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Will Systems Biology Transform Clinical Decision Support?
Published in Paul Cerrato, John Halamka, Reinventing Clinical Decision Support, 2020
Studying network medicine’s essential components is also providing useful insights into the nature of asthma, as we discussed earlier. Oligonucleotide microarrays and sequencing are homing in on single-nucleotide polymorphisms (SNPs) that may be involved in the pathophysiology of asthma, for instance. Some of the strongest evidence comes from genome-wide association studies (GWAS) that focus on the 17q21 locus, referring to chromosome 17—the lower q section, position 21. Four genes in this section of the chromosome—ORMDL3, GSDMB, ZPBP2, and IKZF3—have been linked to inflammatory response, a major problem for patients with asthma. GWAS also suggest that specific gene variants in the FLG gene contribute to atopic dermatitis in Europeans and Asians. The mutations are not usually found in Africans, as demonstrated by whole exome sequencing. (The exome is that fraction of the genome that contains protein-encoding DNA.)18
Precision medicine in myelodysplastic syndromes
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
CRBN is a member and substrate receptor of the cullin 4 RING E3 ubiquitin ligase complex (CRL4). CRBN recruits substrate proteins to the CRL4 complex for ubiquitination and the subsequent degradation in proteasomes. IMiDs binds to CRBN in CRL4 complex and block normal endogenous substrates (CRBN and the homeobox transcription factor MEIS2 in MM) from binding to CRL4 for ubiquitination and degradation (Fischer et al., 2014). After IMID binding to CRBN, CRL4 complex is recruiting transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) for ubiquitination and degradation in MM cells (Krönke et al., 2014). Degradation of these transcription factors explains lenalidomide's growth inhibition of MM cells and increased interleukin-2 (IL-2) release from T cells. However, it is unlikely that degradation of IKZF1 and IKZF3 accounts for lenalidomide's activity in MDS with del(5q). Krönke et al. (2015) identified a novel target casein kinase1A1 (CSNK1A1) by quantitative proteomics in the myeloid cell line KG-1. CSNK1A1 is encoded in the del(5q) commonly deleted region and the gene is haploinsufficient. Lenalidomide treatment leads to increased ubiquitination of the remaining CSNK1A1 and decreased protein abundance. CSNK1A1 negatively regulates β-catenin, which drives stem cell self-renewal, and CSNK1A1 haploinsufficiency causes the initial clonal expansion in patients with the del(5q) MDS and contributes to the pathogenesis of del(5q) MDS. The further inhibition of CSNK1A1 in del(5q) MDS is associated with del(5q) failure and p53 activation. The inhibition of CSNK1A1 reduced RPS6 phosphorylation, induced p53 expression and growth inhibition, and triggered the myeloid differentiation program. TP53-null leukemia did not respond to CSNK1A1 inhibition, strongly supporting the importance of the p53 expression for the yield of CSNK1A1 inhibition. CSNK1A1 mutations have been recently found in 5%–18% of MDS patients with del(5q) (Schneider et al., 2014). These mutations are associated similarly to the effect of TP53 mutations with rise to a poor prognosis in del(5q) MDS (Smith et al., 2015). Other studies did not find impact of CSNK1A1 mutations on lenalidomide treatment in del(5q) MDS (Heuser et al., 2015; Negoro et al., 2016).
Association between 17q21 variants and asthma predisposition in Pashtun population from Pakistan
Published in Journal of Asthma, 2023
Sibtain Afzal, Khushnooda Ramzan, Sajjad Ullah, Arshad Jamal, Sulman Basit, Khaled M. AlKattan, Ahmed Bilal Waqar
Ikaros family zinc finger protein 3 (IKZF3) gene, at the 17q21, encodes hematopoietic transcription factors that play an essential role in lymphocyte differentiation besides maintaining differentiation, proliferation, and maturation of B and T cells (61). It is highly expressed in peripheral blood leukocytes, spleen, and thymus. Multiple SNPs in IKZF3 had been associated with asthma in previous studies including rs907092 (59), rs9635726 (62), rs9303277 (59,63), and rs3816470 (30). Our findings showed that TT genotype of rs3816470 was significantly (p values < .0125) associated with asthma disease; whereas the CT genotype was associated with a protective effect in the recessive and overdominant genetic models, respectively (Table 3). Furthermore, the stratified interaction analysis revealed a higher odds ratio for TT genotype with a highly significant association with female asthmatics, i.e. (OR = 6.01, 95%CI = 2.48–14.60, p values = .000147*). Recently rs3816470 was positively associated with asthmatic patients in a study from Lahore, Pakistan (30) that supports our results.
New drugs in early development for treating multiple myeloma: all that glitters is not gold
Published in Expert Opinion on Investigational Drugs, 2020
Luca Bertamini, Francesca Bonello, Mario Boccadoro, Sara Bringhen
IMDs represent the backbone of many standard-of-care treatments for NDMM and RRMM. Three IMDs are currently approved for clinical practice: thalidomide and its derivatives lenalidomide and pomalidomide. IMDs are so called because of their ability to modulate immune cell functions (mainly lymphocytes) through their activation and secretion of cytokines [16]. The biological target of IMDs is CRBN E3 ligase complex, which normally induces the ubiquitination and degradation of transcription factors known as IKZF1 (Ikaros) and IKZF3 (Aiolos), which are important for the normal differentiation of B and T lymphocytes and plasma cells via the downregulation of IRF4 and c/Myc [17–21]. Moreover, IKZF3 regulates the production of IL-2 by T cells [18]. The inhibition of these transcription factors is crucial to stop MM cell proliferation and modulate bone marrow microenvironment.
HLA ligandome analysis of primary chronic lymphocytic leukemia (CLL) cells under lenalidomide treatment confirms the suitability of lenalidomide for combination with T-cell-based immunotherapy
Published in OncoImmunology, 2018
Annika Nelde, Daniel J. Kowalewski, Linus Backert, Heiko Schuster, Jan-Ole Werner, Reinhild Klein, Oliver Kohlbacher, Lothar Kanz, Helmut R. Salih, Hans-Georg Rammensee, Stefan Stevanović, Juliane S. Walz
As the IKZF1-derived HLA class I ligand APHARNGLSL419–428 showed significant upmodulation under lenalidomide treatment (UPN1, Fig. 3C), we aimed to analyze whether the direct inhibition of CLL cell proliferation via cereblon caused by lenalidomide is reflected in the HLA ligandome of treated primary CLL cells. We screened the HLA ligandome of UPN1 for the presence of IKZF1- and IKZF3-derived ligands, as these two transcription factors undergo increased proteasomal degradation under lenalidomide treatment.34,43 We identified two length variants of an IKZF1-derived HLA class I ligand (APHARNGLSL419–428, B#07:02; APHARNGL419-426, B#07:02) and one IKZF3-derived HLA class I ligand (AEMGSERAL246–254, B#44:02). Strikingly, the IKZF3-derived ligand was detected exclusively on CLL cells after lenalidomide treatment and the IKZF1-derived ligands showed substantial upmodulation under lenalidomide treatment with median log2 fold-changes (treated/untreated, mean of three replicates) of 1.25 and 1.72 at t24h and t48h, respectively (Fig. 5C). In the single replicate volcano plot analysis comparing the HLA ligandomes of lenalidomide-treated cells with cells before treatment, the IKZF1-derived ligand APHARNGLSL reached significance thresholds (log2 fold-change ≥ 2, p ≤ 0.01 after multi-testing correction) for upmodulation in 2/3 biological replicates at both, t24h and t48h (Figs. 5D and E).