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Overview of the mucosal immune system structure
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Reinhard Pabst, Per Brandtzaeg
The cellular interactions involve lymphotoxins (LTs), which are members of the tumor necrosis factor (TNF) superfamily, as well as the two TNF receptors (TNF-Rs) I and II (55 and 75 kDa). A crucial differentiating event is membrane expression of LTα1β2 on the CD3−CD4+CD45+IL-7R+ LTi cells after stimulation of the receptor activator of nuclear factor (NF) κB (RANK)–TNF receptor associated factor family 6 (TRAF6) pathway and—especially in PPs—alternative cytokine signaling through the interleukin-7 receptor (IL-7R). This event is followed by LTi cell interaction with the LTβ receptor (LTβR)−positive stromal cells, which are positive for vascular cell adhesion molecule (VCAM)-1 and are called lymphoid tissue organizer cells but display a different activation profile in the organogenesis of lymph nodes and PPs. Knockout mice deficient in LTα or LTβ virtually lack lymph nodes and have no detectable PPs. The organ development also involves several feedback loops with chemokines and adhesion molecules such as CXC chemokine ligand 13 (CXCL13)–CXCR5 and CXCR5-induced α4β1integrin–VCAM-1 interactions.
Nutrition, the Mediterranean Diet and Selected Supplements for the Prevention and Treatment of Coronary Heart Disease
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2022
One of the mechanisms by which the TMD, particularly if supplemented with EVOO at 50 g/day, can exert CV health benefits is through changes in the transcriptomic response of genes related to cardiovascular risk that include genes for atherosclerosis, inflammation, oxidative stress vascular immune dysfunction, T2DM and hypertension [16,17,21–23]. This includes genes such as ADR-B2 (adrenergic beta 2 receptor), IL7R (interleukin 7 receptor), IFN gamma (interferon), MCP1 (monocyte chemotactic protein), TNFα (tumor necrosis factor alpha), interleukin 6 (IL-6) and hsCRP [16,17,20–23]. In summary, the TMD has been shown to have the following effects [15–17,21–23]: Lowers blood pressure.Improves serum lipids: lowers total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG); increases high-density lipoprotein (HDL); lowers oxidized LDL (oxLDL) and lipoprotein a (Lp(a)); and improves LDL size and decreases the LDL particle number (LDL P) to a less atherogenic profile.Improves T2DM and dysglycemia.Improves oxidative defense and reduces oxidative stress: F-2 isoprostanes and 8-Oxo-2ʹ-deoxyguanosine (8OHDG).Reduces inflammation: lowers hsCRP, interleukin-6 (IL6), soluble vascular cell adhesion molecule (sl-VCAM) and soluble cell adhesion molecule (sl-CAM).Reduces thrombosis and factor VII after meals.Decreases brain natriuretic peptide (BNP).Increases nitrates/nitrites.Improves membrane fluidity.Reduces risks of MI, CHD and CVA.Reduces homocysteine.
Nutrition Part I
Published in Mark C Houston, The Truth About Heart Disease, 2023
One of the mechanisms by which the TMD, particularly if supplemented with extra-virgin olive oil at 50 grams per day, can exert CV health benefits is through changes in the expression of cardiovascular genes related to cardiovascular risk that include genes for atherosclerosis, inflammation, oxidative stress, vascular immune dysfunction, T2DM, and hypertension(16,17,21–23). This includes genes such as ADRB2 (adrenergic beta 2 receptor), IL7R (interleukin 7 receptor), IFN gamma (interferon gamma), MCP1 (monocyte chemotactic protein), TNFα (tumor necrosis factor alpha), interleukin 6 (IL-6) and HS-CRP (high-sensitivity C reactive protein) (16,17,20–23). In summary, the TMD has been shown to have the following effects (15–17,21–23):Lowers blood pressure.Improves serum lipids: lowers total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG); increases high-density lipoprotein (HDL); lowers oxidized LDL (oxLDL) and lipoprotein a (Lp(a)). In addition, the TMD increases LDL size and decreases the LDL particle number (LDL P) to a less atherogenic profile that reduces the risk for CHD and MI.Improves T2DM and dysglycemia.Improves oxidative defense and reduces oxidative stress.Reduces inflammation.Reduces the risks of clots or thrombosis.Decreases the risk of congestive heart failure.Increases nitrates/nitrites that increase nitric oxide in the arteries.Improves membrane health of all the cells.Reduces MI, CHD, and CVA.Reduces homocysteine, which is a risk factor related to CHD and folic acid metabolism.
Investigational treatment options in phase I and phase II trials for relapsed or refractory acute lymphoblastic leukemia in pediatric patients
Published in Expert Opinion on Investigational Drugs, 2021
Julie M. Asare, Cara A. Rabik, Bradley Muller, Patrick A. Brown, Stacy Cooper
Philadelphia chromosome-like ALL (Ph-like ALL) occurs in approximately 15% of HR pediatric ALL and 30% of AYA ALL patients [70,71] and is associated with high rates of relapse. In the AALL0232 study, EFS was 62.6% for the Ph-like ALL patients compared to 85.8% in the non–Ph-like patients [70]. Ph-like ALL has similar gene expression profiles as BCR ABL1–rearranged (Ph+) B-ALL [72,73] and has a variety of genetic mutations and fusions associated with activated cytokine receptor signaling. Approximately half of patients with Ph-like B-ALL have rearrangements of cytokine receptor–like factor 2 (CRLF2), and about 50% of these patients have mutations in the Janus kinases, JAK1 or JAK2 [70,74,75]. A subset of CRLF2-R cases has concomitant interleukin-7 receptor-alpha (IL7RA) mutations [76].
Enhancing venetoclax activity in hematological malignancies
Published in Expert Opinion on Investigational Drugs, 2020
Janus kinase family is a kinase that links cytokine receptors and the transcription factor STAT which regulates gene expression. As aberrant activation of this JAK/STAT pathway is often seen in myeloproliferative neoplasms (MPNs) including myelofibrosis, the JAK1/2 inhibitor, ruxolitinib, is used clinically in the treatment of these diseases. In pre-clinical studies, Karjalainen and colleagues found ex vivo culture of AML patient samples exhibited resistance to venetoclax in the presence of bone marrow-derived stromal cell cultures, and this effect was reversed in part by JAK inhibitors. Resistance to venetoclax was mediated by up-regulation of BCLXL induced by bone marrow-derived stromal culture conditions, whereas ruxolitinib restored BCL2 dependence and venetoclax sensitivity. In a mouse xenograft model, venetoclax and ruxolitinib interacted synergistically [124]. Senkevitch and colleagues also demonstrated synergism between venetoclax and ruxolitinib in T-ALL cells with interleukin 7 receptor mutations [125]. Currently, a phase 1 trial evaluating the venetoclax + ruxolitinib combination in patients with R/R AML or AML secondary to MDS is underway (NCT03874052).
Towards a comprehensive etiopathogenetic and pathophysiological theory of multiple sclerosis
Published in International Journal of Neuroscience, 2020
Viral and bacterial agents such as Epstein–Barr virus (EBV), human herpesvirus type 6, and mycoplasma pneumonia have been reported to be involved in the disease etiology [19]. Smoking [20,21] vitamin D (VD] deficiency [22] and exposure to UV radiation [23] have been associated with the onset of MS. An autoimmune hypothesis of MS has been proposed. Interleukin 7 receptor alpha chain (IL7R) and interleukin-2 (IL-2) have been found to be associated with MS [24,25]. Research indicates that CD8+ T cells play a role in MS pathogenesis [26]. Myelin antigen-specific CD4+ and CD8+ T cells migrate via the BBB and provoke the disease [26,27]. Research indicates that γδ T cells, t helper type 1 (th1) and impaired Treg cells play a role in MS [28]. CD4+ T cell-driven organ-specific autoimmunity and Th17 cells have also been implicated in the disease [28,29]. Cytokines dysregulation have been observed in MS [30], and oligodendrocyte death, axon damage, and neuronal loss have been associated with MS neuroinflammatory attacks [31].