Interleukin-1 (IL-1) and the inflammasome in cancer.

Canakinumab, a monoclonal antibody targeting pro-inflammatory cytokine interleukin (IL)-1β, improved hemoglobin levels while preventing recurrent cardiovascular events in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). This cardiovascular (CV) preventive effect was greater in patients with TET2 mutations associated with clonal hematopoiesis (CH). The current proteogenomic analysis aimed to understand the clinical response to canakinumab and underlying proteomic profiles in the context of CH and anemia. The analysis included 4595 patients from the CANTOS study who received either canakinumab or placebo and evaluated multiplexed proteomics (4785 proteins) using Somascan@ and targeted deep sequencing for CH mutations. Incident anemia was more common in the presence of CH mutations but reduced by canakinumab treatment. Canakinumab treatment was significantly associated with higher hemoglobin increment in patients with concurrent CH mutations and anemia compared to patients with CH mutations without anemia or without CH mutations. Compared to those without CH mutations, the presence of CH mutations was associated with proteomic signatures of inflammation and defense response to infection, as well as markers of high-risk CV disease which was further enhanced by the presence of anemia. Canakinumab suppressed hepcidin, pro-inflammatory cytokines, myeloid activation, and complement pathways, and reversed pathologically deregulated pathways to a greater extent in patients with CH mutations and anemia. These molecular findings provide evidence of the clinical utility of IL-1β blockade and support further study of canakinumab in patients with concurrent anemia and CH mutations. The study was funded by Novartis Corporation, US and registered at clinicaltrials.gov (NCT01327846).

Effects of IL-1β inhibition on anemia and clonal hematopoiesis in the randomized CANTOS trial.

Abstract Reactive oxygen species (ROS) serve as typical metabolic byproducts of aerobic life and play a pivotal role in redox reactions and signal transduction pathways. Contingent upon their concentration, ROS production not only initiates or stimulates tumorigenesis but also causes oxidative stress (OS) and triggers cellular apoptosis. Mounting literature supports the view that ROS are closely interwoven with the pathogenesis of a cluster of diseases, particularly those involving cell proliferation and differentiation, such as myelodysplastic syndromes (MDS) and chronic/acute myeloid leukemia (CML/AML). OS caused by excessive ROS at physiological levels is likely to affect the functions of hematopoietic stem cells, such as cell growth and self-renewal, which may contribute to defective hematopoiesis. We review herein the eminent role of ROS in the hematological niche and their profound influence on the progress of MDS. We also highlight that targeting ROS is a practical and reliable tactic for MDS therapy. Graphical Abstract 

Role of reactive oxygen species in myelodysplastic syndromes

Inflammation impacts human hematopoiesis across physiologic and pathologic conditions, as signals derived from the bone marrow microenvironment, such as pro-inflammatory cytokines and chemokines, have been shown to alter hematopoietic stem cell (HSCs) homeostasis. Dysregulated inflammation can skew HSC fate-related decisions, leading to aberrant hematopoiesis and potentially contributing to the pathogenesis of hematological disorders such as myelodysplastic syndromes (MDS). Recently, emerging studies have used single-cell sequencing and muti-omic approaches to investigate HSC cellular heterogeneity and gene expression in normal hematopoiesis as well as in myeloid malignancies. This review summarizes recent reports mechanistically dissecting the role of inflammatory signaling and innate immune response activation due to MDS progression. Furthermore, we highlight the growing importance of using multi-omic techniques, such as single-cell profiling and deconvolution methods, to unravel MDSs’ heterogeneity. These approaches have provided valuable insights into the patterns of clonal evolution that drive MDS progression and have elucidated the impact of inflammation on the composition of the bone marrow immune microenvironment in MDS.

Emerging Insights into Molecular Mechanisms of Inflammation in Myelodysplastic Syndromes

Belegbare verbindungsindividuelle Schalteinrichtungen verschiedener Arten geben fur artabhangig unterschiedlich dringlich zu verarbeitende Informationen Verarbeitungsanforderungen mit verschiedenen Dringlichkeitsgraden an zentrales Schaltwerk ab. Assignable connection-switching devices of various types provide for species-dependent different from urgency to process information processing requirements with different degrees of urgency to a central switching station. Nach Masgabe einer laufend gemessenen momentanen Schaltwerksbelastung in einer Belegungs-Abweiseinrichtung einstellbarer Grenzwert dient als vergleichsnormal und bewirkt, das Verarbeitungsanforderungen abgewiesen (angenommen werden, wenn der Dringlichkeitswert kleiner (groser) als Grenzwert ist. Gemas einem in einer Anforderungsabweiseinrichtung fur jede der verschiedenen Arten von Verarbeitungsanforderungen gespeicherten konstanten artindividuellen Restakzeptanzwertes wird bei Uberschreiten des kritschen Grenzwertes uber den Dringlichkeitswert der jeweiligen Verarbeitungsanforderung der betr. Art in zyklischer Folge einer jeweils einem Zyklus entsprechenden Anzahl von mehreren Verarbeitungsanforderungen mit Ausnahme von einer derselben jeweils ein Abweisungskennzeichen, dagegen der einen Verarbeitungsanforderung ein Annahmekennzeichen zugeteilt. In accordance with a continuously measured current derailleur load in a occupancy stand-off adjustable threshold value serving as a comparison standard, and causes processing requests rejected (assumed when the urgency value is smaller (larger) than threshold value. According to one in a request rejection device for each of the various types of processing requests stored constant artindividuellen residual acceptance value is assigned when exceeding the Kritschen limit on the urgency value of the respective processing request of hold. kind in cyclic sequence of one cycle each corresponding number of a plurality of processing requirements, with the exception of one of them each represent a rejection indicator, whereas the a processing request an acceptance indicator.

Circuit arrangement for telecommunication exchanges, particularly for telephone exchanges equipped with control processors and traffic-measuring devices

Abstract Aberrant innate immune signaling has been identified as a potential key driver of the complex pathophysiology of myelodysplastic neoplasms (MDS). This study of a large, clinically and genetically well-characterized cohort of treatment-naïve MDS patients confirms intrinsic activation of inflammatory pathways in general mediated by caspase-1, interleukin (IL)-1β and IL-18 in low-risk (LR)-MDS bone marrow and reveals a previously unrecognized heterogeneity of inflammation between genetically defined LR-MDS subgroups. Principal component analysis resolved two LR-MDS phenotypes with low (cluster 1) and high (cluster 2) levels of IL1B gene expression, respectively. Cluster 1 contained 14/17 SF3B1 -mutated cases, while cluster 2 contained 8/8 del(5q) cases. Targeted gene expression analysis of sorted cell populations showed that the majority of the inflammasome-related genes, including IL1B , were primarily expressed in the monocyte compartment, consistent with a dominant role in determining the inflammatory bone marrow environment. However, the highest levels of IL18 expression were found in hematopoietic stem and progenitor cells (HSPCs). The colony forming activity of healthy donor HSPCs exposed to monocytes from LR-MDS was increased by the IL-1β-neutralizing antibody canakinumab. This work reveals distinct inflammatory profiles in LR-MDS that are of likely relevance to the personalization of emerging anti-inflammatory therapies. 

/pdf/activation-of-distinct-inflammatory-pathways-in-subgroups-of-1g25eqxo.pdf

Activation of distinct inflammatory pathways in subgroups of LR-MDS.

Activation of Distinct Inflammatory Pathways in LR-MDS Is Determined By Genetics

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Activation of distinct inflammatory pathways in subgroups of LR-MDS.

Activation of Distinct Inflammatory Pathways in LR-MDS Is Determined By Genetics

Priority polling algorithm