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Inhibitor tolerance induction

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https://www.readbyqxmd.com/read/28651073/hemophilia-a-inhibitor-treatment-the-promise-of-engineered-t-cell-therapy
#1
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...
June 9, 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
#2
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...
June 20, 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
#3
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
#4
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
https://www.readbyqxmd.com/read/28612430/igg-subclasses-of-fviii-inhibitors-in-an-argentine-cohort-of-severe-hemophilia-a-patients-analysis-by-flow-cytometry
#5
M B Irigoyen, L Primiani, M Felippo, M Candela, M M E de Bracco, N V Galassi
INTRODUCTION: FVIII inhibitors consist of a polyclonal population of antibodies. Previous studies have demonstrated different distribution of IgG subclasses. IgG4 was associated to high level of FVIII inhibitors and failure of immune tolerance induction (ITI) treatment. This study monitored the relative distribution of IgG subclasses of anti-FVIII in patients with severe hemophilia A (SHA). METHODS: Anti-FVIII antibodies were measured employing an immunomethod, developed in our laboratory, that combines flow cytometry (FC) with microspheres coupled (FVIII-m) or not (Control-m) to FVIII...
June 14, 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28609185/discovery-and-preclinical-development-of-netarsudil-a-novel-ocular-hypotensive-agent-for-the-treatment-of-glaucoma
#6
Cheng-Wen Lin, Bryan Sherman, Lori A Moore, Carmen L Laethem, Da-Wen Lu, Padmanabhan P Pattabiraman, Ponugoti Vasantha Rao, Mitchell A deLong, Casey C Kopczynski
PURPOSE: Rho-associated protein kinase (ROCK) inhibitors lower intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork (TM). The preclinical characterization of netarsudil, a new ROCK/norepinephrine transporter (NET) inhibitor currently in clinical development, is presented herein. METHODS: The kinase inhibitory activity of netarsudil was compared to its esterase metabolite, netarsudil-M1, and 3 other ROCK inhibitors using a commercially available kinase assay kit...
June 13, 2017: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28574205/first-line-immune-tolerance-induction-for-children-with-severe-haemophilia-a-a-protocol-from-the-uk-haemophilia-centre-doctors-organisation-inhibitor-and-paediatric-working-parties
#7
P Collins, E Chalmers, J Alamelu, C Hay, R Liesner, M Makris, M Mathias, J Payne, S Rangarajan, M Richards, K Talks, O Tunstall, M Williams, D P Hart
No abstract text is available yet for this article.
June 2, 2017: Haemophilia: the Official Journal of the World Federation of Hemophilia
https://www.readbyqxmd.com/read/28572668/cathelicidin-trypsin-inhibitor-loop-conjugate-represents-a-promising-antibiotic-candidate-with-protease-stability
#8
Haining Yu, Chen Wang, Lan Feng, Shasha Cai, Xuelian Liu, Xue Qiao, Nannan Shi, Hui Wang, Yipeng Wang
Cathelicidins are regarded as promising antibiotics due to their capability against antibiotic-resistant bacteria without cytotoxicity. However, some concerns about the balance of cytotoxicity and antimicrobial activity, weak stability and enzymatic susceptibility sually restrict their therapeutic use. Here, we designed a series of shortened variants, Hc1~15, based on our previously characterized Hc-CATH. Hc3, the one with the best activity, after point mutation was engineered with a trypsin inhibitor loop, ORB-C, to obtain four hybrid peptides: H3TI, TIH3, H3TIF and TIH3F...
June 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28570653/improved-efficacy-of-allergen-specific-immunotherapy-by-jak-inhibition-in-a-murine-model-of-allergic-asthma
#9
Antonio Aguilar-Pimentel, Anke Graessel, Francesca Alessandrini, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Dennis Russkamp, Adam Chaker, Markus Ollert, Simon Blank, Jan Gutermuth, Carsten B Schmidt-Weber
BACKGROUND: Allergen-specific immunotherapy (AIT) is the only curative treatment for type-1 allergies, but sometimes shows limited therapeutic response as well as local and systemic side effects. Limited control of local inflammation and patient symptoms hampers its widespread use in severe allergic asthma. OBJECTIVE: Our aim was to evaluate whether AIT is more effective in suppression of local inflammation if performed under the umbrella of short-term non-specific immunomodulation using a small molecule inhibitor of JAK pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28552763/prevention-of-food-allergy-development-and-suppression-of-established-food-allergy-by-neutralization-of-tslp-il-25-and-il-33
#10
Marat V Khodoun, Sunil Tomar, Joel E Tocker, Yui Hsi Wang, Fred D Finkelman
BACKGROUND: Food allergy (FA) is an increasing problem that has no approved treatment. The pro-Th2 cytokines, IL-25, IL-33 and TSLP, are associated with FA and monoclonal antibodies (mAbs) to these cytokines are reported to suppress murine FA development. OBJECTIVE: Determine whether anti-pro-Th2 cytokine mAbs can block both FA maintenance and induction. METHODS: IgE-mediated FA was induced in BALB/c mice by oral gavage (o.g.) with medium chain triglycerides plus egg white (MCT/EW) and was characterized by increased numbers of lamina propria Th2 cells, mast cells shock, and eosinophils, shock (hypothermia), mast cell degranulation (increased serum MMCP1), increased serum IgG1 anti-EW and IgE, and increased IL-4 and IL-13 secretion following MCT/EW challenge...
May 25, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28552407/a-novel-platform-for-immune-tolerance-induction-in-hemophilia-a-mice
#11
Simone Merlin, Elvira Stefania Cannizzo, Ester Borroni, Valentina Bruscaggin, Piercarla Schinco, Warut Tulalamba, Marinee K Chuah, Valder R Arruda, Thierry VandenDriessche, Maria Prat, Guido Valente, Antonia Follenzi
Hemophilia A (HA) is an X-linked bleeding disease caused by factor VIII (FVIII) deficiency. We previously demonstrated that FVIII is produced specifically in liver sinusoid endothelial cells (LSECs) and to some degree in myeloid cells, and thus, in the present work, we seek to restrict the expression of FVIII transgene to these cells using cell-specific promoters. With this approach, we aim to limit immune response in a mouse model by lentiviral vector (LV)-mediated gene therapy encoding FVIII. To increase the target specificity of FVIII expression, we included miRNA target sequences (miRTs) (i...
May 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28539592/atorvastatin-promotes-phagocytosis-and-attenuates-pro-inflammatory-response-in-human-retinal-pigment-epithelial-cells
#12
Bo Tian, Ahmad Al-Moujahed, Peggy Bouzika, Yijun Hu, Shoji Notomi, Pavlina Tsoka, Joan W Miller, Haijiang Lin, Demetrios G Vavvas
Phagocytosis of daily shed photoreceptor outer segments is an important function of the retinal pigment epithelium (RPE) and it is essential for retinal homeostasis. RPE dysfunction, especially impairment of its phagocytic ability, plays an essential role in the pathogenesis of age-related macular degeneration (AMD). Statins, or HMG CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, are drugs with multiple properties that have been extensively used to treat hyperlipidemia. However, their effect on RPE cells has not been fully elucidated...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28535410/effect-of-enzyme-inhibition-on-perampanel-pharmacokinetics-why-study-design-matters
#13
Barry E Gidal, Rama Maganti, Antonio Laurenza, Haichen Yang, David A Verbel, Edgar Schuck, Jim Ferry
OBJECTIVES: Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t1/2) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions-enzyme inhibition or induction-and anticipating their occurrence are important for management of patients with epilepsy...
April 26, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/28530706/akt-is-indispensable-for-coordinating-par-4-jnk-cross-talk-in-p21-downmodulation-during-er-stress
#14
R U Rasool, D Nayak, S Chakraborty, M M Faheem, B Rah, P Mahajan, V Gopinath, A Katoch, Z Iqra, S K Yousuf, D Mukherjee, L D Kumar, A Nargotra, A Goswami
The double-edged role of p21 to command survival and apoptosis is emerging. The current investigation highlights ER stress-mediated JNK activation that plausibly triggers cell death by attenuating endogenous p21 level. Here, we demonstrated that ER stress activator 3-AWA diminishes the p21 levels in cancer cells by averting the senescent phenotype to commence G2/M arrest. In essence, the deceleration in p21 level occurs through ER stress/JNK/Caspase-3 axis via activation/induction of proapoptotic Par-4 and inhibition of AKT...
May 22, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28508096/-off-label-biologic-therapy-of-anca-associated-and-non-anca-associated-small-vessel-vasculitis-efficacy-and-safety-analysis-of-a-national-registry-graid2
#15
N Venhoff, F Proft, H Schulze-Koops, J Holle, R E Voll, C Iking-Konert, A M Jacobi, J Henes, L Unger, O Kneitz, T Dörner, J Thiel
OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals...
May 15, 2017: Zeitschrift Für Rheumatologie
https://www.readbyqxmd.com/read/28503781/assessment-of-effect-of-cyp3a-inhibition-cyp-induction-oatp1b-inhibition-and-high-fat-meal-on-pharmacokinetics-of-the-jak1-inhibitor-upadacitinib
#16
Mohamed-Eslam F Mohamed, Steven Jungerwirth, Armen Asatryan, Ping Jiang, Ahmed A Othman
AIMS: Upadacitinib (ABT-494) is a selective Janus kinase 1 inhibitor developed for treatment of auto-immune inflammatory disorders. This work evaluated effects of high-fat meal, cytochrome P450 (CYP) 3A inhibition, CYP induction, and organic anion transporting polypeptide (OATP) 1B inhibition on upadacitinib pharmacokinetics. METHODS: Two Phase 1 evaluations were conducted, each in 12 healthy subjects. In Study 1, using a randomized, 2-sequence cross-over design, a 3 mg dose of upadacitinib (immediate-release capsules) was administered alone under fasting conditions, after high-fat meal, or on Day 4 of a 6-day regimen of 400 mg once-daily ketoconazole...
May 14, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28495880/sox4-allows-facultative-%C3%AE-cell-proliferation-through-repression-of-cdkn1a
#17
Eric E Xu, Shugo Sasaki, Thilo Speckmann, Cuilan Nian, Francis C Lynn
The HMG-box transcription factor, SOX4, is the most highly expressed SOX family protein in pancreatic islets, and mutations in Sox4 are associated with an increased risk of developing type 2 diabetes. We utilized an inducible β-cell knockout mouse model to test the hypothesis that Sox4 is essential for the maintenance of β-cell number during the development of type 2 diabetes. Knockout of Sox4 at 6 weeks of age resulted in time-dependent worsening of glucose tolerance, impairment of insulin secretion, and diabetes by 30 weeks of age...
May 11, 2017: Diabetes
https://www.readbyqxmd.com/read/28489678/safety-and-efficacy-of-the-antiganglioside-gd3-antibody-ecromeximab-kw2871-combined-with-high-dose-interferon-%C3%AE-2b-in-patients-with-metastatic-melanoma
#18
Ahmad A Tarhini, Stergios J Moschos, Yan Lin, Hui-Min Lin, Cindy Sander, Yan Yin, Ralph Venhaus, Thomas F Gajewski, John M Kirkwood
This study evaluated the safety and clinical benefit of ecromeximab (KW2871) combined with high-dose interferon-α2b (HDI) in patients with metastatic melanoma. We also carried out pharmacokinetic and immune monitoring studies of this combination. This was an open-label, phase 1/2 study of ecromeximab plus HDI in patients with measurable metastatic melanoma. Eligible patients received ecromeximab-HDI combination therapy: ecromeximab administered intravenously once every 2 weeks and HDI at a dose of 20 million units (MU)/m administered intravenously for 5 consecutive days per week for the first 4 weeks (induction phase) and then at 10 MU/m subcutaneously thrice weekly through week 14 (maintenance phase)...
August 2017: Melanoma Research
https://www.readbyqxmd.com/read/28474399/l-cysteine-desulfhydrase-related-h2-s-production-is-involved-in-osse5-promoted-ammonium-tolerance-in-roots-of-oryza-sativa
#19
Hongming Guo, Heng Zhou, Jing Zhang, Wenxue Guan, Sheng Xu, Wenbiao Shen, Guohua Xu, Yanjie Xie, Christine Helen Foyer
Previous studies revealed that rice heme oxygenase PHOTOPERIOD SENSITIVITY 5 (OsSE5) is involved in the regulation of tolerance to excess ammonium by enhancing antioxidant defence. In this study, the relationship between OsSE5 and hydrogen sulfide (H2 S), a well-known signalling molecule was investigated. Results showed that NH4 Cl triggered the induction of L -cysteine desulfhydrase (L -DES)-related H2 S production in rice seedling roots. A H2 S donor, not only alleviated the excess ammonium-triggered inhibition of root growth, but also reduced endogenous ammonium, both of which were aggravated by the hypotaurine (HT, a H2 S scavenger) or DL -propargylglycine (PAG, a L -DES inhibitor)...
May 5, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28462453/preclinical-screening-for-treatments-for-infantile-spasms-in-the-multiple-hit-rat-model-of-infantile-spasms-an-update
#20
Aristea S Galanopoulou, Wenzhu B Mowrey, Wei Liu, Qianyun Li, Oleksii Shandra, Solomon L Moshé
Infantile spasms are the typical seizures of West syndrome, an infantile epileptic encephalopathy with poor outcomes. There is an increasing need to identify more effective and better tolerated treatments for infantile spasms. We have optimized the rat model of infantile spasms due to structural etiology, the multiple-hit rat model, for therapy discovery. Here, we test three compounds administered after spasms induction in the multiple hit model for efficacy and tolerability. Specifically, postnatal day 3 (PN3) male Sprague-Dawley rats were induced by right intracerebral injections of doxorubicin and lipopolysaccharide...
May 2, 2017: Neurochemical Research
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