IL-1 receptor antagonism reveals a yin-yang relationship between NFκB and interferon signaling in chronic lymphocytic leukemia DOI Creative Commons
Tina YuXuan Luo,

Boyang Su,

Vincent Hung

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(33)

Published: Aug. 9, 2024

Nuclear factor kappa B (NFκB) is a pathogenic in chronic lymphocytic leukemia (CLL) that not addressed specifically by current therapies. NFκB activated inflammatory factors stimulate toll-like receptors (TLRs) and for interleukin-1 (IL-1) family members. IL-1 considered master regulator of inflammation, receptor signaling inhibited the antagonist anakinra. These considerations suggested anakinra might have role treatment CLL. Consistent with this idea, spontaneous TLR7-mediated activation canonical pathway CLL cells vitro. However, exhibited only weak responses to itself, was found inhibit along oxidative stress an receptor-independent manner. Anakinra then administered minimal toxicity 11 previously untreated patients phase I dose-escalation trial (NCT04691765). A stereotyped clinical response observed all patients. lowered blood lymphocytes lymph node sizes within first month were associated downregulation cells. inhibition accompanied upregulation type 1 interferon (IFN) signaling, c-MYC-regulated genes proteins, loss initial response. increased IFN survival cells vitro were, respectively, phenocopied mitochondrial antioxidants reversed blocking antibodies. observations suggest has activity may be useful adjunct conventional therapies as long compensatory blocked at same time.

Language: Английский

Single-cell RNA-sequencing and genome-wide Mendelian randomisation along with abundant machine learning methods identify a novel B cells signature in gastric cancer DOI Creative Commons

Qi Ma,

Jie Gao, Yuan Hui

et al.

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 6, 2025

Gastric cancer (GC) has a poor prognosis, considerable cellular heterogeneity, and ranks fifth among malignant tumours. Understanding the tumour microenvironment (TME) intra-tumor heterogeneity (ITH) may lead to development of novel GC treatments. The single-cell RNA sequencing (scRNA-seq) dataset was obtained from Gene Expression Omnibus (GEO) database, where diverse immune cells were isolated re-annotated based on cell markers established in original study ascertain their individual characteristics. We conducted weighted gene co-expression network analysis (WGCNA) identify genes with significant correlation GC. Utilising bulk data, we employed machine learning integration methods train specific biomarkers for diagnostic combinations. A two-sample Mendelian randomisation performed investigate causal effect gastric (GC). Ultimately, utilised DSigDB database acquire associations between signature pharmaceuticals. 18 that made up as follows: ZFAND2A, PBX4, RAMP2, NNMT, RNASE1, CD93, CDH5, NFKBIE, VWF, DAB2, FAAH2, VAT1, MRAS, TSPAN4, EPAS1, AFAP1L1, DNM3. Patients categorised into high-risk low-risk groups according risk scores. Individuals cohort exhibited dismal outlook. demonstrated individuals genetic predisposition elevated NFKBIE levels heightened likelihood acquiring Molecular docking indicates gemcitabine chloropyramine serve effective therapeutics against NFKBIE. developed validated utilising scRNA-seq data patients. function biomarker therapeutic target

Language: Английский

Citations

0
G-protein coupled receptor kinase-2 regulates the migration of chronic lymphocytic leukaemia cells to sphingosine-1 phosphate in vitro and their trafficking in vivo DOI Creative Commons
Maria Francesca Cassarino,

Ana Colado,

Valeria Sarapura Martínez

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 24, 2025

Language: Английский

Citations

0
Selinexor’s Immunomodulatory Impact in Advancing Multiple Myeloma Treatment DOI Creative Commons

Kereshmeh Tasbihi,

Heiko Bruns

Cells, Journal Year: 2025, Volume and Issue: 14(6), P. 430 - 430

Published: March 13, 2025

Despite the major advancements in repertoire for multiple myeloma (MM) treatment, this disease remains a chronically progressive plasma cell malignancy. Drug resistance and high relapse rates complicate extended treatment strategies. However, tumor microenvironment (TME) MM is decisive success of therapy or relapse. Aiming to improve outcome relapsed refractory patients, Selinexor has entered drug arsenal through implementation novel therapeutic approach by selectively inhibiting nuclear export receptor Exportin-1 (XPO1). leads inactivation cancer-related proteins induces apoptosis disrupting nucleocytoplasmic flow cells. While cytotoxic neoplastic cells, Selinexor’s immunomodulatory impact on TME currently being investigated. The aim review was elucidate capacity influence interaction network from an immunological perspective. Deciphering complex interplay highly plastic immune cells provides contribution molecular–biological exploration initiation progression MM. Unraveling targets evaluating advanced immunotherapeutic regimens implementing will shape future directions immune-oncotherapy

Language: Английский

Citations

0
Recent Advances in the Molecular Biology of Chronic Lymphocytic Leukemia: How to Define Prognosis and Guide Treatment DOI Open Access
Annalisa Arcari, Lucia Morello,

Elena Borotti

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(20), P. 3483 - 3483

Published: Oct. 14, 2024

Chronic Lymphocytic Leukemia (CLL) is the most frequent type of leukemia in Western countries. In recent years, there have been important advances knowledge molecular alterations that underlie disease's pathogenesis. Very heterogeneous prognostic subgroups identified by mutational status immunoglobulin heavy variable genes (

Language: Английский

Citations

2
T-bet suppresses proliferation of malignant B cells in chronic lymphocytic leukemia DOI
Philipp M. Roessner, Isabelle Seufert, Vicente Chapaprieta

et al.

Blood, Journal Year: 2024, Volume and Issue: 144(5), P. 510 - 524

Published: April 29, 2024

Language: Английский

Citations

2
Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome DOI Open Access
Ivan Negara, Ciprian Tomuleasa, Sanda Buruiana

et al.

Cancers, Journal Year: 2024, Volume and Issue: 16(12), P. 2170 - 2170

Published: June 7, 2024

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications DLBCL have been resolved based on mutational patterns indicative pathways transformation. However, complicated costly nature classifiers has precluded their inclusion into routine practice. In view this, status TP53 gene, which mutated or deleted in 20–30% cases, emerged as an important prognostic factor for patients, setting itself apart from other predictors. lesions are particularly enriched subtype that shares genomic features with Richter Syndrome, highlighting possibility subset arising transformation occult chronic lymphocytic leukemia-like malignancy, such monoclonal lymphocytosis. Patients TP53-mutated DLBCL, including those poor prognosis display inferior responses to standard chemoimmunotherapy regimens. The data presented this manuscript argue need improved more practical risk-stratification models patients show potential use prognostication and, prospect, treatment stratification DLBCL.

Language: Английский

Citations

1
NFKBIE is a predictive factor of survival and is correlated with immune infiltration and antigen processing and presentation in hepatocellular carcinoma DOI Open Access
Yang Zhang,

Jinqi Tu,

Jian Wang

et al.

Oncology Letters, Journal Year: 2024, Volume and Issue: 28(4)

Published: Aug. 6, 2024

The important role of the nuclear factor κB (NFκB) pathway in tumour development has long been recognized; however, NFκB inhibitor family liver cancer not elucidated. Hepatocellular carcinoma (HCC) is a serious public health burden with high incidence, poor prognosis, and early detection, especially Asia, where hepatitis prevalent. In present study, mRNA expression level was assessed HCC normal tissues using Metabolic Gene Rapid Visualizer, University Alabama at Birmingham Cancer Data Analysis Portal, Tumor Immune Estimation Resource database (TIMER). Survival curves κ light polypeptide gene enhancer B-cells (NFKBI)E were obtained Kaplan-Meier method. Genes co-expressed NFKBIE samples studied data from LinkedOmics Carcinoma Databases. Protein-protein interaction networks, Ontology Kyoto Encyclopedia Genomes enrichment analyses used to assess mechanism HCC. Using TIMER database, association between immune infiltration determined. RNA-sequencing (RNA-seq) evaluate function its impact on proliferation migration. Western blotting confirm cell lines. addition, overexpression demonstrated tissue microarrays encompassing 80 pairs tissues. only an improved prognosis compared other inhibitors. correlated clinical characteristics, such as grade, protein P53 mutation status stage. Set suggested that may inhibit PI3K/AKT, RAS/MAPK, RTK TSC/mTOR pathways. significantly associated B-cell RNA-seq knockdown affected 'Antigen processing presentation' 'hepatocellular carcinoma' Immunohistochemistry revealed overexpressed several stages Finally, inhibition decreased migration cells. conclusion, due prognostic value HCC, distinguished itself As such, it provide novel indicator immunotherapeutic target for

Language: Английский

Citations

1
Identification of a novel immune checkpoint-related gene signature predicts prognosis and immunotherapy in breast cancer and experiment verification DOI Creative Commons

Yin Ke,

Y. Guo,

Jinqiu Wang

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Dec. 28, 2024

Breast cancer (BRCA) is one of the pivotal causes female death worldwide. And morbidity and mortality breast have increased rapidly. Immune checkpoints are important to maintain immune tolerance regarded as therapeutic targets. However, research for BRCA were limited single checkpoint-related gene (ICG) few studies systematically explored expression profile genes or attempted construct a prognostic risk model based on genes. We identified differentially expressed (DEGs) in normal tissues from TCGA database. A 7-gene signature was created by utilizing univariate Cox regression with least absolute shrinkage selection operator (LASSO) method. In addition, we conducted nomogram predict significance. This tool enables quantitative prediction patient prognosis, serving valuable reference clinical decision-making, thereby improving outcomes. Relationships between our indicators, TME (Tumor Microenvironment), cell infiltration, response drug susceptibility investigated. set vitro assays decipher relationship MAP2K6 proliferation, invasion, migration, colony formation apoptosis rate cells. As result, established composed seven ICGs BRCA. Based median score, patients equally assigned into two groups high- low-risk. High-risk poorer OS (overall survival) than low-risk patients. there remarkable differences these clinicopathological features, TME, susceptibility. The results GO KEGG analyses indicated that DEGs involved immune-related biological processes pathways. GSEA analysis also showed number pathways notably enriched group. Finally, cell-based may play role initiation progression tumor suppressor gene. conclusion, novel ICG has potential survival sensitivity Furthermore, this study serve target therapy.

Language: Английский

Citations

1
IL-1 receptor antagonism reveals a yin-yang relationship between NFκB and interferon signaling in chronic lymphocytic leukemia DOI Creative Commons
Tina YuXuan Luo,

Boyang Su,

Vincent Hung

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(33)

Published: Aug. 9, 2024

Nuclear factor kappa B (NFκB) is a pathogenic in chronic lymphocytic leukemia (CLL) that not addressed specifically by current therapies. NFκB activated inflammatory factors stimulate toll-like receptors (TLRs) and for interleukin-1 (IL-1) family members. IL-1 considered master regulator of inflammation, receptor signaling inhibited the antagonist anakinra. These considerations suggested anakinra might have role treatment CLL. Consistent with this idea, spontaneous TLR7-mediated activation canonical pathway CLL cells vitro. However, exhibited only weak responses to itself, was found inhibit along oxidative stress an receptor-independent manner. Anakinra then administered minimal toxicity 11 previously untreated patients phase I dose-escalation trial (NCT04691765). A stereotyped clinical response observed all patients. lowered blood lymphocytes lymph node sizes within first month were associated downregulation cells. inhibition accompanied upregulation type 1 interferon (IFN) signaling, c-MYC-regulated genes proteins, loss initial response. increased IFN survival cells vitro were, respectively, phenocopied mitochondrial antioxidants reversed blocking antibodies. observations suggest has activity may be useful adjunct conventional therapies as long compensatory blocked at same time.

Language: Английский

Citations

0