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https://www.readbyqxmd.com/read/28644066/express-combination-targeted-pulmonary-hypertension-therapy-in-the-resolution-of-dasatinib-associated-pulmonary-arterial-hypertension
#1
Arun Jose, Hind Rafei, Jalil Ahari
No abstract text is available yet for this article.
January 1, 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28639957/pulmonary-arterial-hypertension-induced-by-tyrosine-kinase-inhibitors
#2
Jason Weatherald, Marie-Camille Chaumais, David Montani
PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several neoplastic conditions; however, pulmonary arterial hypertension (PAH) has been reported as a complication of TKIs, predominantly with dasatinib. Recent studies have elucidated the potential mechanisms of TKI-induced PAH and have better clarified the long-term outcomes. RECENT FINDINGS: In addition to the known association between dasatinib and PAH, several other TKIs have recently been reported to cause PAH, including ponatinib, bosutinib and lapatinib...
July 20, 2017: Current Opinion in Pulmonary Medicine
https://www.readbyqxmd.com/read/28638122/synergistic-effects-of-various-her-inhibitors-in-combination-with-igf-1r-c-met-and-src-targeting-agents-in-breast-cancer-cell-lines
#3
Aryan Stanley, G Hossein Ashrafi, Alan M Seddon, Helmout Modjtahedi
Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER-family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28637715/tyrosine-kinase-inhibitors-protect-the-salivary-gland-from-radiation-damage-by-inhibiting-activation-of-protein-kinase-c-%C3%AE
#4
Sten M Wie, Elizabeth Wellberg, Sana D Karam, Mary E Reyland
In patients undergoing irradiation therapy, injury to non-tumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined Protein Kinase C-delta (PKCδ) as a regulator of DNA damage induced apoptosis and have shown that phosphorylation of PKCδ by c-Abl and c-Src activates its pro-apoptotic function.  Here we have explored the use of tyrosine kinase inhibitors (TKIs) of c-Src and c-Abl to block activation of PKCδ for radioprotection of the salivary gland.  Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKCδ and inhibited IR-induced apoptosis in vitro  To determine if TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation...
June 21, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28622336/a-knowledge-based-t2-statistic-to-perform-pathway-analysis-for-quantitative-proteomic-data
#5
En-Yu Lai, Yi-Hau Chen, Kun-Pin Wu
Approaches to identify significant pathways from high-throughput quantitative data have been developed in recent years. Still, the analysis of proteomic data stays difficult because of limited sample size. This limitation also leads to the practice of using a competitive null as common approach; which fundamentally implies genes or proteins as independent units. The independent assumption ignores the associations among biomolecules with similar functions or cellular localization, as well as the interactions among them manifested as changes in expression ratios...
June 16, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28608850/cellular-senescence-drives-age-dependent-hepatic-steatosis
#6
Mikolaj Ogrodnik, Satomi Miwa, Tamar Tchkonia, Dina Tiniakos, Caroline L Wilson, Albert Lahat, Christoper P Day, Alastair Burt, Allyson Palmer, Quentin M Anstee, Sushma Nagaraja Grellscheid, Jan H J Hoeijmakers, Sander Barnhoorn, Derek A Mann, Thomas G Bird, Wilbert P Vermeij, James L Kirkland, João F Passos, Thomas von Zglinicki, Diana Jurk
The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state of irreversible cell-cycle arrest combined with the secretion of proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute to age-related tissue degeneration. Here we show that the accumulation of senescent cells promotes hepatic fat accumulation and steatosis. We report a close correlation between hepatic fat accumulation and markers of hepatocyte senescence. The elimination of senescent cells by suicide gene-meditated ablation of p16(Ink4a)-expressing senescent cells in INK-ATTAC mice or by treatment with a combination of the senolytic drugs dasatinib and quercetin (D+Q) reduces overall hepatic steatosis...
June 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28606127/augmentation-of-the-anticancer-activity-of-cyt997-in-human-prostate-cancer-by-inhibiting-src-activity
#7
Yong Teng, Yafei Cai, Wenhu Pi, Lixia Gao, Chloe Shay
BACKGROUND: Abnormalities of tubulin polymerization and microtubule assembly are often seen in cancer, which make them very suitable targets for the development of therapeutic approach against rapidly dividing and aggressive cancer cells. CYT997 is a novel microtubule-disrupting agent with anticancer activity in multiple cancer types including prostate cancer. However, the molecular mechanisms of action of CYT997 in prostate cancer have not been well characterized. METHODS: Src knockdown cells were achieved by lentiviral-mediated interference...
June 12, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28599428/bosutinib-as-a-fourth-line-therapy-for-a-patient-with-t315i-positive-lymphoid-blastic-phase-chronic-myeloid-leukemia-a-case-report
#8
Yukiko Komeno, Naoyuki Uchida, Yumiko Satoh, Hideki Uryu, Yuko Iwata, Akiko Masuda, Kuniko Iihara, Yutaka Yatomi, Shuichi Taniguchi, Tomiko Ryu
A 35-year-old male was diagnosed with chronic myeloid leukemia in the chronic phase and was prescribed 100 mg daily dasatinib. However, dasatinib was discontinued due to thrombocytopenia, and within six months, the disease progressed to the lymphoid blastic phase. Hyper-cyclophosphamide, vincristine, adriamycin and dexamethasone chemotherapy combined with 140 mg dasatinib or 600 mg imatinib was prescribed. The two inhibitors were soon discontinued due to severe thrombocytopenia and jaundice, respectively. Myelosuppression persisted subsequent to the nadir...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28599273/targeting-bcr-abl-stem-progenitor-cells-and-bcr-abl-t315i-mutant-cells-by-effective-inhibition-of-the-bcr-abl-tyr177-grb2-complex
#9
Min Chen, Ali G Turhan, Hongxia Ding, Qingcong Lin, Kun Meng, Xiaoyan Jiang
Treatment of BCR-ABL+ human leukemia has been significantly improved by ABL tyrosine kinase inhibitors (TKIs), but they are not curative for most patients and relapses are frequently associated with BCR-ABL mutations, warranting new targets for improved treatments. We have now demonstrated that protein expression of human estrogen receptor alpha 36 (ERα36), an alternative splicing variant of human estrogen receptor alpha 66 (ERα66), is highly increased in TKI-insensitive CD34+ chronic myeloid leukemia (CML) cells and BCR-ABL-T315I mutant cells, and is abnormally localized in plasma membrane and cytoplasm...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28592067/-combination-of-pp242-and-dasatinib-suppresses-the-progression-of-acute-myeloid-leukemia-in-a-mouse-model
#10
Y H Qu, H T Liu, F C He
Objective: To establish the acute myeloid leukemia (AML) mouse model, and to preliminarily investigate the efficiency of dasatinib, a tryosine kinase inhibitor, and PP242, an inhibitor of PI3K/Akt/mTOR signaling pathway in the development of AML. Methods: The lineage(-) (Lin(-)) cells of C57BL/6J were transduced with retrovirus carrying MSCV-MLL-AF9-IRES-GFP fusion gene. The transduced cells were transplanted into lethally irradiated recipient mice to induce AML, and then the AML mouse model were established...
May 30, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28587364/cytotoxic-effects-of-15-deoxy-%C3%AE-12-14-prostaglandin-j2-alone-and-in-combination-with-dasatinib-against-uterine-sarcoma-in-vitro
#11
Takako Kawakita, Nisimura Masato, Eri Takiguchi, Akiko Abe, Minoru Irahara
Effective chemotherapeutic strategies for uterine sarcoma are lacking; existing therapies achieve poor response rates. Previous studies have identified the prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) as a potential anticancer treatment; however, its effectiveness in uterine sarcoma has not been examined. Furthermore, the molecular mechanisms underlying the cytotoxic mechanism of 15d-PGJ2 remain unclear. Here, we evaluated the effects of 15d-PGJ2 alone and in combination with the tyrosine kinas inhibitor (TKI) dasatinib in uterine sarcoma cell lines (MES-SA, MES-SA/DX5 and SKN)...
June 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28580424/how-and-when-does-an-anticancer-drug-leave-its-binding-site
#12
Pratyush Tiwary, Jagannath Mondal, B J Berne
Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding...
May 2017: Science Advances
https://www.readbyqxmd.com/read/28573668/establishing-a-chemical-genetic-link-between-bruton-tyrosine-kinase-activity-in-malignant-b-cells-and-cell-functions-involved-in-the-micro-environmental-dialogue
#13
Elisa Göckeritz, Verena Vondey, Anna Guastafierro, Maja Pizevska, Floyd Hassenrück, Lars Neumann, Michael Hallek, Günter Krause
To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK-T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment...
June 1, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28566433/mtorc1-inhibition-induces-resistance-to-methotrexate-and-6-mercaptopurine-in-ph-and-ph-like-b-all
#14
Thanh-Trang T Vo, Jong-Hoon S Lee, Duc Nguyen, Brandon Lui, William Pandori, Andrew Khaw, Sharmila Mallya, Mengrou Lu, Markus Müschen, Marina Konopleva, David A Fruman
Elevated activity of the mechanistic target of rapamycin (mTOR) is associated with poor prognosis and higher incidence of relapse in B-cell acute lymphoblastic leukemia (B-ALL). Thus, ongoing clinical trials are testing mTOR inhibitors in combination with chemotherapy in B-ALL. However, the combination of mTOR inhibitors with standard of care chemotherapy drugs has not been studied extensively in high risk B-ALL subtypes. Therefore, we tested whether mTOR inhibition can augment the efficacy of current chemotherapy agents in Ph(+) and Ph-like B-ALL models...
May 31, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28566383/drug-modulators-of-b-cell-signaling-pathways-and-epstein-barr-virus-lytic-activation
#15
John G Kosowicz, Jaeyeun Lee, Brandon Peiffer, Zufeng Guo, Jianmeng Chen, Gangling Liao, S Diane Hayward, Jun O Liu, Richard F Ambinder
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block BCR signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction...
May 31, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28566209/de-escalation-of-tyrosine-kinase-inhibitor-dose-in-patients-with-chronic-myeloid-leukaemia-with-stable-major-molecular-response-destiny-an-interim-analysis-of-a-non-randomised-phase-2-trial
#16
Richard E Clark, Fotios Polydoros, Jane F Apperley, Dragana Milojkovic, Christopher Pocock, Graeme Smith, Jenny L Byrne, Hugues de Lavallade, Stephen G O'Brien, Tony Coffey, Letizia Foroni, Mhairi Copland
BACKGROUND: Discontinuation of tyrosine kinase inhibitor (TKI) therapy is feasible for some patients with chronic myeloid leukaemia with deep molecular responses; however, patients with stable major molecular response (MMR), but not MR4, have not been studied, nor has the effect of treatment de-escalation rather than outright cessation. We aimed to examine the effects of treatment de-escalation as a prelude to complete cessation, not only in patients with MR4 or greater, but also in those with MMR but not MR4...
May 26, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28559019/il6-is-associated-with-response-to-dasatinib-and-cetuximab-phase-ii-clinical-trial-with-mechanistic-correlatives-in-cetuximab-resistant-head-and-neck-cancer
#17
L P Stabile, A M Egloff, M K Gibson, W E Gooding, J Ohr, P Zhou, N J Rothenberger, L Wang, J L Geiger, J T Flaherty, J R Grandis, J E Bauman
OBJECTIVE: Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. PATIENTS AND METHODS: We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA...
June 2017: Oral Oncology
https://www.readbyqxmd.com/read/28557248/ponatinib-induced-widespread-ichthyosiform-eruption
#18
F Derlino, S Barruscotti, P Zappasodi, V Brazzelli, C Vassallo
Ponatinib is a new potent third-generation tyrosine kinase inhibitor (TKI), developed for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukaemia (ALL) resistant to first (imatinib) and second generation (dasatinib and nilotinib) TK-inhibitors. Aimed at wild type and mutant BCR-ABL, ponatinib demonstrates significant anti-leukemic activity and holds much promise in treating other malignancies, including gastrointestinal stromal tumors (GIST)(1;2). This article is protected by copyright...
May 30, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/28556300/development-of-protein-degradation-inducers-of-oncogenic-bcr-abl-protein-by-conjugation-of-abl-kinase-inhibitors-and-iap-ligands
#19
Norihito Shibata, Naoki Miyamoto, Katsunori Nagai, Kenichiro Shimokawa, Tomoya Sameshima, Nobumichi Ohoka, Takayuki Hattori, Yasuhiro Imaeda, Hiroshi Nara, Nobuo Cho, Mikihiko Naito
Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase such as imatinib and dasatinib exhibit remarkable therapeutic effects, though emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to down-regulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named SNIPERs (Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein has been developed recently...
May 26, 2017: Cancer Science
https://www.readbyqxmd.com/read/28554234/molecular-characterization-and-therapeutic-reaction-to-dasatinib-in-a-cml-patient-harboring-a-novel-e8a2-bcr-abl1-transcript-with-a-somatic-mutation-in-tp53bp2-and-cadherin-10-genes
#20
Yang Zhang, Zhao Cheng, Wen-Zhe Yan, Su-Fang Liu, Chun-Hong Hu, Guang-Sen Zhang
No abstract text is available yet for this article.
May 30, 2017: Leukemia & Lymphoma
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