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Botanicals and the Gut Microbiome
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
There has been an unparalleled increase in the number of individuals infected with Type 1 hypersensitization, which includes atopic eczema, atopic asthma, rhinitis and Type 1 food allergies (Okada et al., 2010). Atopic sensitization is believed to occur in the first two years of life and persists a lifetime (Shen et al., 2013). It is believed that a mutation in a particular gene such as the CARD11 gene, which involves the function of the skin barrier as well as the method of birth (cesarean vs. vaginally), is the cause of atopic eczema. It was shown that infants found to be afflicted with the disease during the first month had very low diversity of gut microbiota present specifically with regard to the Bacteroidetes phylum compared with the infants without atopic eczema, as well as lower levels of Proteobacteria at infants 12 months of age with atopic eczema (Abrahamsson et al., 2012). Proteobacteria cell walls contain lipopolysaccharides, which are known to have the ability to elicit a host response and as seen those with low levels of lipopolysaccharides, i.e. low levels of Proteobacteria in infants, are at a higher risk of developing atopic eczema (Gehring et al., 2001).
Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Prognosis in FL may be predicted by a number of clinical, genetic, and molecular factors. Analogous to the IPI in DLBCL, prognostic systems have been developed for use in FL with the FL IPI being the most widely used (Table 30.4).132 The FLIPI stratifies patients into three risk groups based on five variables: age, Ann Arbor stage, hemoglobin, LDH, and the number of sites of nodal disease. The projected 5-year OS in the low-risk (0–1 factors), intermediate-risk (2 factors), and high-risk (3–5 factors) groups are 90.6%, 77.6%, and 52.5%, respectively.132 Importantly, the FLIPI still remains a valid prognostic model in the rituximab era.133 The incorporation of mutation information (EZH2, ARID1A, EP300, FOXO1, MEF2B, CREBBP, and CARD11) in addition to the FLIPI has been combined in a clinicogenetic risk model known as the m7-FLIPI (Table 30.4) which may be able to inform prognosis beyond clinical variables alone.134
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The enhanced understanding of the genetic events and immune microenvironment has facilitated a greater application of targeted and immunological therapies for patients with relapsed and rituximab refractory FL. In such patients, earlier studies with the BTK inhibitor, ibrutinib, resulted in a modest efficacy, possibly due to the presence of coexisting mutations, such as CARD11, which are now considered to confer resistance to ibrutinib. Several novel anti-CD20 monoclonal antibodies, such as veltuzumab, as monotherapy and in combination with the anti-CD74, milatuzumab and ocrartuzumab (AME-133) are ongoing. There appears to be greater promise for epigentically targeted therapies (such as tazemetostat, an EZH2 inhibitor) and vorinostat (a histone deactylase inhibitor). Studies are also testing the inclusion of immune checkpoint inhibitors and CAR T-cell specific for CD19, a differentiation antigen expressed in B-cells and B lineage malignancies. The next generation of novel antibody-based therapies, such as bispecific antibodies, which combine the specificity of two antibodies, so they can bind to different antigens. Bispecific T-cell engager (BiTE) binds CD3 on T-cells and an antigen on tumour cells to activate T-cells to kill the cancer cells. The first-in-class BiTE antibody, blinatumomab, which specifically targets CD19 on B-cells, was approved in 2014 for clinical use in patients with relapsed or refractory ALL and is now being tested in FL, and preliminary results when the drug is administered at very low doses are encouraging.
Very-Early Onset Chronic Active Colitis with Heterozygous Variants in LRBA1 and CARD11, a Case of “Immune TOR-Opathies”
Published in Fetal and Pediatric Pathology, 2023
Mai He, Amanda Wong, Kimberly Sutton, Mercia Jeanne Bezerra Gondim, Charles Samson
Caspase activation and recruitment domain 11 (CARD11) is an adaptor protein in lymphocytes that facilitates signal transduction downstream of T cell or B cell receptor activation to initiate activation of NF-κB and other signaling pathways through forming a scaffold called CBM (CARD11-BCL10-MALT1) signalsome complex [18]. Multiple different types of variants for CARD11 have been described, each of which leads to the development of different clinical phenotypes [19,20]. To validate novel gene variants for pathogenicity, functional assays could be performed utilizing a CARD-11 deficient Jurkat T cell line expressing an NF-κB GFP reporter [19]. Mutations affecting the CARD11-BCL10-MALT1 (cbm) signalosome complex are associated with an abnormal activation of the mtor/s6k signaling pathway [6]. It is true that this variant may be novel as a cause of VEO-IBD, although in a study of severe atopic disease due to different CARD11 mutations, 3 of 8 patients had GI manifestations including eosinophilic proctocolitis in an 18 month old (other two patients were teenagers with ulcerative colitis and chronic diarrhea, respectively) [21]. Another study suggested that the CARD family, including CARD11, was likely to be involved in inflammatory bowel disease [22].
Clonal heterogeneity of polymorphic B-cell lymphoproliferative disease, EBV-positive, iatrogenic/immune senescence: implications on pathogenesis and treatment
Published in Hematology, 2022
Yu-Yan Hwang, Rex Au-Yeung, Rock Y.Y. Leung, Eric Tse, Yok-Lam Kwong
Polymerase chain reaction (PCR) for immunoglobulin heavy chain, and κ and λ light chain genes (IGH, IGK, IGL) was performed. The EBV+ B-cell LPD (first nasopharyngeal biopsy) and the EBV– plasma cell lesion (second nasopharyngeal biopsy) showed identical IGH, IGK and IGL rearrangements (Figure 4). PCR for IGH in the marrow aspirate showed a clonal pattern, but the amplification peaks were weak and could not be conclusively shown to be identical with those of the nasopharyngeal biopsies. Next generation sequencing (NGS) of 35 lymphoid-relevant genes (ALK, ATM, BCL10, BCL2, BCL6, BIRC3, BTK, CARD11, CD79A, CD79B, CRKL, DNMT3A, EZH2, FBXW7, IDH1, IDH2, IRF4, JAK1, JAK2, JAK3, MALT1, MTOR, MYC, MYD88, NOTCH1, POT1, RHOA, SETD2, SF3B1, STAT3, STAT5A, STAT5B, TET2, TP53, and XPO1) was performed (Illumina MiSeq, Illumina, San Diego, CA, U.S.A.). The EBV+ B-cell LPD showed mutations in only one gene (TP53). On the other hand, the EBV– plasma cell lesion showed mutations in five different genes (TP53, SF3B1, STAT5B, CD79B and CRKL) (Table 1).
Treating central nervous system lymphoma in the era of precision medicine
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ytel Garcilazo-Reyes, Maria-José Ibáñez-Juliá, Isaias Hernández-Verdin, Ludovic Nguyen-Them, Nadia Younan, Caroline Houillier, Khê Hoang-Xuan, Agusti Alentorn
Several studies have also assessed the tolerance and the potential efficacy of ibrutinib in PCNSL either alone or in combination. In monotherapy, response was observed in 77% of 13 patients with PCNSL with a median PFS of 4.6 months. This was an open-label dose-escalation study of ibrutinib in patients with PCNSL or secondary central nervous system lymphoma (SCNSL), with R/R disease. The maximum tolerated dose (MTD) of ibrutinib was 840 mg demonstrating higher concentrations in cerebrospinal fluid (CSF) on day 29. Ibrutinib also confirmed higher response rates in PCNSL than reported for DLBCL outside the CNS, suggesting a divergent molecular pathogenesis. Mutations of CARD11 were found in the only patient with resistance and in some patients with partial response (PR). Patients with complete response (CR) did not have CD79B mutations either [30]. A phase Ib conducted in 18 PCNSL patients, ibrutinib was used as a first-line treatment (alone or in combination) and/or as a treatment of R/R disease. Ninety-four percent showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved CR with DA-TEDDi-R (temozolomide, etoposide, doxil, dexamethasone, ibrutinib, and rituximab) with a median PFS of 15.3 months [31]. An important limitation of this article was the fact that it was not possible to know if some patients might have eventually reached CR on ibrutinib monotherapy alone.