Read by QxMD icon Read

Inhibitor tolerance induction

Sana Hibino, Shunsuke Chikuma, Taisuke Kondo, Minako Ito, Hiroko Nakatsukasa, Setsuko Omata-Mise, Akihiko Yoshimura
Enhanced infiltration of regulatory T (Treg) cells into tumor tissue is detrimental to cancer patients and closely associated with poor prognosis as they create an immunosuppressive state that suppresses anti-tumor immune responses. Therefore, breaking Treg-mediated immune tolerance is important when considering cancer immunotherapy. Here we show that the Nr4a nuclear receptors, key transcription factors maintaining Treg cell genetic programs, contribute to Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment...
March 20, 2018: Cancer Research
H-H Brackmann, G C White, E Berntorp, T Andersen, C Escuriola-Ettingshausen
Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates continues to be the most serious complication of haemophilia A management. Induction of immune tolerance by administering high doses of FVIII concentrate (antigen) and prothrombin complex concentrates to control bleeding was originated in the 1970s in Bonn, Germany, by Dr Hans-Hermann Brackmann, and became known as the Bonn protocol. ITI transformed the life of the index patient, who was 19 years of age when he began treatment, and dramatically improved the medical landscape for all patients with haemophilia and inhibitors...
April 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Jan Raska, Lucie Ctverackova, Aneta Dydowiczova, Iva Sovadinova, Ludek Blaha, Pavel Babica
HL1-hT1 cell line represents adult human liver stem cells (LSCs) immortalized with human telomerase reverse transcriptase. In this study, HL1-hT1 cells were found to express mesenchymal markers (vimentin, CD73, CD90/THY-1 and CD105) and an early hepatic endoderm marker FOXA2, while not expressing hepatic progenitor (HNF4A, LGR5, α-fetoprotein) or differentiated hepatocyte markers (albumin, transthyretin, connexin 32). In response to microcystin-LR (MC-LR), a time- and concentration-dependent formation of MC-positive protein bands in HL1-hT1 cells was observed...
March 10, 2018: Toxicology and Applied Pharmacology
Staci L Haney, Yashpal S Chhonker, Michelle L Varney, Geoffrey Talmon, Daryl J Murry, Sarah A Holstein
Geranylgeranyl diphosphate synthase (GGDPS) is the enzyme in the isoprenoid biosynthesis pathway that catalyzes the synthesis of the 20-carbon isoprenoid GGPP, which serves as the isoprenoid donor for protein geranylgeranylation reactions. Rab proteins mediate vesicle trafficking within the cell and their activity is dependent on geranylgeranylation. Our prior work has demonstrated that agents that disrupt Rab geranylgeranylation disrupt monoclonal protein trafficking in myeloma cells, resulting in induction of the unfolded protein response pathway and apoptosis...
March 2, 2018: Investigational New Drugs
Yang Zhao, Xiao-Fei Shen, Ke Cao, Jie Ding, Xing Kang, Wen-Xian Guan, Yi-Tao Ding, Bao-Rui Liu, Jun-Feng Du
How to induce immune tolerance without long-term need for immunosuppressive drugs has always been a central problem in solid organ transplantation. Modulating immunoregulatory cells represents a potential target to resolve this problem. Myeloid-derived suppressor cells (MDSCs) are novel key immunoregulatory cells in the context of tumor development or transplantation, and can be generated in vitro . However, none of current systems for in vitro differentiation of MDSCs have successfully achieved long-term immune tolerance...
2018: Frontiers in Immunology
K Vepsäläinen, P Riikonen, R Lassila, M Arola, P Huttunen, P Lähteenmäki, M Möttönen, T Selander, J Martikainen
AIM: For previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). METHODS: From the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use...
March 1, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
S J Schep, R E G Schutgens, K Fischer, M L Boes
At first sight the bleeding disorder hemophilia A seems to have little in common with immune disorders, but immunology research intersects with other disciplines including hematology. Nowadays, the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered factor VIII (FVIII), which occurs in approximately 30% of all patients with severe hemophilia A. This antibody response renders FVIII replacement therapy ineffective, thereby increasing the risk for uncontrollable bleeding and morbidity, decreasing quality of life and increasing healthcare costs...
February 15, 2018: Blood Reviews
Bram L T Ramaekers, Robert F Wolff, Xavier Pouwels, Marije Oosterhoff, Anoukh Van Giessen, Gill Worthy, Caro Noake, Nigel Armstrong, Jos Kleijnen, Manuela A Joore
The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz® ), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis...
February 26, 2018: PharmacoEconomics
Michael R Savona, Daniel A Pollyea, Wendy Stock, Vivian G Oehler, Mark A Schroeder, Jeffrey E Lancet, James McCloskey, Hagop M Kantarjian, Weidong Wendy Ma, M Naveed Shaik, A Douglas Laird, Mirjana Zeremski, Ashleigh O'Connell, Geoffrey Chan, Jorge E Cortes
PURPOSE: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). EXPERIMENTAL DESIGN: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Kristin Freudenberg, Nadja Lindner, Sebastian Dohnke, Annette I Garbe, Sonja Schallenberg, Karsten Kretschmer
Under physiological conditions, CD4+ regulatory T (Treg) cells expressing the transcription factor Foxp3 are generated in the thymus [thymus-derived Foxp3+ Treg (tTregs) cells] and extrathymically at peripheral sites [peripherally induced Foxp3+ Treg (pTreg) cell], and both developmental subsets play non-redundant roles in maintaining self-tolerance throughout life. In addition, a variety of experimental in vitro and in vivo modalities can extrathymically elicit a Foxp3+ Treg cell phenotype in peripheral CD4+ Foxp3- T cells, which has attracted much interest as an approach toward cell-based therapy in clinical settings of undesired immune responses...
2018: Frontiers in Immunology
C H Miller
Inhibitors are antibodies directed against haemophilia treatment products which interfere with their function. Factor VIII (FVIII) inhibitors in haemophilia A and factor IX (FIX) inhibitors in haemophilia B are significant clinically when they require a change in a patient's treatment regimen. Their persistence may increase morbidity and mortality. Multiple laboratory tests are now available for detecting and understanding inhibitors in haemophilia. Inhibitors are traditionally measured by their interference in clotting or chromogenic factor assays...
February 15, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
M Carcao, A Shapiro, J M Staber, N Hwang, C Druzgal, K Lieuw, M Belletrutti, C D Thornburg, S P Ahuja, J Morales-Arias, J Dumont, G Miyasato, E Tsao, N Jain, S W Pipe
INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI...
February 13, 2018: Haemophilia: the Official Journal of the World Federation of Hemophilia
Eric J Vargas, Carl M Pesta, Ahmad Bali, Eric Ibegbu, Fateh Bazerbachi, Rachel L Moore, Vivek Kumbhari, Reem Z Sharaiha, Trace W Curry, Gina DosSantos, Ramsey Schmitz, Abhishek Agnihotri, Aleksey A Novikov, Tracy Pitt, Margo K Dunlap, Andrea Herr, Louis Aronne, Erin Ledonne, Hoda C Kadouh, Lawrence J Cheskin, Manpreet S Mundi, Andres Acosta, Christopher J Gostout, Barham K Abu Dayyeh
BACKGROUND & AIMS: The Orbera Intragastric Balloon (OIB) is a single fluid-filled intra-gastric balloon approved for induction of weight loss and treatment of obesity. However, little is known about the effectiveness and safety of outside clinical trials, and since approval, the Food and Drug Administration has issued warnings to healthcare providers about risk of balloon hyper-inflation requiring early removal, pancreatitis, and death. We analyzed data on patients who have received the OIB since its approval determine its safety, effectiveness, and tolerance in real-world clinical settings...
February 6, 2018: Clinical Gastroenterology and Hepatology
Ryo Sugiura, Masaki Kuwatani, Kazumichi Kawakubo, Itsuki Sano, Shin Kato, Tomoyuki Endo, Naoya Sakamoto
Endoscopic sphincterotomy (ES) is a standard procedure for bile duct stone removal. However, the safety of ES in patients with hemophilia remains unknown. We treated a 46-year-old man who had choledocholithiasis and severe hemophilia A with high-responding inhibitors during immune tolerance induction therapy. Since coagulation factor VIII inhibitors neutralize and inactivate endogenous and exogenous factor VIII, bleeding risk is higher in hemophilia A patients with inhibitors than in those without inhibitors...
February 2, 2018: Clinical Journal of Gastroenterology
Zhibo Chen, Dehao Yang, Xiao Peng, Jie Lin, Zhongqian Su, Jia Li, Xu Zhang, Yiyun Weng
It is well known that dendritic cells play a key role in producing antigen-specific responses. Inversely, tolerogenic dendritic cells (TolDCs), a specialized subset, induce immune tolerance and negatively regulate autoimmune responses. Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the mevalonate pathway for cholesterol biosynthesis, might be a promising inductive agent for inducing TolDCs. This study aimed to investigate the effectiveness of TolDCs induced by atorvastatin pulsed with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) in experimental autoimmune encephalomyelitis mice established by MOG35-55 immunization and to investigate the potential effects on Th17/Treg balance in the murine model of multiple sclerosis...
February 1, 2018: Neuroreport
Shazia Rehman, Bodil Jørgensen, Søren K Rasmussen, Ejaz Aziz, Wasim Akhtar, Tariq Mahmood
Proteinase inhibitor-II (PI-II) genes are important defense related genes that play critical regulatory roles in plant growth and development. In the present study, the expression of tomato PI-II gene was investigated under the control of a wound-inducible OsRGLP2 (Oryza sativa root germin like protein 2) promoter in transgenic tobacco plants after wounding, ABA and MeJA applications. Transcript level of target gene in transgenic plants was confirmed by quantitative real time PCR (qPCR). In response to ABA treatment at different concentrations, PI-II gene was strongly induced under OsRGLP2 promoter at higher concentration (100 μM), while considerable level of target gene expression was observed with MeJA application at 50 μM concentration...
January 2018: 3 Biotech
Ronan T Swords, Steven Coutre, Michael B Maris, Joshua F Zeidner, James M Foran, Jose Cruz, Harry P Erba, Jesus G Berdeja, Wayne Tam, Saran Vardhanabhuti, Iwona Pawlikowska-Dobler, Hélène M Faessel, Ajeeta B Dash, Farhad Sedarati, Bruce J Dezube, Douglas V Faller, Michael R Savona
Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study (NCT01814826) of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naïve AML, unfit for standard induction therapy, received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5, combined with fixed-dose AZA (75 mg/m2 IV/SC) on days 1-5, 8, and 9, every 28 days...
January 18, 2018: Blood
Courtney D DiNardo, Keith W Pratz, Anthony Letai, Brian A Jonas, Andrew H Wei, Michael Thirman, Martha Arellano, Mark G Frattini, Hagop Kantarjian, Relja Popovic, Brenda Chyla, Tu Xu, Martin Dunbar, Suresh K Agarwal, Rod Humerickhouse, Mack Mabry, Jalaja Potluri, Marina Konopleva, Daniel A Pollyea
BACKGROUND: Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study...
January 12, 2018: Lancet Oncology
Marc L Hyer, Michael A Milhollen, Jeff Ciavarri, Paul Fleming, Tary Traore, Darshan Sappal, Jessica Huck, Judy Shi, James Gavin, Jim Brownell, Yu Yang, Bradley Stringer, Robert Griffin, Frank Bruzzese, Teresa Soucy, Jennifer Duffy, Claudia Rabino, Jessica Riceberg, Kara Hoar, Anya Lublinsky, Saurabh Menon, Michael Sintchak, Nancy Bump, Sai M Pulukuri, Steve Langston, Stephen Tirrell, Mike Kuranda, Petter Veiby, John Newcomb, Ping Li, Jing Tao Wu, Josh Powe, Lawrence R Dick, Paul Greenspan, Katherine Galvin, Mark Manfredi, Chris Claiborne, Benjamin S Amidon, Neil F Bence
The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade...
January 15, 2018: Nature Medicine
Jacob E Schrum, Juliet N Crabtree, Katherine R Dobbs, Michael C Kiritsy, George W Reed, Ricardo T Gazzinelli, Mihai G Netea, James W Kazura, Arlene E Dent, Katherine A Fitzgerald, Douglas T Golenbock
Malarial infection in naive individuals induces a robust innate immune response. In the recently described model of innate immune memory, an initial stimulus primes the innate immune system to either hyperrespond (termed training) or hyporespond (tolerance) to subsequent immune challenge. Previous work in both mice and humans demonstrated that infection with malaria can both serve as a priming stimulus and promote tolerance to subsequent infection. In this study, we demonstrate that initial stimulation with Plasmodium falciparum-infected RBCs or the malaria crystal hemozoin induced human adherent PBMCs to hyperrespond to subsequent ligation of TLR2...
January 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"