Disease progression mechanism in myelodysplastic syndromes: Insight into the role of the microenvironment

AbstractHuntington’s disease is a neurodegenerative disorder caused by the expansion of a polyglutamine (poly Q) repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Htt exon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1. We also present a new chemoenzymatic semisynthetic strategy that enables site-specific phosphorylation of Htt beyond Httex1. These advances yielded novel insights into how PTMs and structured domains beyond Httex1 influence aggregation mechanisms, kinetics, and fibril morphology of longer N-terminal Htt fragments. We demonstrate that phosphorylation at T107 significantly slowed its aggregation, whereases phosphorylation at T107 and S116 accelerated the aggregation of Htt171, underscoring the importance of crosstalk between different PTMs. We demonstrate that mutant Htt171 proteins aggregate via a different mechanism and form oligomers and fibrillar aggregates with morphological properties that are distinct from that of mutant Httex1. These observations suggest that different N-terminal fragments could have distinct mechanisms of aggregation and that a single polyQ-targeting anti-aggregation strategy may not effectively inhibit the aggregation of all N-terminal Htt fragments. Finally, our results underscore the importance of further studies to investigate the aggregation mechanisms of Htt fragments and how the various fragments interact with each other and influence Htt toxicity, pathology formation, and disease progression.Table of content

Download Full-text

A Real-Time Insight Into Disease Progression and the Role of Axonal Injury in Multiple Sclerosis

Archives of Neurology ◽

10.1001/archneur.58.1.37 ◽

2001 ◽

Vol 58 (1) ◽

Cited By ~ 9

Author(s):

Carl Bjartmar ◽

Grahame Kidd ◽

Richard M. Ransohoff

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Real Time ◽

Axonal Injury ◽

Insight Into

Download Full-text

A Phase II Study to Determine the Safety and Efficacy of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase (IDO) Enzyme INCB024360 in Patients with Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v124.21.4653.4653 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4653-4653 ◽

Cited By ~ 6

Author(s):

Rami S Komrokji ◽

Sheng Wei ◽

Adam W Mailloux ◽

Ling Zhang ◽

Eric Padron ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Disease Progression ◽

Phase Ii ◽

Median Duration ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Indoleamine 2,3 Dioxygenase ◽

The Mean

Abstract Introduction: Recent studies emphasized the role of immune dysregulation and innate immune activation in the pathogenesis of myelodysplastic syndromes (MDS). The expansion of T-regulatory cells, namely effector memory cells (Treg EM), in MDS correlates with worse outcome. The expansion of inflammatory hematopoietic suppressive cells called myeloid-derived suppressor cells (MDSC) is sufficient to perturb hematopoiesis and result in the development of MDS in a mouse model. INCB024360 is an oral inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO) which catalyzes the degradation of tryptophan (Trp) to Kynurenine (Kyn). Increased expression of IDO1 was an independent prognostic variable for survival in patients with acute myeloid leukemia (AML). Preclinical data suggests that IDO1 inhibition by INCB024360 will increase T cell proliferation, and decrease T reg cells and will decrease MDSC suppressive activity. We report the results of a phase II clinical study with laboratory correlatives exploring the potential role of INCB024360 for the treatment of MDS patients. Methods: This was a phase II, 2-step design to explore the activity and pharmacodynamics of INCB024360 in previously treated MDS patients. All patients signed informed consent. All patients with WHO defined MDS and AML with a myeloblast percentage between 20-30% (RAEB-t by FAB) were included. All risk categories by international prognostic scoring systems (IPSS) were allowed. The study excluded patients with viral hepatitis, HIV infection, prior solid organ or hematopoietic stem cell transplant or active autoimmune disease. The primary endpoint was overall response rate by the International Working Group criteria (IWG 2006). The secondary endpoints included IDO suppression measured intracellular by flowcytometry, change in Treg EM % with treatment and the percentage of bone marrow MDSC change after treatment with INCB024360 . All patients were treated with 600 mg oral twice a day for 16 weeks unless clear evidence of disease progression or toxicity was evident. Descriptive statistics were used to report baseline characteristics and response rates. The paired t-test was used to compare means. The study was registered at clinicaltrials.gov NCT01822691. Results: Between August 2013 and January 2014, 15 patients were enrolled at Moffitt Cancer Center. The median age was 72 years the majority of whom were white (93%) and male gender (80%). Seven patients were RCMD WHO subtype, 3 RAEB-I and RAEB-II each, and 1 RARS and MDS/MPN each. The IPSS risk was low 27% (4), intermediate-1 47% (7) and intermediate-2 27% (4). By the revised IPSS, 5 patients were intermediate risk (33%), 2 (13%) high and very high risk respectively. Two thirds were intermediate-2 or high risk by global MD Anderson risk model. The median number of prior therapies was 3 (2-10) and all patients had prior azacitidine therapy. The best response was stable disease in 12 (80%); 3 (20%) patients experienced disease progression and no hematological improvement was observed. The median duration of follow up was 10 months, median duration on study treatment 3.9 months, and median overall survival was not reached. Two patients progressed to AML. The treatment was relatively well tolerated; no treatment-emergent grade 3/4 adverse events were reported. One patient developed hypothyroidism and adrenal insufficiency (grade 2) and one patient had a low testosterone level. Mean IDO expression measured intracellular in mononuclear bone marrow cells was 39% at baseline compared to 26% after treatment (n=9, p 0.4). Mean BFU-E recovery improved from 72 to 191 colonies/106 (n=5, p value 0.036) and mean CFU-GM from 62 to180 colonies/106 (n=6, p 0.5). The mean MDSC % (CD33Lin-HLA cells) was 29.5% at baseline compared to 27.6% after treatment (n=9, p 0.7) however most patients experienced some reduction in MDSC%. The mean T Reg EM cell % changed from 9.6% at screening to 7.4% at end of treatment. (n=14, p 0.8) Conclusions: INCB024360 was relatively well tolerated in MDS patients. At the current dosages tested no significant clinical activity was observed. No significant decrease in intracellular IDO expression was observed. No significant decrease in MDSC and T reg EM as potential mechanism of action were observed. . Disclosures Komrokji: Incyte Corporation: Consultancy, Research Funding. Padron:Incyte: Honoraria, Research Funding. Tinsley:Incyte: Speakers Bureau.

Download Full-text

Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648390 ◽

1992 ◽

Vol 67 (01) ◽

pp. 111-116 ◽

Cited By ~ 64

Author(s):

Marcel Levi ◽

Jan Paul de Boer ◽

Dorina Roem ◽

Jan Wouter ten Cate ◽

C Erik Hack

Keyword(s):

Monoclonal Antibodies ◽

Plasminogen Activator ◽

Plasma Levels ◽

Fold Increase ◽

Fibrinolytic System ◽

Plasminogen Activation ◽

Plasminogen Activator Activity ◽

Insight Into

SummaryInfusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

Download Full-text

On Metaphysics and the Political: A Polemics of Reading Baudelaire in the 1930s

Nottingham French Studies ◽

10.3366/nfs.2019.0252 ◽

2019 ◽

Vol 58 (2) ◽

pp. 249-259

Author(s):

Joseph Acquisto

Keyword(s):

Twentieth Century ◽

Political Crisis ◽

The Political ◽

Modern Poetry ◽

Progressive Politics ◽

The World ◽

Relationship Of ◽

The Relationship ◽

Insight Into

This essay examines a polemic between two Baudelaire critics of the 1930s, Jean Cassou and Benjamin Fondane, which centered on the relationship of poetry to progressive politics and metaphysics. I argue that a return to Baudelaire's poetry can yield insight into what seems like an impasse in Cassou and Fondane. Baudelaire provides the possibility of realigning metaphysics and politics so that poetry has the potential to become the space in which we can begin to think the two of them together, as opposed to seeing them in unresolvable tension. Or rather, the tension that Baudelaire animates between the two allows us a new way of thinking about the role of esthetics in moments of political crisis. We can in some ways see Baudelaire as responding, avant la lettre, to two of his early twentieth-century readers who correctly perceived his work as the space that breathes a new urgency into the questions of how modern poetry relates to the world from which it springs and in which it intervenes.

Download Full-text

Faculty Opinions recommendation of TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10045957.10797055 ◽

2011 ◽

Author(s):

Michael Williams

Keyword(s):

Disease Progression ◽

Myelodysplastic Syndromes ◽

Low Risk ◽

Tp53 Mutations ◽

Predict Disease Progression

Download Full-text

Dažu vācu muzikālo tradīciju pārnese latviešu kultūrtelpā 18. gadsimta II pusē

Letonica ◽

10.35539/ltnc.2020.0041.m.g.0003 ◽

2020 ◽

Author(s):

Māra Grudule

Keyword(s):

18Th Century ◽

Musical Instrument ◽

German Society ◽

Original Form ◽

Musical Life ◽

Popular Songs ◽

Death Of Jesus ◽

Musical Traditions ◽

Insight Into

The article gives insight into a specific component of the work of Baltic enlightener Gotthard Friedrich Stender (1714–1796) that has heretofore been almost unexplored — the transfer of German musical traditions to the Latvian cultural space. Even though there are no sources that claim that Stender was a composer himself, and none of his books contain musical notation, the texts that had been translated by Stender and published in the collections “Jaunas ziņģes” (New popular songs, 1774) and “Ziņģu lustes” (The Joy of singing, 1785, 1789) were meant for singing and, possibly, also for solo-singing with the accompaniment of some musical instrument. This is suggested, first, by how the form of the translation corresponds to the original’s form; second, by the directions, oftentimes attached to the text, that indicate the melody; and third, by the genres of the German originals cantata and song. Stender translated several compositions into Latvian including the text of the religious cantata “Der Tod Jesu” (The Death of Jesus, 1755) by composer Karl Heinrich Graun (1754–1759); songs by various composers that were widely known in German society; as well as a collection of songs by the composer Johann Gottlieb Naumann (1741–1801) that, in its original form, was published together with notation and was intended for solo-singing (female vocals) with the accompaniment of a piano. This article reveals the context of German musical life in the second half of the 18th century and explains the role of music as an instrument of education in Baltic-German and Latvian societies.

Download Full-text

The Role of Industry-Academia Collaborative Research in Mineral Exploration

The Canadian Mineralogist ◽

10.3749/canmin.1900086 ◽

2020 ◽

Author(s):

James Marlatt

Keyword(s):

Collaborative Research ◽

New Technologies ◽

Mineral Exploration ◽

Board Members ◽

Technological Innovations ◽

Development Programs ◽

The University ◽

Insight Into ◽

Economic Mineral

ABSTRACT Many people may not be aware of the extent of Kurt Kyser's collaboration with mineral exploration companies through applied research and the development of innovative exploration technologies, starting at the University of Saskatchewan and continuing through the Queen's Facility for Isotope Research. Applied collaborative, geoscientific, industry-academia research and development programs can yield technological innovations that can improve the mineral exploration discovery rates of economic mineral deposits. Alliances between exploration geoscientists and geoscientific researchers can benefit both parties, contributing to the pure and applied geoscientific knowledge base and the development of innovations in mineral exploration technology. Through a collaboration that spanned over three decades, we gained insight into the potential for economic uranium deposits around the world in Canada, Australia, USA, Finland, Russia, Gabon, Namibia, Botswana, South Africa, and Guyana. Kurt, his research team, postdoctoral fellows, and students developed technological innovations related to holistic basin analysis for economic mineral potential, isotopes in mineral exploration, and biogeochemical exploration, among others. In this paper, the business of mineral exploration is briefly described, and some examples of industry-academic collaboration innovations brought forward through Kurt's research are identified. Kurt was a masterful and capable knowledge broker, which is a key criterion for bringing new technologies to application—a grand, curious, credible, patient, and attentive communicator—whether talking about science, business, or life and with first ministers, senior technocrats, peers, board members, first nation peoples, exploration geologists, investors, students, citizens, or friends.

Download Full-text