has transformed the treatment of chronic myeloid leukemia (CML). With four agents currently approved for frontline use in chronic-phase (CP) disease, it follows that treatment decision-making has been rendered more challenging. Here we will review recent advances that help inform the selection of a first-line TKI. RECENT FINDINGS: Extended follow-up of the seminal CML trials has demonstrated the long-term efficacy of TKIs, while also highlighting significant differences in their respective toxicity profiles and potency...
April 23, 2018: Current Hematologic Malignancy Reports
Steven Lacy, Bei Yang, Jace Nielsen, Dale Miles, Linh Nguyen, Matt Hutmacher
PURPOSE: An integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in cabozantinib PK across these populations. METHODS: Plasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies...
April 23, 2018: Cancer Chemotherapy and Pharmacology
Adnan Asif Parvez Ghias, Shahzeem Bhayani, David J Gemmel, Sudershan K Garg
Gastrointestinal stromal tumors (GISTs) are rare and current estimates range from 4,000 to 6,000 number of GIST cases in the USA annually. Imatinib, a tyrosine kinase inhibitor, has shown a survival benefit in GISTs, and the presence of KIT mutation status is predictive of response. The current case discusses rapidly progressive dyspnea and heart failure in an elderly male with metastatic GIST who was started on imatinib. Although reported as a rare and sporadic side effect of imatinib, the current case illustrates rapidity and the clinical significance of cardiotoxicity, with onset at 2 weeks...
2018: Journal of Community Hospital Internal Medicine Perspectives
Jacqulyne P Robichaux, Yasir Y Elamin, Zhi Tan, Brett W Carter, Shuxing Zhang, Shengwu Liu, Shuai Li, Ting Chen, Alissa Poteete, Adriana Estrada-Bernal, Anh T Le, Anna Truini, Monique B Nilsson, Huiying Sun, Emily Roarty, Sarah B Goldberg, Julie R Brahmer, Mehmet Altan, Charles Lu, Vassiliki Papadimitrakopoulou, Katerina Politi, Robert C Doebele, Kwok-Kin Wong, John V Heymach
Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors...
April 23, 2018: Nature Medicine
Kaja Rupar, Sausan A Moharram, Julhash U Kazi, Lars Rönnstrand
KIT is a receptor tyrosine kinase (RTK) involved in several cellular processes such as regulation of proliferation, survival and differentiation of early hematopoietic cells, germ cells and melanocytes. Activation of KIT results in phosphorylation of tyrosine residues in the receptor, and recruitment of proteins that mediate downstream signaling and also modulate receptor signaling. Here we show that the SRC-like adaptor protein 2 (SLAP2) binds to wild-type KIT in a ligand-dependent manner and is furthermore found constitutively associated with the oncogenic mutant KIT-D816V...
April 23, 2018: Scientific Reports
Katrina Suzanne Evers, Andrew Atkinson, Christian Barro, Urs Fisch, Marc Pfister, Evelyn A Huhn, Olav Lapaire, Jens Kuhle, Sven Wellmann
Preeclampsia has been shown to be associated with changes in cerebral structure and cognitive function later in life. Nf (neurofilaments) are specific scaffolding proteins of neurons, and their quantification in serum has been proposed as a biomarker for neuroaxonal injury. We performed a prospective, longitudinal, single-center study at the University Hospital of Basel to determine serum Nf concentrations in pregnant women with singleton pregnancies and with high risk of preeclampsia or with early signs of preeclampsia...
April 23, 2018: Hypertension
Monica Nanni, Danilo Ranieri, Benedetta Rosato, Maria Rosaria Torrisi, Francesca Belleudi
The FGFR2b is a receptor tyrosine kinase expressed exclusively in epithelial cells. We previously demonstrated that FGFR2b induces autophagy and that this process is required for the triggering of FGFR2b-mediated keratinocytes early differentiation. However, the molecular mechanisms regulating this interplay remain to be elucidated. Since we have also recently shown that JNK1 signaling is involved in FGFR2b-induced autophagy and a possible role of JNK pathway in epidermal differentiation has been suggested but it is still debated, here we investigated the crosstalk between FGFR2b-mediated autophagy and differentiation focusing on the downstream JNK signaling...
April 23, 2018: Molecular and Cellular Biology
Joseph J Caumanns, Katrien Berns, G Bea A Wisman, Rudolf S N Fehrmann, Tushar Tomar, Harry Klip, Gert Jan Meersma, E Marielle Hijmans, Annemiek Gennissen, Evelien W Duiker, Desiree Weening, Hiroaki Itamochi, Roelof Jc Kluin, An K L Reyners, Michael J Birrer, Helga B Salvesen, Ignace Vergote, Els Van Nieuwenhuysen, James D Brenton, Elena I Braicu, Jolanta Kupryjanczyk, Beata Spiewankiewicz, Lorenza Mittempergher, Rene Bernards, Ate G J van der Zee, Steven de Jong
PURPOSE: Advanced stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in OCCC patients and test druggability of downstream affected pathways in OCCC models. EXPERIMENTAL DESIGN: In a large set of OCCC patients (n=124), the human kinome (518 kinases) and additional cancer related genes were sequenced and copy number alterations were determined...
April 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Moriz Herzberg, Meinrad Beer, Sudha Anupindi, Kurt Vollert, Thomas Kröncke
BACKGROUND: Gastrointestinal stromal tumors (GIST) are extremely rare in children. Imaging plays a key role in staging and monitoring therapy (surgical and with tyrosine kinase inhibitors). The vast majority of articles addressing imaging of GIST base on adults and are based on CT. The subtype "pediatric GIST" - if at all - is only mentioned in a dependent clause. Although the imaging features in children and adults are similar, histology, clinical course and thus imaging approach are different...
March 29, 2018: Journal of Pediatric Surgery
San-Chi Chen, Tsai-Tsen Liao, Muh-Hwa Yang
BACKGROUND: Epithelial-mesenchymal transition is an important process in embryonic development, fibrosis, and cancer metastasis. During the progression of epithelial cancer, activation of epithelial-mesenchymal transition is tightly associated with metastasis, stemness and drug resistance. However, the role of epithelial-mesenchymal transition in non-epithelial cancer is relatively unclear. MAIN BODY: Epithelial-mesenchymal transition transcription factors are critical in both myeloid and lymphoid development...
April 23, 2018: Journal of Biomedical Science
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