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Inhibitor tolerance induction

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https://www.readbyqxmd.com/read/29139135/phase-1-study-of-quizartinib-in-combination-with-induction-and-consolidation-chemotherapy-in-patients-with-newly-diagnosed-acute-myeloid-leukemia
#1
Jessica K Altman, James M Foran, Keith W Pratz, Denise Trone, Jorge E Cortes, Martin S Tallman
Novel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline-based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single-agent activity in relapsed or refractory (R/R) AML. This phase 1, open-label, sequential group dose-escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML)...
November 15, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/29111717/discovery-of-a-novel-and-selective-indoleamine-2-3-dioxygenase-ido-1-inhibitor-3-5-fluoro-1h-indol-3-yl-pyrrolidine-2-5-dione-eos200271-pf-06840003-and-its-characterization-as-a-potential-clinical-candidate
#2
Stefano Crosignani, Patrick Bingham, Pauline Bottemanne, Hélène Cannelle, Sandra Cauwenberghs, Marie Cordonnier, Deepak Dalvie, Frederik Deroose, Jun Li Feng, Bruno Gomes, Samantha Greasley, Stephen E Kaiser, Manfred Kraus, Michel Négrerie, Karen A Maegley, Nichol Miller, Brion W Murray, Manfred Schneider, James Solowiej, Albert E Stewart, Joseph Tumang, Vince R Torti, Benoit Van den Eynde, Martin Wythes
Tumors use tryptophan-catabolizing enzymes such as Indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. SAR around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode...
November 7, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29106782/expression-and-assembly-of-largest-foreign-protein-in-chloroplasts-oral-delivery-of-human-fviii-made-in-lettuce-chloroplasts-robustly-suppresses-inhibitor-formation-in-hemophilia-a-mice
#3
Kwang-Chul Kwon, Alexandra Sherman, Wan-Jung Chang, Aditya Kamesh, Moanaro Biswas, Roland W Herzog, Henry Daniell
Inhibitor formation is a serious complication of factor VIII (FVIII) replacement therapy for the X-linked bleeding disorder hemophilia A and occurs in 20-30% of patients. No prophylactic tolerance protocol currently exists. Although we reported oral tolerance induction using FVIII domains expressed in tobacco chloroplasts, significant challenges in clinical advancement include expression of the full-length CTB-FVIII sequence to cover the entire patient population, regardless of individual CD4(+) T cell epitope responses...
November 6, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/29094008/total-joint-replacement-in-inhibitor-positive-haemophilia-long-term-outcome-analysis-in-fifteen-patients
#4
Heidi Danielson, Riitta Lassila, Pekka Ylinen, Timo Yrjönen
AIM: To collect data from joint replacement in inhibitor patients, evaluate haemostatic and patient outcomes, and analyse the costs. METHODS: We report our 21-year, single-centre cumulative experience of 15 joint arthroplasties in six inhibitor patients. RESULTS: Two low responder inhibitor patients were in the early days treated with FVIII, whereas bypassing agents were used in the rest of the high responder patients. The primary haemostatic outcome was good in 8/15, fair in 4/15 and poor in 3/15 operations...
October 18, 2017: World Journal of Orthopedics
https://www.readbyqxmd.com/read/29081190/-immune-tolerance-induction-in-a-case-of-hemophilia-b-with-inhibitor-with-prothrombin-complex-concentrate-and-rituximab
#5
F Xue, W Liu, Y F Cheng, X F Liu, Y T Huang, R F Fu, L Zhang, R C Yang
Objective: To explore the immune tolerance induction (ITI) in a case of severe hemophilia B patient with inhibitor. Methods: The F Ⅸ∶C was detected using a one-stage method and FIX inhibitor was assayed using Bethesda method. ITI was performed with prothrombin complex concentrates (PCC) in combination with rituximab. Results: His past exposure days (ED) with PCC were 20 ED and his peak FⅨ inhibitor titer was 56 BU/ml. When his FIX inhibitor titer decreased to 10.4 BU/ml in Nov. 2015 and after receiving the informed consent from his parents, ITI was started...
September 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29054599/indoleamine-2-3-dioxygenase-expression-in-primary-cutaneous-melanoma-correlates-with-breslow-thickness-and-is-of-significant-prognostic-value-for-progression-free-survival
#6
Felicia Rubel, Johannes S Kern, Kristin Technau-Hafsi, Sibylle Uhrich, Kaethe Thoma, Georg Häcker, Nikolas von Bubnoff, Frank Meiss, Dagmar von Bubnoff
The enzyme indoleamine 2,3-dioxygenase (IDO) is emerging as a facilitator of cancer development through its effects on cancer-associated inflammation. Recent studies report a significant improvement of the response rates in melanoma patients to PD-1 antibodies when IDO-inhibitors were added to the regimen. Data on IDO-expression in primary human melanomas are however incomplete and conflicting. Here, we show that the level of IDO-expression in primary human melanoma cells significantly correlates with Breslow thickness (p = 0...
October 17, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29038460/a-novel-immunohistochemical-score-to-predict-early-mortality-in-acute-myeloid-leukemia-patients-based-on-indoleamine-2-3-dioxygenase-expression
#7
Abhishek Mangaonkar, Ashis Kumar Mondal, Sadanand Fulzule, Chetan Pundkar, Eun Jeong Park, Anand Jillella, Vamsi Kota, Hongyan Xu, Natasha M Savage, Huidong Shi, David Munn, Ravindra Kolhe
Indoleamine 2,3 dioxygenase-1 (IDO-1) is an enzyme in the kynurenine pathway which augments tumor-induced immune tolerance. Previous studies in childhood acute myeloid leukemia (AML) have shown a negative correlation of IDO-1 mRNA expression with outcomes. The aim of our study was to develop a practical and objective immunohistochemical technique to quantify IDO-1 expression on diagnostic bone marrow biopsies of AML patients in order to facilitate its use in routine clinical practice. IDO-1 mRNA was extracted from diagnostic bone marrow specimens from 29 AML patients...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29034454/successful-treatment-of-sapho-syndrome-with-apremilast
#8
S Adamo, J Nilsson, A Krebs, U Steiner, A Cozzio, L E French, A G A Kolios
Synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome is a rare disease with inflammatory osteoarticular and skin involvement. The pathogenesis of SAPHO syndrome remains unclear, but evidence suggests it may be an autoinflammatory disease triggered upon exposure to infectious agents in genetically predisposed individuals. Induction of the IL-23/Th17 axis as well as neutrophil activation seem to play a key role, and therapies targeting these immunological pathways, including TNF-inhibitors, ustekinumab, secukinumab and the IL-1 inhibitor anakinra are potential treatment options that need further investigation...
October 16, 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/29034009/a-multicenter-randomized-study-of-decitabine-as-epigenetic-priming-with-induction-chemotherapy-in-children-with-aml
#9
Lia Gore, Timothy J Triche, Jason E Farrar, Daniel Wai, Christophe Legendre, Gerald C Gooden, Winnie S Liang, John Carpten, David Lee, Frank Alvaro, Margaret E Macy, Carola Arndt, Philip Barnette, Todd Cooper, Laura Martin, Aru Narendran, Jessica Pollard, Soheil Meshinchi, Jessica Boklan, Robert J Arceci, Bodour Salhia
BACKGROUND: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints. RESULTS: Twenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A = epigenetic priming induction, 14 in Arm B = standard induction)...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28968939/methane-alleviates-alfalfa-cadmium-toxicity-via-decreasing-cadmium-accumulation-and-reestablishing-glutathione-homeostasis
#10
Quan Gu, Ziping Chen, Weiti Cui, Yihua Zhang, Huali Hu, Xiuli Yu, Qingya Wang, Wenbiao Shen
Although methane (CH4) generation triggered by some environmental stimuli, displays the protective response against oxidative stress in plants, whether and how CH4 regulates plant tolerance against cadmium stress is largely unknown. Here, we discovered that cadmium (Cd) stimulated the production of CH4 in alfalfa root tissues. The pretreatment with exogenous CH4 could alleviate seedling growth inhibition. Less amounts of Cd accumulation was also observed. Consistently, in comparison with Cd stress alone, miR159 transcript was down-regulated by CH4, and expression levels of its target gene ABC transporter was increased...
January 2018: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/28963790/phase-i-study-of-induction-chemotherapy-with-afatinib-ribavirin-and-weekly-carboplatin-and-paclitaxel-for-stage-iva-ivb-human-papillomavirus-associated-oropharyngeal-squamous-cell-cancer
#11
Lara A Dunn, Matthew G Fury, Eric J Sherman, Alan A Ho, Nora Katabi, Sofia S Haque, David G Pfister
BACKGROUND: The human papillomavirus (HPV) E6 oncoprotein enhances the oncogenic potential of ErbB proteins in HPV-related malignancies. This phase I study evaluates the addition of afatinib, an ErbB family inhibitor, and ribavirin to paclitaxel and carboplatin induction chemotherapy in HPV-associated, locally advanced oropharyngeal squamous cell carcinoma (SCC). METHODS: This dose escalation study included 2 doses of oral afatinib: 30 and 40 mg daily. Ribavirin dosing was weight based...
September 30, 2017: Head & Neck
https://www.readbyqxmd.com/read/28960207/bh3-mimetics-efficiently-induce-apoptosis-in-mouse-basophils-and-mast-cells
#12
Ramona Reinhart, Lionel Rohner, Simone Wicki, Michaela Fux, Thomas Kaufmann
Basophil granulocytes and mast cells are recognized for their roles in immunity and are central effectors of diverse immunological disorders. Despite their similarities, there is emerging evidence for non-redundant roles of the circulating yet scarce basophils and tissue-resident mast cells, respectively. Because of their importance in allergic pathogenesis, specific induction of apoptosis in basophils and mast cells may represent an interesting novel treatment strategy. The pro-inflammatory cytokine interleukin-3 serves as a key factor for basophil and mouse mast cell survival...
September 29, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28955969/capsicum-annuum-proteinase-inhibitor-ingestion-negatively-impacts-the-growth-of-sorghum-pest-chilo-partellus-and-promotes-differential-protease-expression
#13
Abhilash R Jadhav, Abdul R War, Ashwini N Nikam, Anmol S Adhav, Vidya S Gupta, Hari C Sharma, Ashok P Giri, Vaijayanti A Tamhane
BACKGROUND: Chilo partellus is an important insect pest infesting sorghum and maize. The larvae internalize in the stem, rendering difficulties in pest management. We investigated the effects of Capsicum annuum proteinase inhibitors (CanPIs) on C. partellus larvae by in-vitro and in-vivo experiments. METHODS: Recombinant CanPI-7 (with four-Inhibitory Repeat Domains, IRDs), -22 (two-IRDs) and insect proteinase activities were estimated by proteinase assays, dot blot assays and in gel activity assays...
December 2016: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28920105/the-impact-of-von-willebrand-factor-on-factor-viii-memory-immune-responses
#14
Juan Chen, Jocelyn A Schroeder, Xiaofeng Luo, Qizhen Shi
Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis were used to study FVIII-primed CD4(+) T cells...
August 22, 2017: Blood Advances
https://www.readbyqxmd.com/read/28874440/blocking-gp130-signaling-suppresses-autotaxin-expression-in-adipocytes-and-improves-insulin-sensitivity-in-diet-induced-obesity
#15
Shuhong Sun, Ran Wang, Jianwen Song, Ming Guan, Na Li, Xiaotian Zhang, Zhenwen Zhao, Junjie Zhang
Autotaxin (ATX), which is highly expressed and secreted by adipocytes, functions as the key enzyme to generate lysophosphatidic acid (LPA) from lysophosphatidylcholine. Adipose tissue is the main source of circulating ATX that modulates plasma LPA levels. Upregulation of ATX expression in obese patients and mice is closely related with insulin resistance and impaired glucose tolerance. However, the mechanism of ATX expression in adipocytes remains largely unknown. In this study, we found that glycoprotein 130 (gp130)-mediated Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) activation was required for abundant ATX expression in adipocytes...
November 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28864263/mechanism-of-chimeric-vaccine-stimulation-of-indoleamine-2-3-dioxygenase-biosynthesis-in-human-dendritic-cells-is-independent-of-tgf-%C3%AE-signaling
#16
Grace E Esebanmen, William H R Langridge
Cholera toxin B subunit fusion to autoantigens such as proinsulin (CTB-INS) down regulate dendritic cell (DC) activation and stimulate synthesis of DC immunosuppressive cytokines. Recent studies of CTB-INS induction of immune tolerance in human DCs indicate that increased biosynthesis of indoleamine 2,3-dioxygenase (IDO1) may play an important role in CTB-INS vaccine suppression of DC activation. Studies in murine models suggest a role for transforming growth factor beta (TGF-β) in the stimulation of IDO1 biosynthesis, for the induction of tolerance in DCs...
September 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28863186/fusion-of-taq-dna-polymerase-with-single-stranded-dna-binding-like-protein-of-nanoarchaeum-equitans-expression-and-characterization
#17
Marcin Olszewski, Marta Śpibida, Maciej Bilek, Beata Krawczyk
DNA polymerases are present in all organisms and are important enzymes that synthesise DNA molecules. They are used in various fields of science, predominantly as essential components for in vitro DNA syntheses, known as PCR. Modern diagnostics, molecular biology and genetic engineering need DNA polymerases which demonstrate improved performance. This study was aimed at obtaining a new NeqSSB-TaqS fusion DNA polymerase from the Taq DNA Stoffel domain and a single-stranded DNA binding-like protein of Nanoarchaeum equitans in order to significantly improve the properties of DNA polymerase...
2017: PloS One
https://www.readbyqxmd.com/read/28856745/using-known-drug-interactions-to-manage-supratherapeutic-calcineurin-inhibitor-concentrations
#18
REVIEW
Nicholas W Lange, David M Salerno, Karen Berger, Demetra S Tsapepas
OBJECTIVES: To summarize the available body of evidence guiding the management of supratherapeutic concentrations of calcineurin inhibitors (CNI) using cytochrome P450 (CYP450) enzyme inducers. METHODS: A nondate restricted literature search within MEDLINE, Embase, and Scopus was performed using the terms "cyclosporine," "tacrolimus," "calcineurin inhibitor," "toxicity," "pharmacokinetics," "carbamazepine," "rifampin," "phenytoin," and "phenobarbital." Additional references were identified from a review of all included citations...
August 30, 2017: Clinical Transplantation
https://www.readbyqxmd.com/read/28835351/emerging-therapeutic-modalities-for-acute-myeloid-leukemia-aml-in-older-adults
#19
Li-Wen Huang, Rebecca L Olin
Treatment for the older adult with acute myeloid leukemia (AML) is challenging, due to both more aggressive disease biology as well as patient-related risk factors that limit tolerance of intensive chemotherapy. The use of prognostic models and comprehensive geriatric assessments can help hematologists evaluate the suitability of intensive chemotherapy for individual patients. For older patients considered fit for intensive chemotherapy, standard induction therapy should be given, followed by consideration of reduced intensity allogeneic stem cell transplantation...
November 2017: Journal of Geriatric Oncology
https://www.readbyqxmd.com/read/28826742/a-comprehensive-review-and-update-on-crohn-s-disease
#20
Mahesh Gajendran, Priyadarshini Loganathan, Anthony P Catinella, Jana G Hashash
The term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups...
August 18, 2017: Disease-a-month: DM
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