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https://www.readbyqxmd.com/read/29243946/ibrutinib-and-its-use-in-the-treatment-of-chronic-lymphocytic-leukemia
#1
Anna Maria Frustaci, Alessandra Tedeschi, Marina Deodato, Maddalena Mazzucchelli, Roberto Cairoli, Marco Montillo
Ibrutinib represents a revolution in chronic lymphocytic leukemia treatment scenario providing results never seen before and offering an effective therapy even in high-risk patients with really poor outcome after chemoimmunotherapy. Thanks to longer updates, on one hand, ibrutinib has confirmed its efficacy continuing to show clinical benefits over time; on the other hand, resistance mechanisms are slowly emerging. Moreover, clinicians should be aware of ibrutinib-related side effects, paying attention to screen patients that could benefit more from the drug and try to prevent adverse events...
December 15, 2017: Future Oncology
https://www.readbyqxmd.com/read/29243413/clinical-response-to-apatinib-monotherapy-in-advanced-non-small-cell-lung-cancer
#2
Jianping Xu, Xiaoyan Liu, Sheng Yang, Xiangru Zhang, Yuankai Shi
AIM: Apatinib, an oral tyrosine kinase inhibitor mainly targeting VEGFR-2, exerts both antiangiogenesis and antiproliferation effects. Apatinib shows clinical benefit in advanced non-small cell lung cancer (NSCLC) at an initial dose of 750 mg qd. We further assessed the efficacy and safety of apatinib at a more frequently used dose of 500 mg qd. The preliminary clinical outcome of apatinib in patients with brain metastases was also reported. METHODS: We retrospectively reviewed the clinical data of 25 patients who received apatinib between August 2015 and May 2016...
December 15, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29243084/quantification-of-breast-cancer-protein-biomarkers-at-different-expression-levels-in-human-tumors
#3
Yi Chen, David Britton, Elizabeth R Wood, Stephen Brantley, Michelle Fournier, Marek Wloch, Vonetta L Williams, Joseph Johnson, Anthony Magliocco, Ian Pike, John M Koomen
Liquid chromatography-selected reaction monitoring (LC-SRM) mass spectrometry has developed into a versatile tool for quantification of proteins with a wide range of applications in basic science, translational research, and clinical patient assessment. This strategy uniquely complements traditional pathology approaches, like hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC). The multiplexing capabilities offered by mass spectrometry are currently unmatched by other techniques. However, quantification of biomarkers in tissue specimens without the other data obtained from H&E-stained slides or IHC, including tumor cellularity or percentage of positively stained cells inter alia, may not provide as much information that is needed to fully understand tumor biology or properly assess the patient...
December 15, 2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29242991/mechanisms-of-resistance-to-targeted-therapies-in-chronic-myeloid-leukemia
#4
Federico Lussana, Tamara Intermesoli, Paola Stefanoni, Alessandro Rambaldi
Patients with newly diagnosed chronic myeloid leukemia (CML) usually received as first-line treatment a first- or second-generation tyrosine kinase inhibitor (TKI). Although initial responses are high, therapy fails in up to 40% of patients and initial response is lost within 2 years in approximately 25% of patients. In the last few years, intensive efforts have been spent to explain treatment failure, and different mechanisms of resistance have been identified, ranging from BCR-ABL1 kinase domain mutations to lack of adherence to therapy...
December 15, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29242937/paclitaxel-with-and-without-pazopanib-for-persistent-or-recurrent-ovarian-cancer-a-randomized-clinical-trial
#5
Debra L Richardson, Michael W Sill, Robert L Coleman, Anil K Sood, Michael L Pearl, Siobhan M Kehoe, Michael E Carney, Parviz Hanjani, Linda Van Le, Xun C Zhou, Angeles Alvarez Secord, Heidi J Gray, Lisa M Landrum, Heather A Lankes, Wei Hu, Carol Aghajanian
Importance: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors α and β; and proto-oncogene receptor tyrosine kinase (c-KIT). Objective: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer...
December 14, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/29242380/insights-into-the-proteome-of-gastrointestinal-stromal-tumors-derived-exosomes-reveals-new-potential-diagnostic-biomarkers
#6
Safinur Atay, Daniel W Wilkey, Mohammed M Milhem, Michael Merchant, Andrew K Godwin
Developing tumors continuously release nano-sized vesicles that represent circulating "fingerprints" of the tumor's identity.  In gastrointestinal stromal tumor (GIST), we have previously reported that these tumors release "oncosomes" carrying the constitutively activated tyrosine kinase (TK) receptor KIT.  Despite the clinical utility of TK inhibitors, such as imatinib mesylate (IM), recurrence and metastasis are clinical problems that urge the need to identify new tumor-derived molecules.  To this aim, we performed the first high quality proteomic study of GIST-derived exosomes (GDEs) and identified 1,060 proteins composing the core GDE proteome (cGDEp)...
December 14, 2017: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29242301/in-vitro-and-in-vivo-evidence-for-uncoupling-of-bcr-internalization-and-signaling-in-chronic-lymphocytic-leukemia
#7
Eve M Coulter, Andrea Pepper, Silvia Mele, Najeem'deen Folarin, William Townsend, Kirsty Cuthill, Elizabeth Phillips, Piers Patten, Stephen Devereux
B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand-receptor complexes. In the present study we investigated the relationship between these two processes in normal and leukemic B-cells. We found that leukemic B-cells, particularly anergic cases lacking the capacity to initiate downstream signaling, internalize and accumulate ligand in acidified endosomes more efficiently than normal B-cells...
December 14, 2017: Haematologica
https://www.readbyqxmd.com/read/29242281/fda-benefit-risk-assessment-of-osimertinib-for-the-treatment-of-metastatic-non-small-cell-lung-cancer-harboring-epidermal-growth-factor-receptor-t790m-mutation
#8
Lauretta Odogwu, Luckson Mathieu, Kirsten B Goldberg, Gideon M Blumenthal, Erin Larkins, Mallorie H Fiero, Lisa Rodriguez, Karen Bijwaard, Eunice Y Lee, Reena Philip, Ingrid Fan, Martha Donoghue, Patricia Keegan, Amy McKee, Richard Pazdur
On March 30, 2017, the U.S. Food and Drug Administration (FDA) approved osimertinib for the treatment of patients with metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive, non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed following EGFR tyrosine kinase inhibitor (TKI) therapy. Approval was based on demonstration of a statistically significant difference in the primary endpoint of progression-free survival (PFS) when comparing osimertinib with chemotherapy in an international, multicenter, open-label, randomized trial (AURA3)...
December 14, 2017: Oncologist
https://www.readbyqxmd.com/read/29242170/a-shift-in-the-il-6-stat3-signalling-pathway-imbalance-towards-the-shp2-pathway-in-severe-asthma-results-in-reduced-proliferation-process
#9
Ikhlass Haj Salem, Sophie Plante, Abdelilah S Gounni, Mahmoud Rouabhia, Jamila Chakir
BACKGROUND: Bronchial fibroblasts are the main structural cells responsible for extracellular matrix production and turnover in lung tissue. They play a key role in airway remodelling in asthma through different cytokines including interleukin (IL-6). OBJECTIVE: To decipher IL-6 signalling in bronchial fibroblasts obtained from severe eosinophilic asthmatics compared to mild asthmatics and healthy controls. METHODS: Human bronchial fibroblasts were isolated from bronchial biopsies of mild and severe eosinophilic asthmatics and non-atopic healthy controls...
December 11, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/29242050/mutant-fgfr3-associated-with-saddan-disease-causes-cytoskeleton-disorganization-through-plc%C3%AE-1-src-mediated-paxillin-hyperphosphorylation
#10
R Montone, M G Romanelli, A Baruzzi, F Ferrarini, E Liboi, P M-J Lievens
K650M/E substitutions in the Fibroblast growth factor receptor 3 (FGFR3) are associated with Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN) and Thanatophoric Dysplasia type II (TDII), respectively. Both SADDAN and TDII present with affected endochondral ossification marked by impaired chondrocyte functions and growth plate disorganization. In vitro, K650M/E substitutions confer FGFR3 constitutive kinase activity leading to impaired biosynthesis and accumulation of immature receptors in endoplasmic reticulum (ER)/Golgi...
December 11, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29241979/acalabrutinib-in-relapsed-or-refractory-mantle-cell-lymphoma-ace-ly-004-a-single-arm-multicentre-phase-2-trial
#11
Michael Wang, Simon Rule, Pier Luigi Zinzani, Andre Goy, Olivier Casasnovas, Stephen D Smith, Gandhi Damaj, Jeanette Doorduijn, Thierry Lamy, Franck Morschhauser, Carlos Panizo, Bijal Shah, Andrew Davies, Richard Eek, Jehan Dupuis, Eric Jacobsen, Arnon P Kater, Steven Le Gouill, Lucie Oberic, Taduesz Robak, Todd Covey, Richa Dua, Ahmed Hamdy, Xin Huang, Raquel Izumi, Priti Patel, Wayne Rothbaum, J Greg Slatter, Wojciech Jurczak
BACKGROUND: Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. METHODS: In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants...
December 11, 2017: Lancet
https://www.readbyqxmd.com/read/29241811/syk-and-src-targeted-anti-inflammatory-activity-of-aripiprazole-an-atypical-antipsychotic
#12
Sulgi Yoo, Mi-Yeon Kim, Jae Youl Cho
Aripiprazole (ARP) is a partial agonist of dopamine D2 receptors that is commonly prescribed to treat schizophrenia and bipolar disorder. The anti-inflammatory effect of ARP was recently documented in a few studies, but its molecular mechanisms have not been fully elucidated. In this study, peptidoglycan (PGN)-treated macrophages (RAW264.7 cells), reporter gene assay, an overexpression strategy, immunoprecipitation, and immunoblotting analysis were employed to clarify the anti-inflammatory mechanism of ARP...
December 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29241709/regulation-of-pleiotrophin-and-fyn-in-the-striatum-of-rats-undergoing-l-dopa-induced-dyskinesia
#13
Gimena Gomez, Mariano D Saborido, María A Bernardi, Oscar S Gershanik, Irene R Taravini, Juan E Ferrario
L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats...
December 11, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29241671/mkp-1-protects-mice-against-toxin-induced-liver-damage-by-promoting-the-nrf2-cytoprotective-response
#14
Lin Luo, Yeru Chen, Hongyan Wang, Shengcun Wang, Kaihua Liu, Xin Li, Xiu Jun Wang, Xiuwen Tang
The present study was undertaken to investigate the possible protective effect of mitogen-activated protein kinase phosphatase 1 (Mkp-1) on toxin-induced hepatic injury. Here, we uncovered a positive feedback loop between Mkp-1, a dual threonine/tyrosine phosphatase, and nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial regulator of the defense system in the liver. Mkp-1-/- mice exhibited decreased protein levels of Nrf2, phase II gene products, and reduced glutathione (GSH) in the liver. Induction of detoxifying enzymes by the Nrf2 activator butylated hydroxyanisole (BHA) or sulforaphane, was attenuated in the liver and small intestines of Mkp-1-/- mice, indicating that the Nrf2 signaling pathway is impaired as a result of Mkp-1 deficiency...
December 11, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29241084/neoadjuvant-radiotherapy-combined-with-capecitabine-and-sorafenib-in-patients-with-advanced-kras-mutated-rectal-cancer-a-phase-i-ii-trial-sakk-41-08
#15
Roger von Moos, Dieter Koeberle, Sabina Schacher, Stefanie Hayoz, Ralph C Winterhalder, Arnaud Roth, György Bodoky, Panagiotis Samaras, Martin D Berger, Daniel Rauch, Piercarlo Saletti, Ludwig Plasswilm, Daniel Zwahlen, Urs R Meier, Pu Yan, Paola Izzo, Dirk Klingbiel, Daniela Bärtschi, Kathrin Zaugg
BACKGROUND: KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety...
December 11, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29240787/brd3-4-inhibition-and-flt3-ligand-deprivation-target-pathways-that-are-essential-for-the-survival-of-human-mll-af9-leukemic-cells
#16
Marco Carretta, Annet Z Brouwers-Vos, Matthieu Bosman, Sarah J Horton, Joost H A Martens, Edo Vellenga, Jan Jacob Schuringa
In the present work we aimed to identify targetable signaling networks in human MLL-AF9 leukemias. We show that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival. We evaluated the in vitro and in vivo efficacy of the BRD3/4 inhibitor I-BET151 in various human MLL-AF9 (primary) models and patient samples and analyzed the transcriptome changes following treatment. To further understand the mode of action of BRD3/4 inhibition, we performed ChIP-seq experiments on the MLL-AF9 complex in THP1 cells and compared it to RNA-seq data of I-BET151 treated cells...
2017: PloS One
https://www.readbyqxmd.com/read/29239838/mediator-kinase-phosphorylation-of-stat1-s727-promotes-growth-of-neoplasms-with-jak-stat-activation
#17
Ioana I Nitulescu, Sara C Meyer, Qiang Jeremy Wen, John D Crispino, Madeleine E Lemieux, Ross L Levine, Henry E Pelish, Matthew D Shair
Constitutive JAK-STAT signaling drives the proliferation of most myeloproliferative neoplasms (MPN) and a subset of acute myeloid leukemia (AML), but persistence emerges with chronic exposure to JAK inhibitors. MPN and post-MPN AML are dependent on tyrosine phosphorylation of STATs, but the role of serine STAT1 phosphorylation remains unclear. We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727...
November 21, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29239327/influence-of-vascular-endothelial-growth-factor-and-radiation-on-gap-junctional-intercellular-communication-in-glioblastoma-multiforme-cell-lines
#18
Reinhardt Krcek, Pauline Latzer, Irenäus Anton Adamietz, Helmut Bühler, Carsten Theiss
Glioblastoma multiforme (GBM) is a highly aggressive glial brain tumor with an unfavorable prognosis despite all current therapies including surgery, radiation and chemotherapy. One characteristic of this tumor is a strong synthesis of vascular endothelial growth factor (VEGF), an angiogenesis factor, followed by pronounced vascularization. VEGF became a target in the treatment of GBM, for example with bevacizumab or the tyrosine kinase inhibitor axitinib, which blocks VEGF receptors. To improve patients' prognosis, new targets in the treatment of GBM are under investigations...
November 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/29239193/-checkpoint-inhibitors-in-the-treatment-of-upper-gastrointestinal-tract-tumors
#19
R Obermannova
Chemotherapy prolongs overall survival (OS) in esophageal (EC) and gastric cancer (GC). Unsatisfactory results of systemic therapy initiated a search for new treatment options. In metastatic disease, a number of targeted drugs were tested; however, several phase III studies assessing receptor tyrosin kinase-related signaling pathways, such as EGFR, MET/HGF or mTOR, failed. Trastuzumab remains the only targeted drug with a known molecular predictor, which extended the OS in metastatic gastric adenocarcinoma and adenocarcinoma of esophago-gastric junction...
2017: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/29239110/association-of-prognostic-features-and-treatment-on-survival-time-of-dogs-with-systemic-mastocytosis-a-retrospective-analysis-of-40-dogs
#20
S J Moirano, S F Lima, K R Hume, E M Brodsky
Systemic mastocytosis is a rare phenomenon, with limited information regarding prognostic features and effective treatment of canine patients with this disease. The objective of this study is to determine the impact of certain features and treatments on dogs with systemic mastocytosis. The medical records of 40 dogs from 4 northeastern US veterinary hospitals, with evidence of systemic mast cell disease, were evaluated retrospectively. Variables analysed with relation to overall survival and prognostic significance included treatment protocol used, substage, presence of a cutaneous or visceral tumour, presence of multiple cutaneous Mast cell tumours, grade of the primary tumour and metastatic site(s)...
December 14, 2017: Veterinary and Comparative Oncology
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