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Inhibitor tolerance induction

K Holstein, A Batorova, M Carvalho, K Fijnvandraat, P Holme, K Kavakli, T Lambert, A Rocino, V Jiménez-Yuste, J Astermark
INTRODUCTION: Inhibitor development in people with haemophilia is a serious complication that may require intensive and costly interventions. The goal of inhibitor management should be permanent inhibitor eradication through immune tolerance induction (ITI), but well-designed studies are lacking and the management of patients is therefore defined by the experience and views of the clinician. OBJECTIVES: To explore the current clinical practice and outcome of ITI therapy in Europe and how this may have changed over the last decade, as well as to provide consensus recommendations to guide clinicians in their clinical practice...
October 15, 2016: Thrombosis Research
Erika Heninger, Timothy E G Krueger, Stephanie M Thiede, Jamie M Sperger, Brianna L Byers, Madison R Kircher, David Kosoff, Bing Yang, David F Jarrard, Douglas G McNeel, Joshua M Lang
Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2'-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589...
October 17, 2016: Oncotarget
Ching-Tzu Yen, Meng-Ni Fan, Yung-Li Yang, Sheng-Chieh Chou, I-Shing Yu, Shu-Wha Lin
Hemophilia is the most well-known hereditary bleeding disorder, with an incidence of one in every 5000 to 30,000 males worldwide. The disease is treated by infusion of protein products on demand and as prophylaxis. Although these therapies have been very successful, some challenging and unresolved tasks remain, such as reducing bleeding rates, presence of target joints and/or established joint damage, eliminating the development of inhibitors, and increasing the success rate of immune-tolerance induction (ITI)...
2016: Thrombosis Journal
Jun Li, Jie Ao, Kai Li, Jie Zhang, Yanyan Li, Le Zhang, Yuyan Wei, Di Gong, Junping Gao, Weiwei Tan, Lugang Huang, Lunxu Liu, Ping Lin, Yuquan Wei
Multidrug resistance (MDR) is one of the most important contributors to the high mortality of cancer and remains a major concern. We previously found that zinc finger protein 32 (ZNF32), an important transcription factor associated with cancer in Homo sapiens, protects tumor cells against cell death induced by oxidative stress and other stimuli. We thus hypothesized that ZNF32 might enable the tolerance of cancer cells to anti-tumor drugs because higher ZNF32 expression has been found in cancer tissues and in drug-resistant lung adenocarcinoma (AC) cells...
October 20, 2016: Cell Death & Disease
Wataru Obara, Takashi Karashima, Kazuyoshi Takeda, Renpei Kato, Yoichiro Kato, Mitsugu Kanehira, Ryo Takata, Keiji Inoue, Toyomasa Katagiri, Taro Shuin, Yusuke Nakamura, Tomoaki Fujioka
PURPOSE: Through genome-wide expression profile analysis, hypoxia-inducible protein 2 (HIG2) has previously been identified as an oncoprotein involved in development/progression of renal cell carcinoma (RCC). We subsequently identified a highly immunogenic HLA-A*0201/0206-restricted epitope peptide (HIG2-9-4) corresponding to a part of HIG2 and applied it as a therapeutic vaccine. We conducted a phase I clinical trial using the HIG2-9-4 peptide for patients with advanced RCC. MATERIALS AND METHODS: Nine patients having HLA-A*0201 or HLA-A*0206 with metastatic or unresectable RCC after failure of the cytokine and/or tyrosine kinase inhibitor therapies were enrolled in this study...
October 18, 2016: Cancer Immunology, Immunotherapy: CII
Tong Zhu, Xingguang Deng, Xue Zhou, Lisha Zhu, Lijuan Zou, Pengxu Li, Dawei Zhang, Honghui Lin
Crosstalk between phytohormone pathways is essential in plant growth, development and stress responses. Brassinosteroids (BRs) and ethylene are both pivotal plant growth regulators, and the interaction between these two phytohormones in the tomato response to salt stress is still unclear. Here, we explored the mechanism by which BRs affect ethylene biosynthesis and signaling in tomato seedlings under salt stress. The activity of 1-aminocyclopropane-1-carboxylate synthase (ACS), an ethylene synthesis enzyme, and the ethylene signaling pathway were activated in plants pretreated with BRs...
October 14, 2016: Scientific Reports
Rehab Mohmed El-Gharbawy, Ashraf Mahmoud Emara, Sally El-Sayed Abu-Risha
The aim of this study was to use Zinc oxide nanoparticles and a standard antidiabetic drug to restore the function and structure of beta cells in a rat model of Type-2 diabetes and compare the effects of a DPP-IV inhibitor with or without zinc oxide nanoparticles (ZnONPs) using a model of type 2 diabetes (rats fed a high fat diet that was treated with a low dose of streptozotocin). Ninety male Wistar rats were randomly divided into three groups 10days after the induction of diabetes: group I: non-diabetic animals that received only the chow diet plus 2ml of 0...
October 7, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Petra Bonova, Miroslava Nemethova, Milina Matiasova, Martin Bona, Miroslav Gottlieb
Ischemic tolerance (IT) has gained attention as an attractive strategy for improving stroke outcome. Recently, it was shown that signal responsible for rapid IT induction (tolerance induction factor- TIF) is transmitted via circulating blood. In the present paper, we have hypothesized about the role of the blood cell compartment in TIF production. We used hind limb ischemia to generate TIF as a rapid preconditioning against transient middle cerebral artery occlusion (MCAO). The essential properties of protein synthesis inhibitors actinomycin D and cycloheximide were utilized to obtain the following results: 1...
October 5, 2016: European Journal of Neuroscience
Sean E Collins, Philip M Grant, Francois Uwinkindi, Annie Talbot, Eric Seruyange, Deborah Slamowitz, Adeline Mugeni, Eric Remera, Simon Pierre Niyonsenga, Josbert Nyirimigabo, Jean Paul Uwizihiwe, Pierre Dongier, Ribakare Muhayimpundu, Jean-Baptiste Mazarati, Andrew Zolopa, Sabin Nsanzimana
Background.  Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods.  We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors...
September 2016: Open Forum Infectious Diseases
Quinte Braster, Carlos Silvestre Roig, Helene Hartwig, Linda Beckers, Myrthe den Toom, Yvonne Döring, Mat J Daemen, Esther Lutgens, Oliver Soehnlein
Obesity-associated diseases such as Type 2 diabetes, liver disease and cardiovascular diseases are profoundly mediated by low-grade chronic inflammation of the adipose tissue. Recently, the importance of neutrophils and neutrophil-derived myeloperoxidase and neutrophil elastase on the induction of insulin resistance has been established. Since neutrophil elastase and myeloperoxidase are critically involved in the release of neutrophil extracellular traps (NETs), we here hypothesized that NETs may be relevant to early adipose tissue inflammation...
2016: PloS One
Zhaofeng Wang, Qien Li, Weiguo Wu, Jie Guo, Yingli Yang
Ascorbic acid (AsA) and nitric oxide (NO) are well known and widespread antioxidants and gaseous molecules that regulate plant tolerance to several stresses. However, the relationship between them in plant response to stress, especially heavy stress, is largely unclear. This study demonstrated that both AsA and NO could enhance the tolerance of wheat seedlings to cadmium stress evidenced by root length change, which resulted from their roles in maintaining the balance in reactive oxygen species (ROS) and reducing the absorption of Cd...
September 29, 2016: Ecotoxicology and Environmental Safety
Moanaro Biswas, Geoffrey L Rogers, Alexandra Sherman, Barry J Byrne, David M Markusic, Haiyan Jiang, Roland W Herzog
Development of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses...
September 29, 2016: Thrombosis and Haemostasis
Susan M Hiniker, Sunil A Reddy, Holden T Maecker, Priyanka B Subrahmanyam, Yael Rosenberg-Hasson, Susan M Swetter, Saurabh Saha, Lei Shura, Susan J Knox
PURPOSE: Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses. METHODS AND MATERIALS: In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles...
November 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Tushar Garimella, Xiaoli You, Reena Wang, Shu-Pang Huang, Hamza Kandoussi, Marc Bifano, Richard Bertz, Timothy Eley
: The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug-drug interactions (DDIs). Daclatasvir (DCV)-the benchmark pangenotypic nonstructural protein 5A inhibitor-has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir...
September 23, 2016: Advances in Therapy
Katsunori Murota, Hanako Shimura, Minoru Takeshita, Chikara Masuta
Cucumber mosaic virus (CMV) can induce a specific necrosis on Arabidopsis through the interaction between the CMV 2b protein and host catalase, in which the ubiquitin-proteasome pathway may be involved. We previously reported that the CMV 2b protein, the viral RNA silencing suppressor, interacted with the H2O2 scavenger catalase (CAT3), leading to necrosis on CMV-inoculated Arabidopsis leaves. We here confirmed that CMV could more abundantly accumulate in the CAT3-knockout mutant (cat3), and that CAT3 makes host plants a little more tolerant to CMV...
September 22, 2016: Plant Cell Reports
Endy Adnan, Takuya Matsumoto, Jun Ishizaki, Sachiko Onishi, Koichiro Suemori, Masaki Yasukawa, Hitoshi Hasegawa
Tolerogenic dendritic cells (tDCs) are a promising therapeutic tool for specific induction of immunological tolerance. Human tDCs can be generated ex vivo using various compounds. However, the compound(s) most suitable for clinical application remain undefined. We compared the tolerogenic properties of tDCs treated with protein kinase C inhibitor (PKCI), dexamethasone, vitamin D3 (Vit D3), rapamycin (Rapa), interleukin (IL)-10, transforming growth factor (TGF)-β, and a combination of peroxisome proliferator-activated receptor γ agonist and retinoic acid...
September 19, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Ammar Kurdi, Mireille De Doncker, Arthur Leloup, Hugo Neels, Jean-Pierre Timmermans, Katrien Lemmens, Sandra Apers, Guido R Y De Meyer, Wim Martinet
BACKGROUND AND PURPOSE: Everolimus is an allosteric inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1) widely known for its potent autophagy stimulating properties. Because everolimus shows poor solubility and stability in aqueous solutions, long-term in vivo administration in preclinical models is challenging. The aim of the present study was to evaluate the effects of short-term and long-term everolimus administration on mTORC1 inhibition and autophagy induction in mice...
September 16, 2016: British Journal of Pharmacology
Yuan Feng, Jihong Zhou, Zhanhua Li, Ying Jiang, Ying Zhou
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation...
2016: PloS One
Tarek Magdy, Brian T Burmeister, Paul W Burridge
The cardiotoxicity of certain chemotherapeutic agents is now well-established, and has led to the development the field cardio-oncology, increased cardiac screening of cancer patients, and limitation of patients' maximum cumulative chemotherapeutic dose. The effect of chemotherapeutic regimes on the heart largely involves cardiomyocyte death, leading to cardiomyopathy and heart failure, or the induction of arrhythmias. Of these cardiotoxic drugs, those resulting in clinical cardiotoxicity can range from 8 to 26% for doxorubicin, 7-28% for trastuzumab, or 5-30% for paclitaxel...
September 5, 2016: Pharmacology & Therapeutics
Chao Li, Li-Min Zhang, Xue Zhang, Xia Huang, Yong Liu, Ming-Qiang Li, Shuai Xing, Tao Yang, Lin Xie, Feng-Chao Jiang, Han-Ying Jiang, Wen-Tao He, Ping Zhou
BACKGROUND: Most strategies for anti-rejection and tolerance induction in clinical transplantation have focused on modifying adaptive immunity, it is unclear whether pharmacological suppressing the innate immune system can promote transplant tolerance. METHODS: We inhibited innate immunity by using our self-generated inhibitor of myeloid differentiation factor 88 (MyD88), TJ-M2010-5, and investigated its therapeutic effects and mechanisms in cardiac and skin transplant models...
September 8, 2016: Transplantation
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