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Fusion inhibitors

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https://www.readbyqxmd.com/read/28087229/disease-associated-mutations-identify-a-novel-region-in-human-sting-necessary-for-the-control-of-type-i-interferon-signaling
#1
Isabelle Melki, Yoann Rose, Carolina Uggenti, Lien Van Eyck, Marie-Louise Frémond, Naoki Kitabayashi, Gillian I Rice, Emma M Jenkinson, Anaïs Boulai, Nadia Jeremiah, Marco Gattorno, Sefano Volpi, Olivero Sacco, Suzanne W J Terheggen-Lagro, Harm A W M Tiddens, Isabelle Meyts, Marie-Anne Morren, Petra De Haes, Carine Wouters, Eric Legius, Anniek Corveleyn, Frederic Rieux-Laucat, Christine Bodemer, Isabelle Callebaut, Mathieu P Rodero, Yanick J Crow
BACKGROUND: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI). OBJECTIVES: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease...
January 3, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28078583/generation-and-application-of-bioluminescent-cd95-ligand-fusion-proteins
#2
Isabell Lang, Juliane Kums, Harald Wajant
The quantitative evaluation of the interaction of soluble CD95L with CD95 is not only important for a detailed understanding of CD95 biology but is also of special relevance for the characterization and development of inhibitors of this interaction. The assembly of a CD95L-CD95 complex capable to recruit intracellular factors not only involves pre-assembly of CD95 molecules in the absence of CD95L but is also modulated by cellular factors such as interaction with the actin cytoskeleton and plasma membrane compartmentation of CD95...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28077299/anaplastic-lymphoma-kinase-alk-inhibitors-in-the-treatment-of-alk-driven-lung-cancers
#3
REVIEW
Robert Roskoski
Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors...
January 8, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28076791/mll-af4-spreading-identifies-binding-sites-that-are-distinct-from-super-enhancers-and-that-govern-sensitivity-to-dot1l-inhibition-in-leukemia
#4
Jon Kerry, Laura Godfrey, Emmanouela Repapi, Marta Tapia, Neil P Blackledge, Helen Ma, Erica Ballabio, Sorcha O'Byrne, Frida Ponthan, Olaf Heidenreich, Anindita Roy, Irene Roberts, Marina Konopleva, Robert J Klose, Huimin Geng, Thomas A Milne
Understanding the underlying molecular mechanisms of defined cancers is crucial for effective personalized therapies. Translocations of the mixed-lineage leukemia (MLL) gene produce fusion proteins such as MLL-AF4 that disrupt epigenetic pathways and cause poor-prognosis leukemias. Here, we find that at a subset of gene targets, MLL-AF4 binding spreads into the gene body and is associated with the spreading of Menin binding, increased transcription, increased H3K79 methylation (H3K79me2/3), a disruption of normal H3K36me3 patterns, and unmethylated CpG regions in the gene body...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28076686/small-molecule-hiv-1-entry-inhibitors-targeting-gp120-and-gp41-a-patent-review-2010-2015
#5
Wen Li, Lu Lu, Weihua Li, Shibo Jiang
It is essential to discover and develop small-molecule HIV-1 entry inhibitors with suitable pharmaceutical properties. Areas covered: We review the development of small-molecule HIV-1 entry inhibitors as evidenced in patents, patent applications, and related research articles published between 2010 and 2015. Expert opinion: HIV-1 Env gp120 and gp41 are important targets for development of HIV-1 entry inhibitors. The Phe43 pocket in gp120 and the highly conserved hydrophobic pocket on gp41 NHR-trimer are important targets for identification of HIV-1 attachment and fusion inhibitors, respectively...
January 11, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28073897/identification-of-alk-ros1-and-ret-fusions-by-a-multiplexed-mrna-based-assay-in-formalin-fixed-paraffin-embedded-samples-from-advanced-non-small-cell-lung-cancer-patients
#6
Noemí Reguart, Cristina Teixidó, Ana Giménez-Capitán, Laia Paré, Patricia Galván, Santiago Viteri, Sonia Rodríguez, Vicente Peg, Erika Aldeguer, Nuria Viñolas, Jordi Remon, Niki Karachaliou, Esther Conde, Fernando Lopez-Rios, Ernest Nadal, Sabine Merkelbach-Bruse, Reinhard Büttner, Rafael Rosell, Miguel A Molina-Vila, Aleix Prat
BACKGROUND: Anaplastic lymphoma receptor tyrosine kinase (ALK), ROS protooncogene 1, receptor tyrosine kinase (ROS1), and ret protooncogene (RET) fusions are present in 5%-7% of patients with advanced non-small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies. FISH and immunohistochemistry (IHC) are considered the gold standards to determine gene fusions, they have limitations. The nCounter platform is a potentially useful genomic tool for multiplexed detection of gene fusions, but has not been validated in the clinical setting...
January 10, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/28070720/safety-tolerability-and-pharmacokinetics-of-the-fibroblast-growth-factor-receptor-inhibitor-azd4547-in-japanese-patients-with-advanced-solid-tumours-a-phase-i-study
#7
Hideo Saka, Chiyoe Kitagawa, Yoshihito Kogure, Yasuo Takahashi, Koshi Fujikawa, Tamotsu Sagawa, Satoru Iwasa, Naoki Takahashi, Taro Fukao, Catherine Tchinou, Dónal Landers, Yasuhide Yamada
Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization...
January 10, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28069948/genomic-targeting-of-epigenetic-probes-using-a-chemically-tailored-cas9-system
#8
Glen P Liszczak, Zachary Z Brown, Samuel H Kim, Rob C Oslund, Yael David, Tom W Muir
Recent advances in the field of programmable DNA-binding proteins have led to the development of facile methods for genomic localization of genetically encodable entities. Despite the extensive utility of these tools, locus-specific delivery of synthetic molecules remains limited by a lack of adequate technologies. Here we combine the flexibility of chemical synthesis with the specificity of a programmable DNA-binding protein by using protein trans-splicing to ligate synthetic elements to a nuclease-deficient Cas9 (dCas9) in vitro and subsequently deliver the dCas9 cargo to live cells...
January 9, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28069723/a-novel-murine-gitr-ligand-fusion-protein-induces-antitumor-activity-as-a-monotherapy-which-is-further-enhanced-in-combination-with-an-ox40-agonist
#9
Rebecca Leyland, Amanda Watkins, Kathy Mulgrew, Nicholas Holoweckyj, Lisa Bamber, Natalie J Tigue, Emily Offer, John Andrews, Li Yan, Stefanie Mullins, Michael D Oberst, Jane Coates Ulrichsen, David A Leinster, Kelly A McGlinchey, Lesley Young, Michelle Morrow, Scott A Hammond, Philip R Mallinder, Athula Herath, Ching Ching Leow, Robert W Wilkinson, Ross Stewart
PURPOSE: To generate and characterize a murine GITR ligand fusion protein (mGITRL-FP) designed to maximize valency and the potential to agonize the GITR receptor for cancer immunotherapy. EXPERIMENTAL DESIGN: The EC50 value of the mGITRL-FP was compared to an anti-GITR antibody in an in vitro agonistic cell based reporter assay. We assessed the impact of dose, schedule and Fc isotype on antitumor activity and T-cell modulation in the CT26 tumor model. The activity of the mGITRL-FP was compared to an agonistic murine OX40L-FP targeting OX40, in CT26 and B16F10-Luc2 tumor models...
January 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28063378/overexpression-of-ptp4a3-in-etv6-runx1-acute-lymphoblastic-leukemia
#10
Toni Grönroos, Susanna Teppo, Juha Mehtonen, Saara Laukkanen, Thomas Liuksiala, Matti Nykter, Merja Heinäniemi, Olli Lohi
Cell signalling, which is often derailed in cancer, is a network of multiple interconnected pathways with numerous feedback mechanisms. Dynamics of cell signalling is intimately regulated by addition and removal of phosphate groups by kinases and phosphatases. We examined expression of members of the PTP4A family of phosphatases across acute leukemias. While expression of PTP4A1 and PTP4A2 remained relatively unchanged across diseases, PTP4A3 showed marked overexpression in ETV6-RUNX1 and BCR-ABL1 subtypes of precursor B cell acute lymphoblastic leukemia...
December 26, 2016: Leukemia Research
https://www.readbyqxmd.com/read/28059704/cooperative-and-acute-inhibitionby-multiple-c-terminal-motifs-of-l-type-ca-2-channels
#11
Nan Liu, Yaxiong Yang, Lin Ge, Min Liu, Henry M Colecraft, Xiaodong Liu
Inhibitions and antagonists of L-type Ca(2+) channels are important to both research and therapeutics. Here, we report C-terminus mediated inhibition (CMI) for CaV1.3 that multiple motifs coordinate to tune down Ca(2+) current and Ca(2+) influx toward the lower limits determined by end-stage CDI (Ca(2+)-dependent inactivation). Among IQV (preIQ3-IQ domain), PCRD and DCRD (proximal or distal C-terminal regulatory domain), spatial closeness of any two modules, e.g., by constitutive fusion, facilitates the trio to form the complex, compete against calmodulin, and alter the gating...
January 6, 2017: ELife
https://www.readbyqxmd.com/read/28056055/hdac-and-proteasome-inhibitors-synergize-to-activate-pro-apoptotic-factors-in-synovial-sarcoma
#12
Aimée N Laporte, Jared J Barrott, Ren Jie Yao, Neal M Poulin, Bertha A Brodin, Kevin B Jones, T Michael Underhill, Torsten O Nielsen
Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents...
2017: PloS One
https://www.readbyqxmd.com/read/28053347/functions-of-bromodomain-containing-proteins-and-their-roles-in-homeostasis-and-cancer
#13
Takao Fujisawa, Panagis Filippakopoulos
Bromodomains (BRDs) are evolutionarily conserved protein-protein interaction modules that are found in a wide range of proteins with diverse catalytic and scaffolding functions and are present in most tissues. BRDs selectively recognize and bind to acetylated Lys residues - particularly in histones - and thereby have important roles in the regulation of gene expression. BRD-containing proteins are frequently dysregulated in cancer, they participate in gene fusions that generate diverse, frequently oncogenic proteins, and many cancer-causing mutations have been mapped to the BRDs themselves...
January 5, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28051846/selective-intracellular-delivery-of-ganglioside-gm3-binding-peptide-through-caveolae-raft-mediated-endocytosis
#14
Teruhiko Matsubara, Ryohei Otani, Miki Yamashita, Haruka Maeno, Hanae Nodono, Toshinori Sato
Glycosphingolipids are major components of the membrane raft, and several kinds of viruses and bacterial toxins are known to bind to glycosphingolipids in the membrane raft. Since the viral genes and pathogenic proteins that are taken into cells are directly delivered to their target organelles, caveolae/raft-mediated endocytosis represents a promising pathway for specific delivery. In the present study, we demonstrated the ability of an artificial pentadecapeptide, which binds to ganglioside GM3, to deliver protein into cells by caveolae/raft-mediated endocytosis...
January 4, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28050598/alk-a-tyrosine-kinase-target-for-cancer-therapy
#15
REVIEW
Vijaykumar R Holla, Yasir Y Elamin, Ann Marie Bailey, Amber M Johnson, Beate C Litzenburger, Yekaterina B Khotskaya, Nora S Sanchez, Jia Zeng, Md Abu Shufean, Kenna R Shaw, John Mendelsohn, Gordon B Mills, Funda Meric-Bernstam, George R Simon
The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors...
January 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28044258/tumor-vascular-infarction-prospects-and-challenges
#16
REVIEW
Rana Jahanban-Esfahlan, Khaled Seidi, Nosratollah Zarghami
Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Formation of fibrin clots may be sufficient to occlude the blood vessels that feed tumor cells, contributing to massive ischemia, vascular infarction, and the subsequent necrosis and apoptosis of neoplastic cells. This approach called as tumor vascular infarction was pioneered by Huang et al. (Science 275:547-550, 1997). Since then, different vascular targeting moieties were linked to a truncated form of human tissue factor (tTF), to generate coaguligands with selective thrombotic activities on tumor neovasculature...
January 2, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28039177/differential-protein-stability-and-clinical-responses-of-eml4-alkfusion-variants-to-various-alk-inhibitors-in-advanced-alk-rearranged-non-small-cell-lung-cancer
#17
C G Woo, S Seo, S W Kim, S J Jang, K S Park, J Y Song, B Lee, M W Richards, R Bayliss, D H Lee, J Choi
: BackgroundAnaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors...
December 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28034880/polyclonal-secondary-fgfr2-mutations-drive-acquired-resistance-to-fgfr-inhibition-in-patients-with-fgfr2-fusion-positive-cholangiocarcinoma
#18
Lipika Goyal, Supriya K Saha, Leah Y Liu, Giulia Siravegna, Ignaty Leshchiner, Leanne G Ahronian, Jochen K Lennerz, Phuong Vu, Vikram Deshpande, Avinash Kambadakone, Benedetta Mussolin, Stephanie Reyes, Laura Henderson, Jiaoyuan Elisabeth Sun, Emily E Van Seventer, Joseph M Gurski, Sabrina Baltschukat, Barbara Schacher-Engstler, Louise Barys, Christelle Stamm, Pascal Furet, David P Ryan, James R Stone, A John Iafrate, Gad Getz, Diana Graus Porta, Ralph Tiedt, Alberto Bardelli, Dejan Juric, Ryan B Corcoran, Nabeel Bardeesy, Andrew X Zhu
Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases...
December 29, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/28034454/comprehensive-genomic-sequencing-and-the-molecular-profiles-of-clinically-advanced-breast-cancer
#19
Jeffrey S Ross, Laurie M Gay
Targeting specific mutations that have arisen within a tumour is a promising means of increasing the efficacy of treatments, and breast cancer is no exception to this new paradigm of personalised medicine. Traditional DNA sequencing methods used to characterise clinical cancer specimens and impact treatment decisions are highly sensitive, but are often limited in their scope to known mutational hot spots. Next-generation sequencing (NGS) technologies can also test for these well-known hot spots, as well as identifying insertions and deletions, copy number changes such as ERBB2 (HER2) gene amplification, and a wide array of fusion or rearrangement events...
December 26, 2016: Pathology
https://www.readbyqxmd.com/read/28032081/philadelphia-chromosome-positive-acute-lymphoblastic-leukemia-8-years-experience-from-a-tertiary-care-center-in-india
#20
Madhav Danthala, Sadashivudu Gundeti, Laxmi Srinivas Maddali, Ashok Pillai, Krishna Chaitanya Puligundla, Raja Praveen Adusumilli
INTRODUCTION: The Philadelphia chromosome (Ph) is the most common cytogenetic abnormality associated with adult acute lymphoblastic leukemia (ALL) occurring in 20% to 40% of patients. It is also detected in 2% to 5% of children with ALL. Historically, patients with Ph-positive ALL carried a dismal prognosis, with poor response to most chemotherapy combinations, short remission durations, and long-term disease-free survival rates of 10% to 20%. The advent of tyrosine kinase inhibitors (TKIs) has revolutionized therapy of Ph-positive ALL...
October 2016: South Asian Journal of Cancer
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