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Inhibitor tolerance induction

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https://www.readbyqxmd.com/read/28874440/blocking-gp130-signaling-suppresses-autotaxin-expression-in-adipocytes-and-improves-insulin-sensitivity-in-diet-induced-obesity
#1
Shuhong Sun, Ran Wang, Jianwen Song, Ming Guan, Na Li, Xiaotian Zhang, Zhenwen Zhao, Junjie Zhang
Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Up-regulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. However, the mechanism of ATX expression in adipocytes remains largely unknown. In this study, we found that gp130-mediated JAK-STAT3 activation was required for abundant ATX expression in adipocytes...
September 5, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28864263/mechanism-of-chimeric-vaccine-stimulation-of-indoleamine-2-3-dioxygenase-biosynthesis-in-human-dendritic-cells-is-independent-of-tgf-%C3%AE-signaling
#2
Grace E Esebanmen, William H R Langridge
Cholera toxin B subunit fusion to autoantigens such as proinsulin (CTB-INS) down regulate dendritic cell (DC) activation and stimulate synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased biosynthesis of indoleamine 2,3-dioxygenase (IDO1) may play an important role in CTB-INS vaccine suppression of DC activation. Studies in murine models suggest a role for transforming growth factor beta (TGF-β) in the stimulation of IDO1 biosynthesis, for the induction of tolerance in DCs...
August 21, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28863186/fusion-of-taq-dna-polymerase-with-single-stranded-dna-binding-like-protein-of-nanoarchaeum-equitans-expression-and-characterization
#3
Marcin Olszewski, Marta Śpibida, Maciej Bilek, Beata Krawczyk
DNA polymerases are present in all organisms and are important enzymes that synthesise DNA molecules. They are used in various fields of science, predominantly as essential components for in vitro DNA syntheses, known as PCR. Modern diagnostics, molecular biology and genetic engineering need DNA polymerases which demonstrate improved performance. This study was aimed at obtaining a new NeqSSB-TaqS fusion DNA polymerase from the Taq DNA Stoffel domain and a single-stranded DNA binding-like protein of Nanoarchaeum equitans in order to significantly improve the properties of DNA polymerase...
2017: PloS One
https://www.readbyqxmd.com/read/28856745/using-known-drug-interactions-to-manage-supratherapeutic-calcineurin-inhibitor-concentrations
#4
REVIEW
Nicholas W Lange, David M Salerno, Karen Berger, Demetra S Tsapepas
OBJECTIVES: To summarize the available body of evidence guiding the management of supratherapeutic concentrations of calcineurin inhibitors (CNI) using cytochrome P450 (CYP450) enzyme inducers. METHODS: A non-date restricted literature search within MEDLINE, Embase, and Scopus was performed using the terms "cyclosporine", "tacrolimus", "calcineurin inhibitor", "toxicity", "pharmacokinetics", "carbamazepine", "rifampin", "phenytoin", and "phenobarbital." Additional references were identified from a review of all included citations...
August 30, 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/28835351/emerging-therapeutic-modalities-for-acute-myeloid-leukemia-aml-in-older-adults
#5
Li-Wen Huang, Rebecca L Olin
Treatment for the older adult with acute myeloid leukemia (AML) is challenging, due to both more aggressive disease biology as well as patient-related risk factors that limit tolerance of intensive chemotherapy. The use of prognostic models and comprehensive geriatric assessments can help hematologists evaluate the suitability of intensive chemotherapy for individual patients. For older patients considered fit for intensive chemotherapy, standard induction therapy should be given, followed by consideration of reduced intensity allogeneic stem cell transplantation...
August 20, 2017: Journal of Geriatric Oncology
https://www.readbyqxmd.com/read/28826742/a-comprehensive-review-and-update-on-crohn-s-disease
#6
Mahesh Gajendran, Priyadarshini Loganathan, Anthony P Catinella, Jana G Hashash
The term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups...
August 18, 2017: Disease-a-month: DM
https://www.readbyqxmd.com/read/28820887/identification-of-putative-qtls-for-seedling-stage-phosphorus-starvation-response-in-finger-millet-eleusine-coracana-l-gaertn-by-association-mapping-and-cross-species-synteny-analysis
#7
M Ramakrishnan, S Antony Ceasar, K K Vinod, V Duraipandiyan, T P Ajeesh Krishna, Hari D Upadhyaya, N A Al-Dhabi, S Ignacimuthu
A germplasm assembly of 128 finger millet genotypes from 18 countries was evaluated for seedling-stage phosphorus (P) responses by growing them in P sufficient (Psuf) and P deficient (Pdef) treatments. Majority of the genotypes showed adaptive responses to low P condition. Based on phenotype behaviour using the best linear unbiased predictors for each trait, genotypes were classified into, P responsive, low P tolerant and P non-responsive types. Based on the overall phenotype performance under Pdef, 10 genotypes were identified as low P tolerants...
2017: PloS One
https://www.readbyqxmd.com/read/28776122/mechanisms-involved-in-the-remyelinating-effect-of-sildenafil
#8
Daniela Díaz-Lucena, María Gutierrez-Mecinas, Beatriz Moreno, José Lupicinio Martínez-Sánchez, Paula Pifarré, Agustina García
Remyelination occurs in demyelinated lesions in multiple sclerosis (MS) and pharmacological treatments that enhance this process will critically impact the long term functional outcome in the disease. Sildenafil, a cyclic GMP (cGMP)-specific phosphodiesterase 5 inhibitor (PDE5-I), is an oral vasodilator drug extensively used in humans for treatment of erectile dysfunction and pulmonary arterial hypertension. PDE5 is expressed in central nervous system (CNS) neuronal and glial populations and in endothelial cells and numerous studies in rodent models of neurological disease have evidenced the neuroprotective potential of PDE5-Is...
August 3, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28747745/towards-water-free-biobanks-long-term-dry-preservation-at-room-temperature-of-desiccation-sensitive-enzyme-luciferase-in-air-dried-insect-cells
#9
Shingo Kikuta, Shunsuke J Watanabe, Ryoichi Sato, Oleg Gusev, Alexander Nesmelov, Yoichiro Sogame, Richard Cornette, Takahiro Kikawada
Desiccation-tolerant cultured cells Pv11 derived from the anhydrobiotic midge embryo endure complete desiccation in an ametabolic state and resume their metabolism after rehydration. These features led us to develop a novel dry preservation technology for enzymes as it was still unclear whether Pv11 cells could preserve an exogenous enzyme in the dry state. This study shows that Pv11 cells protect an exogenous desiccation-sensitive enzyme, luciferase (Luc), preserving the enzymatic activity even after dry storage for 372 days at room temperature...
July 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28736194/the-epigenetic-drug-trichostatin-a-ameliorates-experimental-autoimmune-encephalomyelitis-via-t-cell-tolerance-induction-and-impaired-influx-of-t-cells-into-the-spinal-cord
#10
Arathi Jayaraman, Advait Soni, Bellur S Prabhakar, Mark Holterman, Sundararajan Jayaraman
Multiple sclerosis is a T cell mediated chronic demyelinating disease of the central nervous system. Although currently available therapies reduce relapses, they do not facilitate tolerization of myelin antigen-specific T lymphocytes to ensure prolonged protection against multiple sclerosis. Here, we show that treatment of NOD mice with the histone deacetylase inhibitor, Trichostatin A affords robust protection against myelin peptide induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis...
July 20, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28729302/vosaroxin-in-combination-with-decitabine-in-newly-diagnosed-older-patients-with-acute-myeloid-leukemia-or-high-risk-mds
#11
Naval Daver, Hagop Kantarjian, Guillermo Garcia-Manero, Elias Jabbour, Gautam Borthakur, Mark Brandt, Sherry Pierce, Kenneth Vaughan, Jing Ning, Graciela M Nogueras González, Keyur Patel, Jeff Jorgensen, Naveen Pemmaraju, Tapan Kadia, Marina Konopleva, Michael Andreeff, Courtney DiNardo, Jorge Cortes, Renee Ward, Adam Craig, Farhad Ravandi
Vosaroxin is an anti-cancer quinolone derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥ 60 years of age with newly diagnosed acute myeloid leukemia (AML) (n=58) or myelodysplastic syndrome (MDS) (≥ 10% blasts) (n=7) in a phase 2 non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on Days 1 and 4 with decitabine 20 mg/m2 Days 1-5 every 4-6 weeks for up to 7 cycles. Due to high incidence of mucositis the subsequent 43 patients received vosaroxin 70 mg/m2 Days 1 and 4...
July 20, 2017: Haematologica
https://www.readbyqxmd.com/read/28721361/role-of-endoplasmic-reticulum-stress-in-learning-and-memory-impairment-and-alzheimer-s-disease-like-neuropathology-in-the-ps19-and-app-swe-mouse-models-of-tauopathy-and-amyloidosis
#12
Denise Isabelle Briggs, Erwin Defensor, Pooneh Memar Ardestani, Bitna Yi, Michelle Halpain, Guy Seabrook, Mehrdad Shamloo
Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer's disease (AD). Recently, pharmacological modulation of the eukaryotic translation initiation factor-2 (eIF2α) pathway was achieved using an integrated stress response inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28714868/interval-dosing-with-the-hdac-inhibitor-vorinostat-effectively-reverses-hiv-latency
#13
Nancie M Archin, Jennifer L Kirchherr, Julia Am Sung, Genevieve Clutton, Katherine Sholtis, Yinyan Xu, Brigitte Allard, Erin Stuelke, Angela D Kashuba, Joann D Kuruc, Joseph Eron, Cynthia L Gay, Nilu Goonetilleke, David M Margolis
BACKGROUND: The histone deacetylase (HDAC) inhibitor vorinostat (VOR) can increase HIV RNA expression in vivo within resting CD4+ T cells of aviremic HIV+ individuals. However, while studies of VOR or other HDAC inhibitors have reported reversal of latency, none has demonstrated clearance of latent infection. We sought to identify the optimal dosing of VOR for effective serial reversal of HIV latency. METHODS: In a study of 16 HIV-infected, aviremic individuals, we measured resting CD4+ T cell-associated HIV RNA ex vivo and in vivo following a single exposure to VOR, and then in vivo after a pair of doses separated by 48 or 72 hours, and finally following a series of 10 doses given at 72-hour intervals...
August 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28689155/combination-of-hemostatic-therapies-for-treatment-of-patients-with-hemophilia-a-and-inhibitors
#14
Tami Livnat, Ivan Budnik, Sarina Levy-Mendelovich, Einat Avishai, Mudi Misgav, Assaf Arie Barg, Aharon Lubetsky, Tami Brutman-Barazani, Gili Kenet
BACKGROUND: Therapy application and monitoring of patients with hemophilia A (HA) and inhibitors are challenging. In the current study, combined FVIII - bypass therapy was implemented for a cohort of severe HA patients with inhibitors. METHODS: Plasma of 15 HA patients with inhibitors was spiked ex vivo with FVIII, rFVIIa, FEIBA and their combinations and thrombin generation (TG) was studied. Some patients who experienced hemarthroses or required minor surgeries were treated by a combined concomitant administration of FVIII+FEIBA as IV bolus doses...
June 27, 2017: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/28679643/endogenous-heat-shock-protein-induction-with-or-without-radiofrequency-ablation-or-cryoablation-in-patients-with-stage-iv-melanoma
#15
Evidio Domingo-Musibay, James M Heun, Wendy K Nevala, Matthew Callstrom, Thomas Atwell, Evanthia Galanis, Lori A Erickson, Svetomir N Markovic
LESSONS LEARNED: Percutaneous thermal ablation combined with in situ granulocyte-macrophage colony-stimulating factor cytokine therapy was technically feasible and well tolerated.No significant clinical or immunologic responses were seen. BACKGROUND: Melanoma tumor-derived heat-shock proteins (HSPs) and HSP-peptide complexes can elicit protective antitumor responses. The granulocyte-macrophage colony-stimulating factor (GM-CSF) chemokine can also promote uptake and processing by professional antigen presenting cells (APCs)...
July 5, 2017: Oncologist
https://www.readbyqxmd.com/read/28655785/a-small-molecule-inhibitor-of-wee1-azd1775-synergizes-with-olaparib-by-impairing-homologous-recombination-and-enhancing-dna-damage-and-apoptosis-in-acute-leukemia
#16
Tamara B Garcia, Jonathan C Snedeker, Dmitry Baturin, Lori Gardner, Susan P Fosmire, Chengjing Zhou, Craig T Jordan, Sujatha Venkataraman, Rajeev Vibhakar, Christopher C Porter
Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies including cytarabine in AML and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine if AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal...
June 27, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28651073/hemophilia-a-inhibitor-treatment-the-promise-of-engineered-t-cell-therapy
#17
REVIEW
Kalpana Parvathaneni, Maha Abdeladhim, Kathleen P Pratt, David W Scott
Hemophilia A is a bleeding disorder caused by mutations in the gene encoding factor VIII (FVIII), a cofactor protein that is essential for normal blood clotting. Approximately, 1 in 3 patients with severe hemophilia A produce neutralizing antibodies (inhibitors) that block its biologic function in the clotting cascade. Current efforts to eliminate inhibitors consist of repeated FVIII injections under what is termed an "ITI" protocol (Immune Tolerance Induction). However, this method is extremely costly and approximately 30% of patients undergoing ITI do not achieve peripheral tolerance...
September 2017: Translational Research: the Journal of Laboratory and Clinical Medicine
https://www.readbyqxmd.com/read/28645776/selective-inhibition-of-flt3-by-gilteritinib-in-relapsed-or-refractory-acute-myeloid-leukaemia-a-multicentre-first-in-human-open-label-phase-1-2-study
#18
Alexander E Perl, Jessica K Altman, Jorge Cortes, Catherine Smith, Mark Litzow, Maria R Baer, David Claxton, Harry P Erba, Stan Gill, Stuart Goldberg, Joseph G Jurcic, Richard A Larson, Chaofeng Liu, Ellen Ritchie, Gary Schiller, Alexander I Spira, Stephen A Strickland, Raoul Tibes, Celalettin Ustun, Eunice S Wang, Robert Stuart, Christoph Röllig, Andreas Neubauer, Giovanni Martinelli, Erkut Bahceci, Mark Levis
BACKGROUND: Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. METHODS: In this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment...
August 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28645296/myd88-dependent-pro-interleukin-1%C3%AE-induction-in-dendritic-cells-exposed-to-food-grade-synthetic-amorphous-silica
#19
Hans Christian Winkler, Julian Kornprobst, Peter Wick, Lea Maria von Moos, Ioannis Trantakis, Elisabeth Maria Schraner, Barbara Bathke, Hubertus Hochrein, Mark Suter, Hanspeter Naegeli
BACKGROUND: Dendritic cells (DCs) are specialized first-line sensors of foreign materials invading the organism. These sentinel cells rely on pattern recognition receptors such as Nod-like or Toll-like receptors (TLRs) to launch immune reactions against pathogens, but also to mediate tolerance to self-antigens and, in the intestinal milieu, to nutrients and commensals. Since inappropriate DC activation contributes to inflammatory diseases and immunopathologies, a key question in the evaluation of orally ingested nanomaterials is whether their contact with DCs in the intestinal mucosa disrupts this delicate homeostatic balance between pathogen defense and tolerance...
June 23, 2017: Particle and Fibre Toxicology
https://www.readbyqxmd.com/read/28641362/estimating-the-potential-cost-of-a-high-dose-immune-tolerance-induction-iti-therapy-relative-to-the-cost-of-a-combined-therapy-of-a-low-dose-iti-therapy-with-bypassing-agent-prophylaxis
#20
G Kenet, A Oladapo, J D Epstein, C Thompson, A Novack, D J Nugent
INTRODUCTION: The International Immune Tolerance Study (I-ITI) demonstrated comparable success rates between low (FVIII 50 IU/kg/TIW) and high dose (FVIII 200 IU/kg/day) regimens. While costlier, the high dose ITI regimen achieved shorter time-to-treatment success with fewer bleeding episodes compared to the low dose ITI regimen. Adding bypassing agent prophylaxis (BAP) to a low dose ITI regimen may reduce bleeding while still being less costly than high dose ITI. AIM AND METHODS: An economic model was developed to compare high dose ITI to low dose ITI with BAP...
June 22, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
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