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Inhibitor tolerance induction

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https://www.readbyqxmd.com/read/28223344/an-intestinal-farnesoid-x-receptor-ceramide-signaling-axis-modulates-hepatic-gluconeogenesis-in-mice
#1
Cen Xie, Changtao Jiang, Jingmin Shi, Xiaoxia Gao, Dongxue Sun, Lulu Sun, Ting Wang, Shogo Takahashi, Mallappa Anitha, Kristopher W Krausz, Andrew D Patterson, Frank J Gonzalez
Increasing evidence supports the view that intestinal farnesoid X receptor (FXR) is involved in glucose tolerance and that FXR signaling can be profoundly impacted by the gut microbiota. Selective manipulation of the gut microbiota-FXR signaling axis was reported to significantly impact glucose intolerance, but the precise molecular mechanism remains largely unknown. Here, caffeic acid phenethyl ester (CAPE), an over-the-counter dietary supplement and an inhibitor of bacterial bile salt hydrolase, increased levels of intestinal tauro-β-muricholic acid, which selectively suppresses intestinal FXR signaling...
March 2017: Diabetes
https://www.readbyqxmd.com/read/28205285/natural-history-and-clinical-characteristics-of-inhibitors-in-previously-treated-haemophilia-a-patients-a-case-series
#2
A Iorio, A M Barbara, M Makris, K Fischer, G Castaman, C Catarino, E Gilman, K Kavakli, T Lambert, R Lassila, T Lissitchkov, E Mauser-Bunschoten, M E Mingot-Castellano, N Ozdemir, I Pabinger, R Parra, J Pasi, K Peerlinck, A Rauch, V Roussel-Robert, M Serban, A Tagliaferri, J Windyga, E Zanon
BACKGROUND: Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development...
February 15, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/28194465/unravelling-the-role-of-protein-kinase-ck2-in-metal-toxicity-using-gene-deletion-mutants
#3
Adam J Johnson, Mohammad S Zaman, Filip Veljanoski, Alex A Phrakaysone, Suhua Li, Patrick J O'Doherty, Gayani Petersingham, Gabriel G Perrone, Mark P Molloy, Ming J Wu
Metal ions, biologically essential or toxic, are present in the surrounding environment of living organisms. Understanding their uptake, homeostasis or detoxification is critical in cell biology and human health. In this study, we investigated the role of protein kinase CK2 in metal toxicity using gene deletion strains of Saccharomyces cerevisiae against a panel of six metal ions. The deletion of CKA2, the yeast orthologue of mammalian CK2α', leads to a pronounced resistant phenotype against Zn(2+) and Al(3+), whilst the deletion of CKB1 or CKB2 results in tolerance to Cr(6+) and As(3+)...
February 14, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28167776/tgf-%C3%AE-inhibitor-smad7-regulates-dendritic-cell-induced-autoimmunity
#4
Dominika Lukas, Nir Yogev, Junda M Kel, Tommy Regen, Ilgiz A Mufazalov, Yilang Tang, Florian Wanke, Boris Reizis, Werner Müller, Florian C Kurschus, Marco Prinz, Ingo Kleiter, Björn E Clausen, Ari Waisman
TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8(+)CD103(+) DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction...
February 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28153098/oral-tolerance-induction-in-hemophilia-b-dogs-fed-with-transplastomic-lettuce
#5
Roland W Herzog, Timothy C Nichols, Jin Su, Bei Zhang, Alexandra Sherman, Elizabeth P Merricks, Robin Raymer, George Q Perrin, Mattias Häger, Bo Wiinberg, Henry Daniell
Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility...
February 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28124406/recombinant-porcine-factor-viii-for-high-risk-surgery-in-paediatric-congenital-haemophilia-a-with-high-titre-inhibitor
#6
S E Croteau, Y L Abajas, A S Wolberg, B I Nielsen, G R Marx, C W Baird, E J Neufeld, P E Monahan
INTRODUCTION: High-titre factor VIII (FVIII) inhibitors complicate peri-operative haemostasis. Recombinant porcine FVIII (r-pFVIII) may provide an alternative haemostatic agent for high-risk procedures and allow FVIII activity monitoring. AIM: Devise an effective haemostatic plan for repair of a progressively symptomatic aortic coarctation in a 5-year-old male with immune tolerance induction (ITI) refractory high-titre FVIII inhibitors. METHODS: Preprocedure human FVIII inhibitor titre was 58 Bethesda Units mL(-1) (BU) and cross-reacted to neutralize porcine FVIII at 30 BU...
January 25, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/28123935/deletion-of-histone-deacetylase-3-in-adult-beta-cells-improves-glucose-tolerance-via-increased-insulin-secretion
#7
Jarrett R Remsberg, Benjamin N Ediger, Wesley Y Ho, Manashree Damle, Zhenghui Li, Christopher Teng, Cristina Lanzillotta, Doris A Stoffers, Mitchell A Lazar
OBJECTIVE: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. METHODS: An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28034990/phase-i-study-of-the-aurora-a-kinase-inhibitor-alisertib-with-induction-chemotherapy-in-patients-with-acute-myeloid-leukemia
#8
Amir T Fathi, Seth A Wander, Traci M Blonquist, Andrew M Brunner, Philip C Amrein, Jeffrey Supko, Nicole M Hermance, Amity L Manning, Hossein Sadrzadeh, Karen K Ballen, Eyal C Attar, Timothy A Graubert, Gabriela Hobbs, Christelle Joseph, Ashley M Perry, Meghan Burke, Regina Silver, Julia Foster, Meghan Bergeron, Aura Y Ramos, Tina T Som, Kaitlyn M Fishman, Kristin L McGregor, Christine Connolly, Donna S Neuberg, Yi-Bin Chen
Aberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts...
December 29, 2016: Haematologica
https://www.readbyqxmd.com/read/28034782/spinal-trpc6-channels-contributes-to-morphine-induced-antinociceptive-tolerance-and-hyperalgesia-in-rats
#9
Hua Jin, Ying-Tong Sun, Guang-Qiong Guo, Da-Lin Chen, Yu-Jin Li, Gao-Peng Xiao, Xin-Nan Li
The chronic administration of opioids results in the development of morphine analgesic tolerance and withdrawl-induced hyperalgesia, which limits their clinical utility in pain treatment. However, the cellular mechanisms underlying opioid-induced tolerance and hyperalgesia are not fully understood. The transient receptor potential canonical channel TRPC6 is important for brain development and function, as it regulates cytosolic, endoplasmic reticulum, and mitochondrial Ca(2+) levels in neural cells. Here, we report that TRPC6 expression in the spinal cord was up-regulated after chronic morphine treatment...
February 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28026145/the-bromodomain-inhibitor-jq1-triggers-growth-arrest-and-apoptosis-in-testicular-germ-cell-tumours-in-vitro-and-in-vivo
#10
Sina Jostes, Daniel Nettersheim, Martin Fellermeyer, Simon Schneider, François Hafezi, Friedemann Honecker, Valerie Schumacher, Matthias Geyer, Glen Kristiansen, Hubert Schorle
Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20-40 years) and are classified as seminoma or non-seminoma. TGCTs are commonly treated by orchiectomy and chemo- or radiotherapy. However, a subset of metastatic non-seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small-molecule inhibitor JQ1 in tumour therapy, which interferes with the function of 'bromodomain and extraterminal (BET)' proteins...
December 27, 2016: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28025939/serotonin-selective-reuptake-inhibitors-ssris-and-female-sexual-dysfunction-fsd-hypothesis-on-its-association-and-options-of-treatment
#11
Nurul Azmi Mahamad Rappek, Hatta Sidi, Jaya Kumar, Sazlina Kamarazaman, Srijit Das, Ruziana Masiran, Najwa Baharudin, Muhammad Hatta
Sexual dysfunctions are commonly seen in women on selective serotonin reuptake inhibitors (SSRIs). The complexities of female sexual functioning are reflected through modulation of inter-playing factors like the neuropsychophysiological factors, inter-personal and relationship issue, psychiatric co-morbidities and physical disorder. The incidence of SSRIs-induced FSD is difficult to estimate because of the potentially confounding effects of SSRIs, presence of polypharmacy, marital effect, socio-cultural factors and due to the design and assessment problems in majority of the studies...
December 27, 2016: Current Drug Targets
https://www.readbyqxmd.com/read/28004478/cs2164-a-novel-multi-target-inhibitor-against-tumor-angiogenesis-mitosis-chronic-inflammation-with-anti-tumor-potency
#12
You Zhou, Song Shan, Zhi-Bin Li, Li-Jun Xin, De-Si Pan, Qian-Jiao Yang, Ying-Ping Liu, Xu-Peng Yue, Xiao-Rong Liu, Ji-Zhou Gao, Jin-Wen Zhang, Zhi-Qiang Ning, Xian-Ping Lu
Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the efforts of finding a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα, and c-Kit), mitosis-related kinase Aurora B, and chronic inflammatory-related kinase CSF-1R in a high potency manner with the IC50 at a single digital nanomolar range...
December 22, 2016: Cancer Science
https://www.readbyqxmd.com/read/27990784/new-findings-on-inhibitor-development-from-registries-to-clinical-studies
#13
REVIEW
F Peyvandi, C E Ettingshausen, J Goudemand, V Jiménez-Yuste, E Santagostino, M Makris
The high incidence of inhibitors against factor VIII (FVIII) concentrates in patients with haemophilia A has encouraged debate as to whether product-type plays a role. There is debate in the literature as to whether rFVIII concentrates are associated with a higher incidence of inhibitors compared to pdFVIII products. The management of haemophilia in patients with inhibitors includes on-demand/prophylaxis treatment with bypassing agents, and/or immune tolerance induction (ITI). However, these options create an economic and emotional burden on patients, their families and healthcare practitioners...
January 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/27990653/population-pharmacokinetic-and-pharmacodynamic-modeling-of-epacadostat-in-patients-with-advanced-solid-malignancies
#14
Jack G Shi, Kevin J Bowman, Xuejun Chen, Janet Maleski, Lance Leopold, Swamy Yeleswaram
Epacadostat (EPA, INCB024360) is a selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and is being developed as an orally active immunotherapy to treat advanced malignancies. In the first clinical study investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of EPA in oncology patients, increasing doses of EPA ranging from 50 mg once daily to 700 mg twice daily were administered as a monotherapy to 52 subjects with advanced solid tumors. The EPA plasma concentration-time profiles were adequately described by a population PK model comprised of the first-order kinetics of oral absorption with 2-compartment distribution and constant clearance from the central compartment...
December 19, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27917591/the-pde4-inhibitor-roflumilast-reduces-weight-gain-by-increasing-energy-expenditure-and-leads-to-improved-glucose-metabolism
#15
Julia Möllmann, Florian Kahles, Corinna Lebherz, Ben Kappel, Christer Baeck, Frank Tacke, Christian Werner, Massimo Federici, Nikolaus Marx, Michael Lehrke
AIMS: The PDE4 inhibitor roflumilast is a clinically approved anti-inflammatory drug used for the treatment of chronic obstructive pulmonary disease. In addition, roflumilast was found to reduce body weight and improve glucose metabolism by a yet unknown mechanism. MATERIALS AND METHODS: Metabolic effects of roflumilast were investigated in C57BL/6J mice on high fat western-type diet treated with or without roflumilast for a period of 12 weeks. RESULTS: Roflumilast led to a marked reduction of body weight gain, which became apparent in the second week following treatment initiation and was attributable to a pronounced increase of energy expenditure...
December 5, 2016: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/27913541/what-is-the-role-of-an-extended-half-life-product-in-immune-tolerance-induction-in-a-patient-with-severe-hemophilia-a-and-high-titer-inhibitors
#16
Maissaa Janbain, Steven Pipe
A 10-year-old boy presents with a history of severe hemophilia A and high-titer inhibitor that had failed high-dose immune tolerance induction (ITI) with a recombinant factor VIII (rFVIII) product and a plasma-derived FVIII product. You are asked by his mother whether he should be tried on ITI with an extended half-life product, in particular, consideration of a rFVIIIFc concentrate.
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27904651/sunitinib-in-the-treatment-of-metastatic-renal-cell-carcinoma
#17
REVIEW
Thomas A Schmid, Martin E Gore
Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that targets various receptors, including vascular endothelial growth factor receptors (VEGFRs). Sunitinib received approval in 2006 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared with interferon alpha (IFN-α). Sunitinib has also shown activity in second-line treatment in several trials. Most of the combination trials with sunitinib with various agents have led to considerable toxicity without improving efficacy...
December 2016: Therapeutic Advances in Urology
https://www.readbyqxmd.com/read/27891139/regulation-of-phytosiderophore-release-and-antioxidant-defense-in-roots-driven-by-shoot-based-auxin-signaling-confers-tolerance-to-excess-iron-in-wheat
#18
Ahmad H Kabir, Most A Khatun, Mohammad M Hossain, Syed A Haider, Mohammad F Alam, Nishit K Paul
Iron (Fe) is essential but harmful for plants at toxic level. However, how wheat plants tolerate excess Fe remains vague. This study aims at elucidating the mechanisms underlying tolerance to excess Fe in wheat. Higher Fe concentration caused morpho-physiological retardation in BR 26 (sensitive) but not in BR 27 (tolerant). Phytosiderophore and 2-deoxymugineic acid showed no changes in BR 27 but significantly increased in BR 26 due to excess Fe. Further, expression of TaSAMS. TaDMAS1, and TaYSL15 significantly downregulated in BR 27 roots, while these were upregulated in BR 26 under excess Fe...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/27889832/effects-of-cytochrome-p450-cyp3a4-and-cyp2c19-inhibition-and-induction-on-the-exposure-of-selumetinib-a-mek1-2-inhibitor-in-healthy-subjects-results-from-two-clinical-trials
#19
Angela W Dymond, Karen So, Paul Martin, Yifan Huang, Paul Severin, David Mathews, Eleanor Lisbon, Gabriella Mariani
PURPOSE: Two phase I, open-label trials in healthy subjects assessed whether co-administration with CYP3A4/CYP2C19 inhibitors, itraconazole/fluconazole (study A), or CYP3A4 inducer, rifampicin (study B), affects the exposure, safety/tolerability and pharmacokinetics of selumetinib and its metabolite N-desmethyl selumetinib. METHODS: In study A (n = 26), subjects received a single dose of selumetinib 25 mg and, after 4 days of washout, were randomized to treatment 1 (itraconazole 200 mg twice daily on days 1-11) or treatment 2 (fluconazole 400 mg on day 1 then 200 mg/day on days 2-11) plus co-administration of single-dose selumetinib 25 mg on day 8 (selumetinib staggered 4 h after itraconazole/fluconazole dose); Twenty-one days after discharge/washout, subjects received the alternate treatment...
February 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27885373/a-new-era-of-treatment-for-patients-with-haemophilia-a
#20
Robert Klamroth
Treatment and prevention of bleeding episodes in patients with severe haemophilia A require frequent intravenous injection of factor VIII. Inhibitory antibodies against factor VIII occur in approximately 30 % of these patients during the first exposure days and immune tolerance induction to eradicate the inhibitor is challenging. Prevention of bleeds in patients with haemophilia A and inhibitors is less effective and there is ongoing research for alternative treatment options. A promising approach in 2016 is the development of emicizumab (ACE910), a bi-specific IgG antibody to factor IXa and factor X, that mimics the cofactor function of factor VIII...
November 25, 2016: Hämostaseologie
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