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Inhibitor tolerance induction

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https://www.readbyqxmd.com/read/28337764/a-national-french-noninterventional-study-to-assess-the-long-term-safety-and-efficacy-of-reformulated-nonacog-alfa
#1
Thierry Lambert, Chantal Rothschild, Fabienne Volot, Annie Borel-Derlon, Marc Trossaërt, Ségolène Claeyssens-Donadel, Sepideh Attal
BACKGROUND: Nonacog alfa, the recombinant Factor IX (F IX) used for the treatment of hemophilia B, was approved in Europe in 1998. A reformulated version was approved for European use in 2007. STUDY DESIGN AND METHODS: This postmarketing study, as recommended by the risk management plan, was conducted to confirm the safety of reformulated nonacog alfa in a usual care setting in France. This open-label, noninterventional, prospective, longitudinal postmarketing study comprised 19 French hemophilia centers...
March 24, 2017: Transfusion
https://www.readbyqxmd.com/read/28295194/anti-leukaemic-activity-of-the-tyk2-selective-inhibitor-ndi-031301-in-t-cell-acute-lymphoblastic-leukaemia
#2
Koshi Akahane, Zhaodong Li, Julia Etchin, Alla Berezovskaya, Evisa Gjini, Craig E Masse, Wenyan Miao, Jennifer Rocnik, Rosana Kapeller, Jeremy R Greenwood, Hong Tiv, Takaomi Sanda, David M Weinstock, A Thomas Look
Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28295182/a-phase-1-trial-of-temsirolimus-and-intensive-re-induction-chemotherapy-for-2nd-or-greater-relapse-of-acute-lymphoblastic-leukaemia-a-children-s-oncology-group-study-advl1114
#3
Susan R Rheingold, Sarah J Tasian, James A Whitlock, David T Teachey, Michael J Borowitz, Xiaowei Liu, Charles G Minard, Elizabeth Fox, Brenda J Weigel, Susan M Blaney
The phosphatidylinositol 3-kinase (PI3K)/mammalian (or mechanistic) target of rapamycin (mTOR) signalling pathway is commonly dysregulated in acute lymphoblastic leukaemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus in combination with UKALL R3 re-induction chemotherapy was conducted in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m(2) weekly × 3 doses. Subsequent patient cohorts received temsirolimus 7·5 mg/m(2) weekly × 3 doses (DL0) or, secondary to toxicity, 7·5 mg/m(2) weekly × 2 doses (DL-1)...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28276629/improved-fetal-hemoglobin-with-mtor-inhibitor-based-immunosuppression-in-a-kidney-transplant-recipient-with-sickle-cell-disease
#4
Noémie Gaudre, Pierre Cougoul, Pablo Bartolucci, Gaëlle Dörr, Alessandra Bura-Riviere, Nassim Kamar, Arnaud Del Bello
Fetal hemoglobin induction is a key-point in the management of sickle-cell disease (SCD). Herein, we report on a kidney-transplant recipient with SCD that was treated with everolimus, a mammalian target of rapamycin inhibitor. At 10 months after initiating therapy, HbF level was dramatically increased (from 4.8% to 15%) and there was excellent tolerance to treatment. This article is protected by copyright. All rights reserved.
March 9, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28265283/exogenous-melatonin-mitigates-photoinhibition-by-accelerating-non-photochemical-quenching-in-tomato-seedlings-exposed-to-moderate-light-during-chilling
#5
Fei Ding, Meiling Wang, Bin Liu, Shuoxin Zhang
Melatonin plays an important role in tolerance to multiple stresses in plants. Recent studies have shown that melatonin relieves photoinhibition in plants under cold stress; however, the mechanisms are not fully understood. Non-photochemical quenching (NPQ) is a key process thermally dissipating excess light energy that plants employ as a protective mechanism to prevent the over reduction of photosystem II. Here, we report the effects of exogenous melatonin on NPQ and mitigation of photoinhibition in tomato seedlings exposed to moderate light during chilling...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28255993/curcuminoid-ef24-enhances-the-anti-tumor-activity-of-akt-inhibitor-mk-2206-through-ros-mediated-er-stress-and-mitochondrial-dysfunction-in-gastric-cancer
#6
Xi Chen, Xuanxuan Dai, Peng Zou, Weiqian Chen, Vinothkumar Rajamanickam, Chen Feng, Weishan Zhuge, Chenyu Qiu, Qingqing Ye, Xiaohua Zhang, Guang Liang
BACKGROUND AND PURPOSE: Gastric cancer is one of the leading causes of morbidity and mortality worldwide. Akt is an anti-apoptotic kinase that plays a dynamic role in cell survival and is implicated gastric cancer pathogenesis. MK-2206, the first allosteric inhibitor of Akt, is in clinical trials for a number of cancers. Although preclinical studies have shown promise, clinical trials reported lack of response when given alone at tolerated doses. The aim of our study is to delineate the effects of MK-2206 in gastric cancer cells and explore combinatorial treatments to enhance the anti-tumor activity of MK-2206...
March 3, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28250911/effects-of-valproic-acid-on-radiation-induced-chromosomal-aberrations-in-human-lymphocytes
#7
María Vittoria Di Tomaso, Eric Gregoire, Wilner Martínez-López
One of the most widely employed histone deacetylases inhibitors in the clinic is the valproic acid (VA), proving to have a good tolerance and low side effects on human health. VA induces changes in chromatin structure making DNA more susceptible to damage induction and influence DNA repair efficiency. VA is also proposed as a radiosensitizing agent. To know if VA is suitable to sensitize human lymphocytes γ-irradiation in vitro, different types of chromosomal aberrations in the lymphocytes, either in the absence or presence of VA, were analyzed...
2017: Genome Integrity
https://www.readbyqxmd.com/read/28223344/an-intestinal-farnesoid-x-receptor-ceramide-signaling-axis-modulates-hepatic-gluconeogenesis-in-mice
#8
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
#9
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...
March 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
#10
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
#11
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
#12
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
#13
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...
March 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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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