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https://www.readbyqxmd.com/read/28087272/synthesis-and-evaluation-of-5-1h-indol-3-yl-n-aryl-1-3-4-oxadiazol-2-amines-as-bcl-2-inhibitory-anticancer-agents
#1
Rania Hamdy, Noha I Ziedan, Samia Ali, Cinzia Bordoni, Mohamed El-Sadek, Elsaid Lashin, Andrea Brancale, Arwyn T Jones, Andrew D Westwell
A series of 5-(1H-indol-3-yl)-N-aryl-1,3,4-oxadiazol-2-amines 8a-j has been designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents based on our previous lead compound 8a. Synthesis of the target compounds was readily accomplished through a cyclisation reaction between indole-3-carboxylic acid hydrazide (5) and substituted isothiocyanates 6a-j, followed by oxidative cyclodesulfurization of the corresponding thiosemicarbazide 7a-j using 1,3-dibromo-5,5-dimethylhydantoin...
December 27, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28076787/impdh2-is-an-intracellular-target-of-the-cyclophilin-a-and-sanglifehrin-a-complex
#2
Khian Hong Pua, Dylan T Stiles, Mathew E Sowa, Gregory L Verdine
Natural products have demonstrated utility in the clinic and can also act as probes to understand complex cellular pathways. Sanglifehrin A (SFA) is a mixed polyketide and non-ribosomal peptide synthase natural product with sub-nano-molar affinity for its receptor cyclophilin A (PPIA). It has been shown to behave in vitro as an immune suppressant. Here, we identify inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as an intracellular target of the PPIA-SFA binary complex. The formation of this ternary complex does not inhibit the enzymatic activity of IMPDH2...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28073960/ligand-characterization-of-cyp4b1-isoforms-modified-for-high-level-expression-in-escherichia-coli-and-hepg2-cells
#3
Katharina Roellecke, Vera D Jäger, Veselin H Gyurov, John P Kowalski, Stephanie Mielke, Allan E Rettie, Helmut Hanenberg, Constanze Wiek, Marco Girhard
Human CYP4B1, a cytochrome P450 monooxygenase predominantly expressed in the lung, inefficiently metabolizes classical CYP4B1 substrates, such as the naturally occurring furan pro-toxin 4-ipomeanol (4-IPO). Highly active animal forms of the enzyme convert 4-IPO to reactive alkylating metabolite(s) that bind(s) to cellular macromolecules. By substitution of 13 amino acids, we restored the enzymatic activity of human CYP4B1 toward 4-IPO and this modified cDNA is potentially valuable as a suicide gene for adoptive T-cell therapies...
January 10, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28067179/cd20-based-immunotherapy-of-b-cell-derived-hematologic-malignancies
#4
Dariush Shanehbandi, Jafar Majidi, Tohid Kazemi, Behzad Baradaran, Leili Aghebati-Maleki
CD20 is a surface antigen which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/relapsed disease...
January 9, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28066900/boosting-of-post-exposure-human-t-and-b-cell-recall-responses-in-vivo-by-burkholderia-pseudomallei-related-proteins
#5
Arnone Nithichanon, Louise J Gourlay, Gregory J Bancroft, Manabu Ato, Yoshimasa Takahashi, Ganjana Lertmemongkolchai
Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease with high incidence and mortality in South East Asia and Northern Australia. To date there is no protective vaccine and antibiotic treatment is prolonged and not always effective. Most people living in endemic areas have been exposed to the bacteria and have developed some immunity, which may have helped prevent disease. Here, we used a humanized mouse model (hu-PBL-SCID), reconstituted with human peripheral blood mononuclear cells (PBMCs) from seropositive donors, to illustrate the potential of three known antigens (FliC, OmpA and N-PilO2) for boosting both T- and B-cell immune responses...
January 9, 2017: Immunology
https://www.readbyqxmd.com/read/28062695/the-clonal-invariant-nkt-cell-repertoire-in-people-with-type-1-diabetes-is-characterized-by-a-loss-of-clones-expressing-high-affinity-tcrs
#6
Anna S Tocheva, Salah Mansour, Tristan G H Holt, Samuel Jones, Andrew Chancellor, Joseph P Sanderson, Efrem Eren, Tim J Elliott, Richard I G Holt, Stephan D Gadola
Invariant NKT (iNKT) cells in healthy people express iNKT-TCRs with widely varying affinities for CD1d, suggesting different roles for high- and low-affinity iNKT clones in immune regulation. However, the functional implications of this heterogeneity have not yet been determined. Functionally aberrant iNKT responses have been previously demonstrated in different autoimmune diseases, including human type 1 diabetes, but their relationship to changes in the iNKT clonal repertoire have not been addressed. In this study, we directly compared the clonal iNKT repertoire of people with recent onset type 1 diabetes and age- and gender-matched healthy controls with regard to iNKT-TCR affinity and cytokine production...
January 6, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28061796/glucose-transporter-4-promotes-head-and-neck-squamous-cell-carcinoma-metastasis-through-the-trim24-ddx58-axis
#7
Yu-Chan Chang, Li-Hsing Chi, Wei-Ming Chang, Chia-Yi Su, Yuang-Feng Lin, Chi-Long Chen, Ming-Huang Chen, Peter Mu-Hsin Chang, Alex T H Wu, Michael Hsiao
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) represents a unique and major health concern worldwide. Significant increases in glucose uptake and aerobic glycolysis have been observed in HNSCC cells. Glucose transporters (GLUTs) represent a major hub in the glycolysis pathway, with GLUT4 having the highest glucose affinity. However, GLUT4's role in HNSCC has not been fully appreciated. METHODS: An in silico analysis was performed in HNSCC cohorts to identify the most significant glucose transporter associated with HNSCC patient prognosis...
January 7, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28057741/factor-viii-v-c-domain-swaps-reveal-discrete-c-domain-roles-in-factor-viii-function-and-intracellular-trafficking
#8
Eduard H T M Ebberink, Eveline A M Bouwens, Esther Bloem, Mariëtte Boon-Spijker, Maartje Van den Biggelaar, Jan Voorberg, Alexander B Meijer, Koen Mertens
Factor VIII C-domains are believed to contain specific function in co-factor activity and in interaction with von Willebrand factor. We have previously shown that factor VIII is co-targeted with von Willebrand factor to the Weibel-Palade bodies in blood outgrowth endothelial cells, even when factor VIII carries mutations in the light chain that are associated with defective von Willebrand factor binding. In this study we furthermore addressed the contribution of individual factor VIII C-domains in intracellular targeting, von Willebrand factor binding and co-factor activity by factor VIII/V C-domain swapping...
January 5, 2017: Haematologica
https://www.readbyqxmd.com/read/28057569/a-novel-peroxidase-purified-from-marsdenia-megalantha-latex-inhibits-phytopathogenic-fungi-mediated-by-cell-membrane-permeabilization
#9
Henrique P Oliveira, Rodolpho G G Silva, Jose T A Oliveira, Daniele O B Sousa, Mirella L Pereira, Pedro F N Souza, Arlete A Soares, Valdirene M Gomes, Ana C O Monteiro-Moreira, Frederico B M B Moreno, Ilka M Vasconcelos
An antifungal class III peroxidase was purified from Marsdenia megalantha latex (named Mo-POX) using DEAE-cellulose and gel filtration chromatography on a Superose 12 HR 10/30 column. Mm-POX has an apparent molecular mass of 67.0kDa and a pI of 5.2, shares identity with other peroxidases, and follows Michaelis-Menten kinetics. It has a high affinity for guaiacol and hydrogen peroxide. The pH and temperature optima for Mm-POX were 5.0-7.0 and 60°C, respectively. The catalytic activity of Mm-POX was decreased in the presence of classic peroxidase inhibitors including azide, dithiothreitol, ethylenediamine tetraacetic acid, and sodium metabisulfite and high concentrations of Na(+), Mn(+), and salicylic acid...
January 3, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28056508/fk506-an-immunosuppressive-drug-induces-autophagy-by-binding-to-the-v-atpase-catalytic-subunit-a-in-neuronal-cells
#10
Dongyoung Kim, Hui-Yun Hwang, Jin Young Kim, Ju Yeon Lee, Jong Shin Yoo, György Marko-Varga, Ho Jeong Kwon
The drug FK506 (tacrolimus, fujimycin) exerts its immunosuppressive effects by regulating the nuclear factor of the activated T-cell (NFAT) family of transcription factors. However, FK506 also exhibits neuroprotective effects, but its direct target proteins that mediate these effects have not been determined. To identify the target proteins responsible for FK506's neuroprotective effects, the drug affinity responsive target stability (DARTS) method was performed using label-free FK506, and LC-MS/MS analysis of the FK506-treated proteome was also performed...
January 6, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28054978/hemoglobin-based-blood-substitutes-and-the-treatment-of-sickle-cell-disease-more-harm-than-help
#11
REVIEW
Abdu I Alayash
Intense efforts have been made by both industry and academia over the last three decades to produce viable hemoglobin (Hb)-based oxygen carriers (HBOCs), also known as "blood substitutes". Human trials conducted so far by several manufactures in a variety of clinical indications, including trauma, and elective surgeries have failed and no product has gained the Food and Drug Administration approval for human use. Safety concerns due to frequent incidences of hemodynamic, cardiac events, and even death led to the termination of some of these trials...
January 4, 2017: Biomolecules
https://www.readbyqxmd.com/read/28054473/-screening-different-host-cell-lines-for-the-dynamic-production-of-measles-virus
#12
Tanja A Grein, Felix Schwebel, Marco Kress, Daniel Loewe, Hauke Dieken, Denise Salzig, Tobias Weidner, Peter Czermak
Measles virus (MV) has a natural affinity for cancer cells and oncolytic MV preparations have therefore been investigated in several clinical trials as a potential treatment for cancer. The main bottleneck in the administration of oncolytic MV to cancer patients is the production process, because very large doses of virus particles are required for each treatment. Here we investigated the productivity of different host cells and found that a high infection efficiency did not necessarily result in high virus yields because virus release is also dependent on the host cell...
January 5, 2017: Biotechnology Progress
https://www.readbyqxmd.com/read/28052935/d120-and-k152-within-the-ph-domain-of-t-cell-adapter-skap55-regulate-plasma-membrane-targeting-of-skap55-and-lfa-1-affinity-modulation-in-human-t-lymphocytes
#13
Amelie Witte, Bernhard Meineke, Jana Sticht, Lars Philipsen, Benno Kuropka, Andreas J Müller, Christian Freund, Burkhart Schraven, Stefanie Kliche
The β2-integrin lymphocyte function-associated antigen-1 (LFA-1) is needed for T cell receptor (TCR) induced activation of LFA-1 to promote T cell adhesion and interaction with antigen presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src Kinase-Associated Phosphoprotein of 55 kDa (SKAP55) is a key regulator of TCR-mediated LFA-1 signaling (inside-out/outside-in signaling). To gain understanding of how SKAP55 controls TCR-mediated LFA-1 activation, we assessed the functional role of its Pleckstrin Homology (PH) domain...
January 4, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28050849/glycin-rich-antimicrobial-peptide-yd1-from-b-amyloliquefaciens-induced-morphological-alteration-in-and-showed-affinity-for-plasmid-dna-of-e-coli
#14
Md Saifur Rahman, Yun Hee Choi, Yoon Seok Choi, Jin Cheol Yoo
Antimicrobial peptides (AMPs), low-molecular-weight proteins with broad-spectrum antimicrobial activity, are the most promising candidates for the development of novel antimicrobials. A powerful cationic glycine-rich AMP YD1 (MW ~ 1.0 kDa) was purified from Bacillus amyloliquefaciens CBSYD1 isolated from traditional Korean fermented food kimchi, for the treatment of multidrug-resistant (MDR) bacteria. Strain CBSYD1 was identified 99.79% similar to Bacillus amyloliquefaciens subsp. plantarum FZB42(T) by 16S rRNA sequence analysis...
December 2017: AMB Express
https://www.readbyqxmd.com/read/28049822/correction-for-lever-et-al-architecture-of-a-minimal-signaling-pathway-explains-the-t-cell-response-to-a-1-million-fold-variation-in-antigen-affinity-and-dose
#15
(no author information available yet)
No abstract text is available yet for this article.
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28048906/su-f-t-666-molecular-targeted-gold-nanorods-enhances-the-rbe-of-proton-therapy
#16
A Khoo, N Sahoo, S Krishnan, P Diagaradjane
PURPOSE: In recent years, proton beam radiation therapy (PBRT) has gained significant attention in the treatment of tumors in anatomically complex locations. However, the therapeutic benefit of PBRT is limited by a relative biological effectiveness (RBE) of just 1.1. The purpose of this study is to evaluate whether this limitation can be overcome by artificially enhancing the RBE using molecular-targeted gold nanorods (GNRs). METHODS: Molecular-targeting of GNRs was accomplished using Cetuximab (antibody specific to epidermal growth factor receptor that is over-expressed in tumors) conjugated GNRs (cGNRs) and their binding affinity to Head and Neck cancer cells was confirmed using dark field microscopy and Transmission Electron Microscopy (TEM)...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28041663/potent-immunomodulatory-activity-of-a-highly-selective-cannabinoid-cb2-agonist-on-immune-cells-from-healthy-subjects-and-patients-with-multiple-sclerosis
#17
Pasquale Annunziata, Chiara Cioni, Claudia Mugnaini, Federico Corelli
COR167, a novel CB2-selective high affinity agonist, was found to significantly inhibit, in a dose-dependent manner, the proliferation of both peripheral blood mononuclear cells and myelin basic protein-reactive T cell lines from normal healthy subjects and patients with relapsing-remitting multiple sclerosis (MS). In MS, a significantly higher inhibition was observed in patients on treatment with disease modifying drugs compared to those naive to treatment. The inhibitory activity of COR167 was exerted through a mixed mechanism involving atypical and incomplete shift of Th1 phenotype towards Th2 phenotype associated with slight reduction of IL-4 and IL-5 as well as strongly reduced levels of Th17-related cytokines...
December 23, 2016: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28038927/cellular-immune-response-to-%C3%AE-2-glycoprotein-i-valine-leucine-247-phenotypes-in-mexican-patients-with-primary-antiphospholipid-syndrome
#18
Carlos A Núñez-Álvarez, Diego F Hernández-Ramírez, Araceli Martinez-Castillo, Virginia Pascual Ramos, Javier Cabiedes, Alicia Ortega, Antonio R Cabral
: Homozygote genotype V(247) of the β2-glycoprotein-I (β2GP-I) gene has been associated with anti-β2GP-I and thrombosis in patients with primary anti-phospholipid syndrome APS (PAPS). However, the cellular immune response to β2GP-I(247) has been little studied. OBJECTIVE: To evaluate the immune cellular proliferation in response to native and non-native β2GP-I(247) valine/leucine phenotype from Mexican patients with PAPS. METHODS: We studied 10 patients with PAPS and 10 healthy control subjects (HC)...
December 27, 2016: Human Immunology
https://www.readbyqxmd.com/read/28031341/differing-requirements-for-malt1-function-in-peripheral-b-cell-survival-and-differentiation
#19
Peishan Lee, Zilu Zhu, Janna Hachmann, Takuya Nojima, Daisuke Kitamura, Guy Salvesen, Robert C Rickert
During a T cell-dependent immune response, formation of the germinal center (GC) is essential for the generation of high-affinity plasma cells and memory B cells. The canonical NF-κB pathway has been implicated in the initiation of GC reaction, and defects in this pathway have been linked to immune deficiencies. The paracaspase MALT1 plays an important role in regulating NF-κB activation upon triggering of Ag receptors. Although previous studies have reported that MALT1 deficiency abrogates the GC response, the relative contribution of B cells and T cells to the defective phenotype remains unclear...
December 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28028314/redirecting-t-cells-to-eradicate-b-cell-acute-lymphoblastic-leukemia-bispecific-t-cell-engagers-and-chimeric-antigen-receptors
#20
REVIEW
I Aldoss, R C Bargou, D Nagorsen, G R Friberg, P A Baeuerle, S J Forman
Recent advances in antibody technology to harness T-cells for cancer immunotherapy, particularly in the difficult-to-treat setting of relapsed or refractory acute lymphoblastic leukemia (r/r ALL), has led to innovative methods for directing cytotoxic T-cells to specific surface antigens on cancer cells. One approach involves administration of soluble bispecific (or dual-affinity) antibody-based constructs that temporarily bridge T-cells and cancer cells. Another approach infuses ex vivo-engineered T-cells that express a surface plasma membrane-inserted antibody construct called a chimeric antigen receptor (CAR)...
December 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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