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Inhibitor tolerance induction

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https://www.readbyqxmd.com/read/29769258/anti-tumor-efficacy-of-a-novel-clk-inhibitor-via-targeting-rna-splicing-and-myc-dependent-vulnerability
#1
Kenichi Iwai, Masahiro Yaguchi, Kazuho Nishimura, Yukiko Yamamoto, Toshiya Tamura, Daisuke Nakata, Ryo Dairiki, Yoichi Kawakita, Ryo Mizojiri, Yoshiteru Ito, Moriteru Asano, Hironobu Maezaki, Yusuke Nakayama, Misato Kaishima, Kozo Hayashi, Mika Teratani, Shuichi Miyakawa, Misa Iwatani, Maki Miyamoto, Michael G Klein, Wes Lane, Gyorgy Snell, Richard Tjhen, Xingyue He, Sai Pulukuri, Toshiyuki Nomura
The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025...
May 16, 2018: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29765321/brain-lipopolysaccharide-preconditioning-induced-gene-reprogramming-mediates-a-tolerance-state-in-electroconvulsive-shock-model-of-epilepsy
#2
Elham Amini, Mojtaba Golpich, Abdoreza S Farjam, Behnam Kamalidehghan, Zahurin Mohamed, Norlinah M Ibrahim, Abolhassan Ahmadiani, Azman A Raymond
There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS)...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29762875/in-vivo-assessment-of-the-effect-of-cyp1a2-inhibition-and-induction-on-pomalidomide-pharmacokinetics-in-healthy-subjects
#3
Yan Li, Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Matthew Hoffmann, Maria Palmisano, Simon Zhou
Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies...
May 15, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29760711/selective-modulation-of-tnf-tnfrs-signaling-insights-for-multiple-sclerosis-treatment
#4
REVIEW
Valentina Pegoretti, Wia Baron, Jon D Laman, Ulrich L M Eisel
Autoimmunity develops when self-tolerance mechanisms are failing to protect healthy tissue. A sustained reaction to self is generated, which includes the generation of effector cells and molecules that destroy tissues. A way to restore this intrinsic tolerance is through immune modulation that aims at refurbishing this immunologically naïve or unresponsive state, thereby decreasing the aberrant immune reaction taking place. One major cytokine has been shown to play a pivotal role in several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS): tumor necrosis factor alpha (TNFα) modulates the induction and maintenance of an inflammatory process and it comes in two variants, soluble TNF (solTNF) and transmembrane bound TNF (tmTNF)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29753302/contribution-of-hepatic-retinaldehyde-dehydrogenase-induction-to-impairment-of-glucose-metabolism-by-high-fat-diet-feeding-in-c57bl-6j-mice
#5
Jiong Xu, Mian Zhang, Xiangping Zhang, Hanyu Yang, Binbin Sun, Zhongjian Wang, Yaqian Zhou, Shuting Wang, Xiaodong Liu, Li Liu
Obesity and insulin resistance are associated with overexpression of retinaldehyde dehydrogenase 1 (RALDH1). We aimed to investigate the roles of hepatic RALDH1 induction in glucose metabolism impairment using mice fed with high-fat diet (HFD). Mice were fed with HFD for 8 weeks and treated with RALDH inhibitor citral for another 4 weeks. Oral glucose tolerance test (OGTT), pyruvate tolerance test (PTT) and insulin tolerance test (ITT) were operated. Expressions of Phosphoenolpyruvate carboxykinase 1 (PCK1), glucokinase (GCK) and RALDH1 were measured...
May 12, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29724168/role-of-abscisic-acid-in-strigolactone-induced-salt-stress-tolerance-in-arbuscular-mycorrhizal-sesbania-cannabina-seedlings
#6
Cheng-Gang Ren, Cun-Cui Kong, Zhi-Hong Xie
BACKGROUND: Strigolactones (SLs) are considered to be a novel class of phytohormone involved in plant defense responses. Currently, their relationships with other plant hormones, such as abscisic acid (ABA), during responses to salinity stress are largely unknown. RESULTS: In this study, the relationship between SL and ABA during the induction of H2 O2 - mediated tolerance to salt stress were studied in arbuscular mycorrhizal (AM) Sesbania cannabina seedlings. The SL levels increased after ABA treatments and decreased when ABA biosynthesis was inhibited in AM plants...
May 3, 2018: BMC Plant Biology
https://www.readbyqxmd.com/read/29718732/avacopan-in-the-treatment-of-anca-associated-vasculitis
#7
Vladimir Tesar, Zdenka Hruskova
ANCA-associated vasculitis (AAV) is a rare but potentially life-threatening disease. Currently used induction treatment (cyclophosphamide or rituximab with high-dose corticosteroids) has significantly improved outcome of AAV, but is associated with high toxicity. Alternative complement pathway activation was shown to play a role in the pathogenesis of AAV, thus providing rationale for the use of avacopan, a selective inhibitor of C5a receptor, in the treatment of AAV. Areas Covered: Pharmacokinetic and pharmocodynamic properties of avacopan, clinical efficacy and safety and tolerability of avacopan in so far performed clinical trials in patients with AAV are reviewed and discussed...
May 2, 2018: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29681200/cost-analysis-of-plasma-derived-factor-viii-von-willebrand-factor-vs-recombinant-factor-viii-for-treatment-of-previously-untreated-patients-with-severe-hemophilia-a-in-the-united-states
#8
Ellis J Neufeld, Robert F Sidonio, Ken O'Day, M Chris Runken, Kellie Meyer, Jeffrey Spears
BACKGROUND: Inhibitor development to factor VIII (FVIII) hemophilia therapy results in increased complications and substantial economic costs. The SIPPET study, the first randomized controlled trial to compare the immunogenicity of plasma-derived FVIII (pdFVIII)/von Willebrand factor (VWF) and recombinant-DNA-derived FVIII (rFVIII), demonstrated higher inhibitor rates in previously untreated patients (PUPs) treated with rFVIII than in PUPs treated with pdFVIII/VWF. OBJECTIVE: To quantify the economic impact of treating PUPs with pdFVIII/VWF versus rFVIII...
April 21, 2018: Journal of Medical Economics
https://www.readbyqxmd.com/read/29669460/current-diagnosis-and-treatment-of-polymyositis-and-dermatomyositis
#9
Hirokazu Sasaki, Hitoshi Kohsaka
Idiopathic inflammatory myopathies (IIMs) are heterogeneous disorders that affect the skeletal muscles. Polymyositis, dermatomyositis, and inclusion body myositis are major IIM subsets. Immune-mediated necrotizing myopathy became recognized as a potentially new IIM subset. Since the new classification criteria published by the International Myositis Classification Criteria Project have higher sensitivity and specificity for IIM classification and subclassification than the previous criteria, they should help precise diagnosis...
April 18, 2018: Modern Rheumatology
https://www.readbyqxmd.com/read/29652676/immune-tolerance-induction-rescue-with-turoctocog-alfa-in-a-poor-risk-haemophilia-a-inhibitor-young-child-the-history-of-a-success
#10
Ezio Zanon, Marta Milan, Samantha Pasca
: The development of alloantibodies against the replacement of Factor VIII (FVIII) is the major complication in haemophilia A treatment. The gold standard to eradicate inhibitors is the immune tolerance induction (ITI), but in some cases it fails requiring another immune tolerance, defined ITI rescue (ITI-R), using a different concentrate, even though it is still debated. We report a successful case of a poor risk (titre of inhibitor at start of ITI > 10 BU/ml, peak titre on ITI > 200 BU/ml, >2 years since the inhibitor diagnosis) haemophilia A child treated with a high-dose regimen (200 UI/kg/day) turoctocog-alfa after a failed first-line ITI with octocog-alfa lasting 29 months...
April 12, 2018: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
https://www.readbyqxmd.com/read/29625593/radiotherapy-induced-anti-tumor-immune-response-and-immune-related-adverse-events-in-a-case-of-recurrent-nasopharyngeal-carcinoma-undergoing-anti-pd-1-immunotherapy
#11
T Finazzi, T Rordorf, K Ikenberg, G F Huber, M Guckenberger, H I Garcia Schueler
BACKGROUND: Treatment of recurrent nasopharyngeal carcinoma is a challenging clinical problem. We report the case of a 46 year old male showing excellent response and signs of immunostimulation following re-re-irradiation for recurrent nasopharyngeal carcinoma under systemic treatment with pembrolizumab. CASE PRESENTATION: Patient was first diagnosed with locoregionally advanced, non-keratinizing nasopharyngeal carcinoma in 2010. After achieving complete remission following induction chemotherapy and concurrent curative chemoradiation, the patient subsequently developed distant and locoregionally recurrent disease...
April 6, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29607607/alpha-1-antitrypsin-in-cell-and-organ-transplantation
#12
Mel Berger, Mingyao Liu, Marc E Uknis, Maria Koulmanda
Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor which limits inflammatory tissue damage. Purified plasma-derived AAT has been well-tolerated in more than 30 years of use to prevent emphysema in AAT deficient individuals...
April 1, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29594044/a-phase-ib-ii-study-of-ganetespib-with-doxorubicin-in-advanced-solid-tumors-including-relapsed-refractory-small-cell-lung-cancer
#13
Deepa S Subramaniam, Stephen V Liu, Jeanette Crawford, Jenna Kramer, Jillian Thompson, Hongkun Wang, Giuseppe Giaccone
Introduction: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29564545/transcriptome-analysis-provides-insights-into-the-delayed-sticky-disease-symptoms-in-carica-papaya
#14
Johana Madroñero, Silas P Rodrigues, Tathiana F S Antunes, Paolla M V Abreu, José A Ventura, A Alberto R Fernandes, Patricia Machado Bueno Fernandes
Global gene expression analysis indicates host stress responses, mainly those mediated by SA, associated to the tolerance to sticky disease symptoms at pre-flowering stage in Carica papaya. Carica papaya plants develop the papaya sticky disease (PSD) as a result of the combined infection of papaya meleira virus (PMeV) and papaya meleira virus 2 (PMeV2), or PMeV complex. PSD symptoms appear only after C. papaya flowers. To understand the mechanisms involved in this phenomenon, the global gene expression patterns of PMeV complex-infected C...
March 21, 2018: Plant Cell Reports
https://www.readbyqxmd.com/read/29559474/inhibition-of-nr4a-receptors-enhances-anti-tumor-immunity-by-breaking-treg-mediated-immune-tolerance
#15
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
https://www.readbyqxmd.com/read/29543371/immune-tolerance-induction-what-have-we-learned-over-time
#16
REVIEW
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
https://www.readbyqxmd.com/read/29534881/tumor-promoting-cyanotoxin-microcystin-lr-does-not-induce-procarcinogenic-events-in-adult-human-liver-stem-cells
#17
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
https://www.readbyqxmd.com/read/29497895/preclinical-investigation-of-a-potent-geranylgeranyl-diphosphate-synthase-inhibitor
#18
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
https://www.readbyqxmd.com/read/29497426/dexamethasone-induced-myeloid-derived-suppressor-cells-prolong-allo-cardiac-graft-survival-through-inos-and-glucocorticoid-receptor-dependent-mechanism
#19
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
https://www.readbyqxmd.com/read/29493848/long-term-clinical-and-economic-outcomes-in-previously-untreated-paediatric-patients-with-severe-haemophilia-a-a-nationwide-real-world-study-with-700-person-years
#20
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
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