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https://www.readbyqxmd.com/read/29351623/development-of-sugar-chain-binding-single-chain-variable-fragment-antibody-to-adult-t-cell-leukemia-cells-using-glyco-nanotechnology-and-phage-display-method
#1
Kaname Muchima, Taro Todaka, Hiroyuki Shinchi, Ayaka Sato, Arisa Tazoe, Rikiya Aramaki, Yuhei Kakitsubata, Risa Yokoyama, Naomichi Arima, Masanori Baba, Masahiro Wakao, Yuji Ito, Yasuo Suda
Adult T-cell leukemia (ATL) is an intractable blood cancer caused by the infection of human T-cell leukemia virus type-1, and effective medical treatment is required. It is known that the structure and expression levels of cell surface sugar chains vary depending on cell states such as inflammation and cancer. Thus, it is expected that the antibody specific for ATL cell surface sugar chain would be an effective diagnostic tool and a strong candidate for the development of an anti-ATL drug. Here, we developed a stable sugar chain binding single chain variable fragment antibody (scFv) that can bind to ATL cells using a fiber type Sugar Chip and phage display method...
January 17, 2018: Journal of Biochemistry
https://www.readbyqxmd.com/read/29350308/the-ppar%C3%AE-agonist-efatutazone-delays-invasive-progression-and-induces-differentiation-of-ductal-carcinoma-in-situ
#2
Virginie Ory, William B Kietzman, Jacob Boeckelman, Bhaskar V Kallakury, Anton Wellstein, Priscilla A Furth, Anna T Riegel
PURPOSE: Ductal carcinoma in situ (DCIS) is a pre-invasive lesion of the breast considered a precursor of invasive ductal carcinoma. This study aimed to determine whether activated PPARγ acts as a tumor suppressor in human DCIS progression. METHODS: We utilized the high-affinity PPARγ agonist, efatutazone, to activate endogenous PPARγ in a well-defined model for the progression of basal (triple negative) DCIS, MCFDCIS cells, cultured under 2D and 3D conditions...
January 19, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29348171/a-cationic-c-terminal-patch-and-structural-rearrangements-in-ebola-virus-matrix-vp40-protein-control-its-interactions-with-phosphatidylserine
#3
Kathryn Del Vecchio, Cary T Frick, Jeevan B Gc, Shun-Ichiro Oda, Bernard S Gerstman, Erica Ollmann Saphire, Prem P Chapagain, Robert V Stahelin
Ebola virus (EBOV) is a filamentous lipid-enveloped virus that causes hemorrhagic fever with a high fatality rate. Viral protein 40 (VP40) is the major EBOV matrix protein and regulates viral budding from the plasma membrane. VP40 is a transformer/morpheein that can structurally rearrange its native homodimer into either a hexameric filament that facilitates viral budding or a RNA-binding octameric ring that regulates viral transcription. VP40 associates with plasma-membrane lipids such as phosphatidylserine (PS), and this association is critical to budding from the host cell...
January 18, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29347185/balancing-specificity-sensitivity-and-speed-of-ligand-discrimination-by-zero-order-ultraspecificity
#4
Masashi K Kajita, Kazuyuki Aihara, Tetsuya J Kobayashi
Specific interactions between receptors and their target ligands in the presence of nontarget ligands are crucial for biological processes such as T cell ligand discrimination. To discriminate between the target and nontarget ligands, cells have to increase specificity to the target ligands by amplifying the small differences in affinity among ligands. In addition, sensitivity to the ligand concentration and quick discrimination are also important to detect low amounts of target ligands and facilitate fast cellular decision making after ligand recognition...
July 2017: Physical Review. E
https://www.readbyqxmd.com/read/29345906/prediction-of-hot-spots-at-myeloid-cell-leukemia-1-inhibitors-interface-using-energy-estimation-and-alanine-scanning-mutagenesis
#5
Parthiban Marimuthu, Kalaimathy Singaravelu
Myeloid cell leukemia 1 (Mcl1) is an anti-apoptotic protein that plays central role in apoptosis regulation. Also, Mcl1 has the potency to resist apoptotic cues resulting in up-regulation and cancer cell protection. A molecular probe that has the potential to specifically target Mcl1, and thereby provoke its down-regulatory activity is very essential. The aim of the current study is to probe the internal conformational dynamics of protein motions and potential binding mechanism in response to a series of picomolar range Mcl1 inhibitors using explicit-solvent molecular dynamics (MD) simulations...
January 18, 2018: Biochemistry
https://www.readbyqxmd.com/read/29343578/a-new-quinoline-brd4-inhibitor-targets-a-distinct-latent-hiv-1-reservoir-for-re-activation-from-other-shock-drugs
#6
Erik Abner, Mateusz Stoszko, Lei Zeng, Heng-Chang Chen, Andrea Izquierdo-Bouldstridge, Tsuyoshi Konuma, Eduard Zorita, Elisa Fanunza, Qiang Zhang, Tokameh Mahmoudi, Ming-Ming Zhou, Guillaume J Filion, Albert Jordan
Upon HIV-1 infection, a reservoir of latently infected resting T cells prevents the eradication of the virus from patients. To achieve complete depletion, the existing virus-suppressing antiretroviral therapy must be combined with drugs that reactivate the dormant viruses. We previously described a novel chemical scaffold compound, MMQO (8-methoxy-6-methylquinolin-4-ol) that is able to reactivate viral transcription in several models of HIV latency including J-Lat cells through an unknown mechanism. MMQO potentiates the activity of known latency-reversing agents (LRAs) or 'shock' drugs such as PKC agonists or HDAC inhibitors...
January 17, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29343548/loss-of-b-cell-anergy-in-type-1-diabetes-is-associated-with-high-risk-hla-and-non-hla-disease-susceptibility-alleles
#7
Mia J Smith, Marynette Rihanek, Clive Wasserfall, Clayton E Mathews, Mark A Atkinson, Peter A Gottlieb, John C Cambier
Although B cells reactive with islet autoantigens are silenced by tolerance mechanisms in healthy individuals, they can become activated and contribute to development of type 1 diabetes. We previously demonstrated that high-affinity insulin-binding B cells (IBCs) occur exclusively in the anergic (BND) compartment in peripheral blood of healthy subjects. Consistent with their activation early in disease development, high-affinity IBCs are absent from the BND compartment of some first-degree relatives (FDRs) as well as all autoantibody positive pre-diabetic and new-onset type 1 diabetes patients, a time when they are found in pancreatic islets...
January 17, 2018: Diabetes
https://www.readbyqxmd.com/read/29343437/memory-b-cells-that-cross-react-with-group-1-and-group-2-influenza-a-viruses-are-abundant-in-adult-human-repertoires
#8
Kevin R McCarthy, Akiko Watanabe, Masayuki Kuraoka, Khoi T Do, Charles E McGee, Gregory D Sempowski, Thomas B Kepler, Aaron G Schmidt, Garnett Kelsoe, Stephen C Harrison
Human B cell antigen-receptor (BCR) repertoires reflect repeated exposures to evolving influenza viruses; new exposures update the previously generated B cell memory (Bmem) population. Despite structural similarity of hemagglutinins (HAs) from the two groups of influenza A viruses, cross-reacting antibodies (Abs) are uncommon. We analyzed Bmem compartments in three unrelated, adult donors and found frequent cross-group BCRs, both HA-head directed and non-head directed. Members of a clonal lineage from one donor had a BCR structure similar to that of a previously described Ab, encoded by different gene segments...
January 16, 2018: Immunity
https://www.readbyqxmd.com/read/29339550/relative-target-affinities-of-t-cell-dependent-bispecific-antibodies-determine-biodistribution-in-a-solid-tumor-mouse-model
#9
Danielle Mandikian, Nene Takahashi, Amy A Lo, Ji Li, Jeffrey Eastham-Anderson, Dionysos Slaga, Jason Ho, Maria Hristopoulos, Robyn Clark, Klara Totpal, Kedan Lin, Sean B Joseph, Mark S Dennis, Saileta Prabhu, Teemu T Junttila, C Andrew Boswell
Anti-HER2/CD3, a T cell-dependent bispecific antibody (TDB) construct, induces T cell-mediated cell death in cancer cells expressing HER2 by cross-linking tumor HER2 with CD3 on cytotoxic T cells, thereby creating a functional cytolytic synapse. TDB design is a very challenging process that requires consideration of multiple parameters. While therapeutic antibody design strategy is commonly driven by striving for the highest attainable antigen binding affinity, little is known about how the affinity of each TDB arm can affect the targeting ability of the other arm and the consequent distribution and efficacy...
January 16, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29339376/tumor-immunity-and-survival-as-a-function-of-alternative-neopeptides-in-human-cancer
#10
Andrew J Rech, David Balli, Alejandro Mantero, Hemant Ishwaran, Katherine L Nathanson, Ben Z Stanger, Robert H Vonderheide
The immune system exerts antitumor activity via T cell-dependent recognition of tumor-specific antigens. Although the number of tumor neopeptides - peptides derived from somatic mutations - often correlates with immune activity and survival, most classically defined high-affinity neopeptides (CDNs) are not immunogenic, and only rare CDNs have been linked to tumor rejection. Thus, the rules of tumor antigen recognition remain incompletely understood. Here, we analyzed neopeptides, immune activity, and clinical outcome from 6,324 patients across 27 tumor types...
January 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29330771/inhibition-of-human%C3%A2-immunodeficiency-type-1-virus-hiv-1-life-cycle-by-different-egg-white-lysozymes
#11
Mandana Behbahani, Mokhtar Nosrati, Hassan Mohabatkar
Lysozyme is a relatively small enzyme with different biological activities, which is found in tears, saliva, egg white, and human milk. In the study, the anti-HIV-1 activity of lysozymes purified from quail, Meleagris, and hen egg white has been determined. For this end, a time-of-drug-addition assay was performed to identify the target of anti-HIV-1 agents and for determination of probable anti HIV-1 mechanism of the studied lysozyme, the binding affinity of the lysozymes to the human CD4 receptor was studied by molecular docking method...
January 13, 2018: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/29330372/non-estrogenic-xanthohumol-derivatives-mitigate-insulin-resistance-and-cognitive-impairment-in-high-fat-diet-induced-obese-mice
#12
Cristobal L Miranda, Lance A Johnson, Oriane de Montgolfier, Valerie D Elias, Lea S Ullrich, Joshua J Hay, Ines L Paraiso, Jaewoo Choi, Ralph L Reed, Johana S Revel, Chrissa Kioussi, Gerd Bobe, Urszula T Iwaniec, Russell T Turner, Benita S Katzenellenbogen, John A Katzenellenbogen, Paul R Blakemore, Adrian F Gombart, Claudia S Maier, Jacob Raber, Jan F Stevens
Xanthohumol (XN), a prenylated flavonoid from hops, improves dysfunctional glucose and lipid metabolism in animal models of metabolic syndrome (MetS). However, its metabolic transformation into the estrogenic metabolite, 8-prenylnaringenin (8-PN), poses a potential health concern for its use in humans. To address this concern, we evaluated two hydrogenated derivatives, α,β-dihydro-XN (DXN) and tetrahydro-XN (TXN), which showed negligible affinity for estrogen receptors α and β, and which cannot be metabolically converted into 8-PN...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29330305/restricted-processing-of-cd16a-fc-%C3%AE-receptor-iiia-n-glycans-from%C3%A2-primary-human-nk-cells-impacts-structure-and-function
#13
Kashyap R Patel, Jacob T Roberts, Ganesh P Subedi, Adam W Barb
CD16a/Fc γ receptor IIIa is the most abundant antibody Fc receptor expressed on human natural killer(NK) cells and activates a protective cytotoxic response following engagement with antibody clustered on the surface of a pathogen or diseased tissue. Therapeutic monoclonal antibodies(mAbs) with greater Fc-mediated affinity for CD16a show superior therapeutic outcome, however, one significant factor that promotes antibody-CD16a interactions, the asparagine-linked carbohydrates(N-glycans), remains undefined...
January 12, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29330050/production-and-characterization-of-a-novel-site-specific-modifiable-anti-ox40-receptor-single-chain-variable-fragment-for-targeted-drug-delivery
#14
Aki Tanabe, Kazumi Nakano, Makoto Nakakido, Satoru Nagatoishi, Yuetsu Tanaka, Kouhei Tsumoto, Kaoru Uchimaru, Toshiki Watanabe
OX40 receptor (tumor necrosis factor receptor superfamily, member 4; CD134) is a T-cell co-stimulatory molecule that plays an important role in T-cell activation and survival. OX40 receptor is activated by its ligand, OX40L; and modulation of the OX40-OX40L interaction is a promising target for the treatment of autoimmune diseases and cancers. Here, we generated a high-affinity anti-OX40 single-chain variable fragment carrying a C-terminal cysteine residue (scFvC). Physicochemical and functional analyses revealed that the scFvC bound to OX40-expressing cells and was internalized via OX40-mediated endocytosis without inducing phosphorylation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), an important complex in the classical NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway...
January 9, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29329361/pyhvis3d-visualising-molecular-simulation-deduced-h-bond-networks-in-3d-application-to-t-cell-receptor-interactions
#15
Bernhard Knapp, Marta Alcala, Hao Zhang, Clare West, P Anton van der Merwe, Charlotte M Deane
Motivation: Hydrogen bonds (H-bonds) play an essential role for many molecular interactions but are also often transient, making visualizing them in a flexible system challenging. Results: We provide pyHVis3D which allows for an easy to interpret 3D visualisation of H-bonds resulting from molecular simulations. We demonstrate the power of pyHVis3D by using it to explain the changes in experimentally measured binding affinities for three T-cell receptor/peptide/MHC complexes and mutants of each of these complexes...
January 10, 2018: Bioinformatics
https://www.readbyqxmd.com/read/29328488/synthesis-and-application-of-131i-fulvestrant-as-a-targeted-radiation-drug-for-endocrine-therapy-in-human-breast-cancer
#16
Guobing Yin, Bin Zeng, Zhiping Peng, Ying Liu, Lu Sun, Changan Liu
The aim of this study was to label fulvestrant (an endocrine therapy drug for breast cancer) with radioiodine and to evaluate the effect of 131I-fulvestrant on inhibiting the growth of human breast cancer and its influence on major organs in nude mice. Fulvestrant was labeled with radioiodine using a modified chloramine T method, and its chemical properties were assessed using traditional methods. The binding affinity of 131I-fulvestrant was measured by radioligand binding assays, and its antiproliferative activity was determined by MTT assays...
January 11, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29323899/optimization-of-potent-and-selective-tricyclic-indole-diazepinone-myeloid-cell-leukemia-1-mcl-1-inhibitors-using-structure-based-design
#17
Subrata Shaw, Zhiguo Bian, Bin Zhao, James C Tarr, Nagarathanam Veerasamy, KyuOk Jeon, Johannes Belmar, Allison L Arnold, Stuart A Fogarty, Evan Perry, John L Sensintaffar, DeMarco V Camper, Olivia W Rossanese, Taekyu Lee, Edward T Olejniczak, Stephen W Fesik
Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1 sensitive cells...
January 11, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29323388/a-novel-thermal-detection-method-based-on-molecularly-imprinted-nanoparticles-as-recognition-elements
#18
Francesco Canfarotta, J Czulak, K Betlem, A Sachdeva, K Eersels, B van Grinsven, T J Cleij, M Peeters
Molecularly Imprinted Polymers (MIPs) are synthetic receptors that are able to selectively bind their target molecule and, for this reason, they are currently employed as recognition elements in sensors. In this work, MIP nanoparticles (nanoMIPs) are produced by solid-phase synthesis for a range of templates with different sizes, including a small molecule (biotin), two peptides (one derived from the epithelial growth factor receptor and vancomycin) and a protein (trypsin). NanoMIPs are then dipcoated on the surface of thermocouples that measure the temperature inside a liquid flow cell...
January 11, 2018: Nanoscale
https://www.readbyqxmd.com/read/29319889/epitope-targeted-macrocyclic-peptide-ligand-with-picomolar-cooperative-binding-to-interleukin-17f
#19
Bert T Lai, Jeré A Wilson, Jacquie Malette Loredo, Suresh M Pitram, Nicole A LaBerge, James R Heath, Heather Agnew
The IL-17 cytokine family is associated with multiple immune and autoimmune diseases and comprises important diagnostic and therapeutic targets. We developed epitope-targeted ligands designed for differential detection of human IL-17F and its closest homologue IL-17A. Non-overlapping and unique epitopes on IL-17F and IL-17A were identified by comparative sequence analysis of the two proteins. Synthetic variants of these epitopes were utilized as targets for in situ click screens against a comprehensive library of synthetic peptide macrocycles with 5-mer variable regions...
January 10, 2018: Chemistry: a European Journal
https://www.readbyqxmd.com/read/29319817/high-affinity-low-capacity-and-low-affinity-high-capacity-n-acetyl-2-aminofluorene-aaf-macromolecular-binding-sites-are-revealed-during-the-growth-cycle-of-adult-rat-hepatocytes-in-primary-culture
#20
K S Koch, T Moran, W T Shier, H L Leffert
Long-term cultures of primary adult rat hepatocytes were used to study the effects of N-acetyl-2-aminofluorene (AAF) on hepatocyte proliferation during the growth cycle; on the initiation of hepatocyte DNA synthesis in quiescent cultures; and, on hepatocyte DNA replication following the initiation of DNA synthesis. Scatchard analyses were used to identify the pharmacologic properties of radiolabeled AAF metabolite binding to hepatocyte macromolecules. Two classes of growth cycle-dependent AAF metabolite binding sites - a high-affinity low-capacity site (designated Site I) and a low-affinity high-capacity site (designated Site II) - associated with two spatially distinct classes of macromolecular targets, were revealed...
January 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
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